Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([S:3]([CH2:6][CH3:7])(=[O:5])=[O:4])=[CH2:2].Br[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([S:3](/[CH:6]=[CH:7]/[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CN1CCC(c2c[nH]c3ccc(Br)cc23)CC1
Reactant: C=CS(=O)(=O)CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)/C=C/c1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 66.1 %

Procedure:
A mixture of ethyl vinyl sulphone (600 mg), 5-bromo-3-(1-methyl-4-piperidinyl)-1H-indole (1.00 g), palladium acetate (50 mg), tri-o-tolylphosphine (244 mg) and triethylamine (700 mg) in dry dimethylformamide (10 ml) was stirred and heated at 100°-110° for 4 h. The dimethylformamide and triethylamine were removed in vacuo. The residual gum was chromatographed on silica (140 g; Merck 9385), using a mixture of dichloromethane, ethanol and ammonia (80:8:1) as the eluant, to give a gum (750 mg). The material was rechromatographed on silica (Merck 9385; 100 g), using a mixture of dichloromethane, ethanol and ammonia (90:8:1) as the eluant. Fractions containing mainly the product were combined and evaporated to give a gum. A few fractions contained small amounts of the pure product. These were kept separate, combined and evaporated. The residual gum was crystallised from a small amount of a mixture of ethyl acetate and cyclohexane. Some of the crystals were then used to seed the crystallisation of the main batch of the product, also from a mixture of ethyl acetate and cyclohexane. The two batches of solid product were combined and dried in vacuo to give the title compound (310 mg) as a powder, with m.p. 98°-102°.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH2:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[C:17]([O:21][C:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C>[C:17]([O:21][C:22](=[O:23])[NH:24][CH2:25][C:26](=[O:27])[NH:16][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NC(c1ccccc1)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A suspension of 7.9 mmol C-(4-chloro-phenyl)-C-phenyl-methylamine hydrochloride (CA [5267-39-0]) in 100 ml acetonitrile was treated successively with 7.9 mmol N-tert.butyloxycarbonyl glycine, 39 mmol DIPEA and 8.7 mmol TBTU. After stirring for 1 hour at room temperature, the mixture was concentrated. Chromatography (SiO2; ethyl acetate/cyclohexane) yielded the title compound as a colorless solid. Yield=84%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Cl[S:28]([C:31]1[CH:36]=[CH:35][C:34]([CH:37]=[CH:38][C:39]([OH:41])=[O:40])=[CH:33][CH:32]=1)(=[O:30])=[O:29].Cl>O1CCOCC1.O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]2[CH2:10][CH2:11][N:12]([S:28]([C:31]3[CH:32]=[CH:33][C:34](/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40])=[CH:35][CH:36]=3)(=[O:30])=[O:29])[CH2:13][CH2:14]2)=[CH:16][CH:17]=1
Reactant: O=C(O)C=Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)/C=C/c1ccc(S(=O)(=O)N2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Yield: 71.8 %

Procedure:
To a suspension of 1-bis(4-fluorophenyl)methyl piperazine (0.47g, 1.62 mmol) in dioxane (5 mL) a solution of NaHCO3 (0.27 g, 3.24 mmol) in water (4 mL) and a solution of 3-(4-chlorosulfonyl-phenyl)-acrylic acid (8) (0.40 g, 1.62 mmol) were added and the resultant mixture was stirred at ambient temperature for 20 hours. The reaction mixture was poured into water (50 mL), the pH of the medium was brought to 4 with 2 N HCl, and extracted with ethyl acetate. The extract was washed successively with water, brine, and dried (Na2SO4). The solvent was removed and the crude product was crystallized from dioxane to give the title compound (0.58 g, 63%) as a white solid. 1H NMR (DMSO-d6, HMDSO), δ: 2.19-2.50 (4H, m, overlapped with a signal of DMSO); 2.80-3.12 (4H, m); 4.42 (1H, s); 6.78 (1H, d, J=16.0 Hz); 7.11 (4H, t, J=9.0 Hz); 7.41 (4H, dd, J=8.6 and 5.6 Hz); 7.72 (1H, d, J=16.0 Hz); 7.78 (2H, d, J=8.2 Hz); 8.00 (2H, d, J=8.2 Hz); 12.68 (1H, br s).
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]=2)[CH2:19][CH2:18]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7]([N:17]2[CH2:18][CH2:19][CH:20]([C:23]3[NH:24][C:25]4[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=4[N:27]=3)[CH2:21][CH2:22]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: c1ccc2[nH]c(C3CCNCC3)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1ccc(-c2ccccc2)cc1)N1CCC(c2nc3ccccc3[nH]2)CC1
Yield: 20.1 %

Procedure:
To a stirred mixture of 4-biphenylsulfonyl chloride (63 mg, 0.25 mmol) and 2-(piperidin-4-yl)-1H-benzimidazole (50 mg, 0.25 mmol) in DCM (10 mL) is added N,N-diisopropylethylamine (62 μL, 0.37 mmol). After 18 h the reaction mixture is washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Trituration with heptane gives 21 mg of 2-[1-(biphenyl-4-ylsulfonyl)piperidin-4-yl]-1H-benzimidazole.
Reaction SMILES: [CH3:1][O:2][C:3]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:22]([Cl:41])(C1C=CC=CC=1)(C1C=CC=CC=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.OCC1C=CC(CCl)=CC=1.C1(C)C=CC=CC=1>Cl.CCCCCCC>[C:16]1([C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:2][CH2:1][C:26]2[CH:27]=[CH:28][C:23]([CH2:22][Cl:41])=[CH:24][CH:25]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: OCc1ccc(CCl)cc1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: ClCc1ccc(COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A 100 mL round bottom flask was charged with triphenylmethyl methyl ether (2.74 g, 10 mmol), trityl chloride (2.79 g, 10 mmol), p-hydroxymethylbenzyl chloride (3.13 g, 20 mmol), toluene (12 mL), heptane (12 mL) and 32% HCl (2 drops). The solution was heated to reflux and 12 mL solvent was distilled over 2 hours. The solution was cooled to room temperature and the resulting slurry diluted with 12 mL heptane. After cooling in an ice bath, the product was isolated by vacuum filtration and dried in vacuo at 40° C. to give 6.27 g (79% yield) of crude product. Recrystallization from 20 mL acetonitrile gave 5.46 g (88% recovery) of the desired product. The product had a melting point of 126°-128° C. 1H NMR spectral data were as follows: (CDCl3, 300 MHz): δ 7.6-7.2 (complex, 19 H), 4.6 (s, 2H), 4.2 (s, 2H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH2:12])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(Cl)C.[C:17]1(=[O:23])[O:22][C:20](=[O:21])[CH2:19][CH2:18]1>>[C:1]1([C:7]2[N:8]=[C:9]([NH:12][C:17](=[O:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)O1
Reactant: Nc1nc(-c2ccccc2)cs1
Solvent: CC(Cl)Cl
Product: O=C(O)CCC(=O)Nc1nc(-c2ccccc2)cs1

Procedure:
35.2 g of 4-phenyl 2-amino thiazole are dissolved in 350 ml of boiling 1-2 dichloroethane. To this solution add 20 g of succinic anhydride. The amide formed crystallizes; keep under reflux for five hours and filter. By recrystallization from alcohol there are recovered 39 g (70%) of the product of the formula ##STR12##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[CH2:10]([CH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH:22]=[O:23])[CH2:17][CH2:16]1)[CH2:11][CH2:12][CH2:13][CH3:14].Cl>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH:22]([OH:23])[CH2:21][CH:18]2[CH2:19][CH2:20][CH:15]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17]2)=[CH:4][CH:3]=1
Reactant: CCCCCC1CCC(CC=O)CC1
Reactant: C#Cc1ccc(F)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCC1CCC(CC(O)C#Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
4-Fluorophenylacetylene (1.3 g) was dissolved in THF (20 ml), followed by dropwise adding a n-butyllithium-hexane solution (1.61M, 0.62 ml) while stirring the above solution under ice-cooling, stirring the reaction solution under ice-cooling for 30 minutes, dropwise adding a solution of 2-(4-pentylcyclohexyl)acetaldehyde (1.5 g) in THF (10 ml), raising the temperature of the reaction solution up to room temperature after completion of the dropwise addition, stirring the mixture for 5 hours, adding dilute hydrochloric acid (5 ml) to the resulting raw solution, extracting with ethyl acetate (50 ml), washing the organic layer with water, drying over anhydrous MgSO4, concentrating under reduced pressure to obtain a brown oil, and recrystallizing this oil from a mixed solution of ethyl acetate-heptane, to obtain 1-(4-fluorophenyl)-4-(4-pentylcyclohexyl)-1-butyn-3-ol (white crystal) (2.3 g) .
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([NH2:17])C#C.C(N=C=NC(C)C)(C)C.O>C1COCC1>[C:11]([NH2:17])(=[O:13])[C:10]#[CH:9].[C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7]
Reactant: C#CCN
Agent: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: C#CC(N)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-Boc-β-alanine (1a) (1.05 g, 5.5 mmol) and propargyl amine (0.90 g, 16.5 mmol) were dissolved in THF (10 mL). Diisopropyl-carbodiimide (DIC, 695 g, 5.5 mmol) was added and the reaction mixture was stirred for 16 h at room temperature. Water was added (20 mL) and the product was extracted into EtOAc (3×30 mL). The combined EtOAc was dried (Na2SO4) and evaporated. The crude product was purified by silica column chromatography eluting with EtOAc:Heptane gradient (2:3)-(3:2.5) (v/v). Product yield 0.925 g, 74%.
Reaction SMILES: N1CCCCC1.[CH2:7]([O:9][C:10](=[O:15])[CH2:11][C:12](O)=O)[CH3:8].[CH3:16][C:17]1[N:22]=[CH:21][C:20](C=O)=[CH:19][CH:18]=1.Cl>N1C=CC=CC=1>[CH2:7]([O:9][C:10](=[O:15])[CH:11]=[CH:12][C:20]1[CH:21]=[N:22][C:17]([CH3:16])=[CH:18][CH:19]=1)[CH3:8]
Reactant: Cc1ccc(C=O)cn1
Reactant: CCOC(=O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CCOC(=O)C=Cc1ccc(C)nc1
Yield: 66.5 %

Procedure:
1.5 ml of piperidine are added to a solution of 25 g (0.19 mole) of malonic acid monoethyl ester in 50 ml of pyridine, followed by the dropwise addition of 17 g (0.14 mole) of 6-methyl-3-pyridine aldehyde. The mixture is refluxed for 5 hours and, after cooling, is poured onto a mixture of ice and concentrated hydrochloric acid. After extraction by shaking with diethyl ether, the organic phase is dried over sodium sulfate and concentrated by evaporation in vacuo, leaving 17.8 g (67%) of the title compound in the form of an oil which is further processed without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][C:18]#[N:19])[CH2:11][CH2:10]1.[H][H]>O1CCOCC1.C(O)C.[Ni]>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11][CH2:10]1
Reactant: [H][H]
Reactant: N#CCCCC1CCN(C(c2ccccc2Cl)c2ccccc2Cl)CC1
Agent: [Ni]
Solvent: C1COCCO1
Solvent: CCO
Product: NCCCCC1CCN(C(c2ccccc2Cl)c2ccccc2Cl)CC1

Procedure:
8.0 g (20.6 mmol) 4-{1-[bis(2-chlorophenyl)-methyl]-piperidin-4-yl}-butyronitrile are dissolved in 240 ml dioxane/ethanol (1/5) and added to 1.5 g Raney-nickel. The mixture is stirred at RT under hydrogen atmosphere until uptake of the theoretical amount of hydrogen. The reaction solution is filtered from the catalyst and the solvent is removed under vacuum. The residue is dispersed between 100 ml 10% sodium hydroxide solution and 300 ml acetic acid ethyl ester. The organic phase is dried with sodium sulfate and the solvent is removed under vacuum. The resin is processed further without additional purification.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)(O)[O-].[Na+]>C(O)(C)C>[Br:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:3][C:4]=2[CH:10]=1
Reactant: C1CNCCN1
Reactant: Clc1nc2ccc(Br)cc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Brc1ccc2nc(N3CCNCC3)sc2c1

Procedure:
2-Chloro-6-bromobenzothiazole (2.29 g), piperazine (1.59 g) and sodium bicarbonate (3.10 g) were combined in isopropanol (75 mL) and the resulting orange solution was heated to reflux overnight, then concentrated to ˜15 mL, diluted with water, and extracted with DCM. The extracts were concentrated to yield an orange solid which was chromatographed (0 to 5% MeOH in DCM) to yield 6-bromo-2-(piperazin-1-yl)benzo[d]thiazole as a slightly pink solid. MS: 297.9 (M+H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[C:12]#[N:13])(=[O:3])[CH3:2].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(OCC)C>[C:1]([O:4][C:5]1[CH:10]=[C:9]([CH2:11][Br:14])[CH:8]=[CH:7][C:6]=1[C:12]#[N:13])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1cc(C)ccc1C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: CC(=O)Oc1cc(CBr)ccc1C#N
Temperature: 25 °C
Yield: 29.7 %

Procedure:
To a solution of (2-cyano-5-methyl-phenyl) acetate (0.72 g, 4.11 mmol) in CCl4 (10 mL) was added recrystallized N-bromosuccinimide (0.767 g, 4.31 mmol) followed by benzoyl peroxide (56 mg, 0.23 mmol). The resultant mixture was heated to reflux for 2.5 hours then cooled to room temperature. The mixture was diluted with diethyl ether (50 mL), filtered through filter paper, and the filtrate was concentrated. Purification of the crude material by column chromatography (6:1 hexanes-EtOAc) provided 0.31 g (30%) of (5-bromomethyl-2-cyano-phenyl) acetate as a colorless oil. 1H NMR (CDCl3) δ2.40 (s, 3H), 4.45 (s, 2H), 7.33 (s, 1H), 7.35 (d, 1H, J=9 Hz), 7.65 (d, 1H, J=9 Hz).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][CH2:10][C:11]([NH:13][C@H:14]([C:22]([NH:24][C@H:25]([C:30]([NH:32][C@H:33]([C:39]([NH:41][C@H:42]([C:60]([NH:62][C@H:63]([C:66]([NH:68][C@H:69]([C:72]([OH:74])=[O:73])[CH2:70][OH:71])=[O:67])[CH2:64][OH:65])=[O:61])[CH2:43][CH2:44][CH2:45][NH:46][C:47](=[NH:59])[NH:48][S:49]([C:52]1[CH:58]=[CH:57][C:55]([CH3:56])=[CH:54][CH:53]=1)(=[O:51])=[O:50])=[O:40])[CH2:34][CH2:35][C:36](=[O:38])[NH2:37])=[O:31])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(O)(=O)C>CO.[Pd]>[NH2:1][C@H:2]([C:7]([NH:9][CH2:10][C:11]([NH:13][C@H:14]([C:22]([NH:24][C@H:25]([C:30]([NH:32][C@H:33]([C:39]([NH:41][C@H:42]([C:60]([NH:62][C@H:63]([C:66]([NH:68][C@H:69]([C:72]([OH:74])=[O:73])[CH2:70][OH:71])=[O:67])[CH2:64][OH:65])=[O:61])[CH2:43][CH2:44][CH2:45][NH:46][C:47](=[NH:59])[NH:48][S:49]([C:52]1[CH:58]=[CH:57][C:55]([CH3:56])=[CH:54][CH:53]=1)(=[O:51])=[O:50])=[O:40])[CH2:34][CH2:35][C:36](=[O:38])[NH2:37])=[O:31])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:12])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)OCc2ccccc2)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)cc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)CNC(=O)[C@@H](N)CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)cc1

Procedure:
600 Milligrams of Z-Leu-Gly-Phe-Leu-Gln-Arg(Tos)-Ser-Ser-OH was dissolved in 50 ml of methanol and 10 ml of 10%-acetic acid, then the mixture was subjected to catalytic reduction in the presence of 500 mg of palladium at a room temperature under an atmospheric pressure to obtain H-Leu-Gly-Phe-Leu-Gln-Arg(Tos)-Ser-Ser-OH.
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].IN1C(=O)CCC1=O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C@H:21]([N:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][N:36]=[C:35]([NH:39][CH:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)[N:34]=3)=[CH:29][C:28]2=[O:46])[CH2:22][O:23][CH2:24]SC)=[CH:17][C:16]=1[F:47]>CN(C=O)C>[P:1]([OH:4])([OH:3])([O:2][CH2:24][O:23][CH2:22][C@H:21]([C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[C:16]([F:47])[CH:17]=1)[N:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([NH:39][CH:40]3[CH2:41][CH2:42][O:43][CH2:44][CH2:45]3)[N:34]=2)=[CH:29][C:28]1=[O:46])=[O:5]
Reactant: O=P(O)(O)O
Reactant: CSCOC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(NC3CCOCC3)n2)cc1=O
Agent: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccnc(NC3CCOCC3)n2)ccn1[C@H](COCOP(=O)(O)O)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 2.3 %

Procedure:
Phosphoric acid (0.40 g, 3.98 mmol), 4 Å molecular sieves (5 g) and N-iodosuccinimide (0.46 g, 1.99 mmol) were added to (S)-1-(1-(4-chloro-3-fluorophenyl)-2-((methylthio)methoxy)ethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.50 g, 1.00 mmol) in DMF (5 mL). The mixture was stirred at room temperature for 2 hours. The mixture was quenched with sodium thiosulfate. Sodium carbonate was added to bring pH to 10, and the solvent was removed. The resultant was purified by HPLC to afford (S)-(2-(4-chloro-3-fluorophenyl)-2-(2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)ethoxy)methyl dihydrogen phosphate (13 mg). M+1=555.1.
Reaction SMILES: C([Li])CCC.[CH2:6]([C@H:13]1[CH2:17][O:16][C:15](=[O:18])[NH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:19](Cl)(=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1COCC1>[O:26]=[C:19]([N:14]1[C@@H:13]([CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:17][O:16][C:15]1=[O:18])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CCCCCCC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
n-Butyl lithium (58 mL, 2.5M in hexanes, 142 mmol) is added to a solution of (S)-4-benzyl-2-oxazolidinone 51 (25 g, 141 mmol) in THF (250 mL) at -78° C. under argon and stirred for 15 min. Heptanoyl chloride 50 (21 g, 141 mmol) is added to the solution dropwise and stirred for 40 min, then warmed to 0° C. for 2 hours. The reaction is quenched with NH4Cl and extracted with EtOAc. The organic layer is washed with 1N HCl, aqueous NaHCO3, aqueous NACl, and dried over MgSO4. The crude product is recrystallized from hexane to give 52.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]([CH:17]([N:19]=[N+]=[N-])[CH3:18])([F:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Ni]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]([CH:17]([NH2:19])[CH3:18])([F:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CC(N=[N+]=[N-])C1(F)CCN(C(=O)OCc2ccccc2)C1
Agent: [Ni]
Solvent: CO
Product: CC(N)C1(F)CCN(C(=O)OCc2ccccc2)C1
Yield: 90.1 %

Procedure:
A solution of 3-(1-azidoethyl)-3-fluoropyrrolidine-1-carboxylic acid benzyl ester (Example A16, 0.16 g, 0.5 mmol) in methanol (10 mL) is treated with Raney nickel (100 mg, wet weight) and shaken in a hydrogen atmosphere at room temperature and at 55 psi for 17 hours. The catalyst is removed by filtration through Celite, and the solvent is removed in vacuo to afford the title compound (0.12 g). 1H NMR (200 MHz, CDCl3): δ 7.30 (s, 5H), 5.12 (s, 2H), 3.84-3.22 (m, 5H), 2.23-1.79 (m, 4H), 1.20 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[CH3:18][N:19]1[C:23]([CH3:24])=[CH:22][C:21]([C:25](O)=[O:26])=[N:20]1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:25]([C:21]3[CH:22]=[C:23]([CH3:24])[N:19]([CH3:18])[N:20]=3)=[O:26])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: Cc1cc(C(=O)O)nn1C
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Product: Cc1cc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OC[C@@H]3F)c2)nn1C

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (CAS 5744-59-2) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=364.3 [M+H]+
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]3[C:23]([CH:24]=[C:25]4[C:30]=2[CH:29]=[CH:28][CH:27]=[CH:26]4)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=1)[C:6]([O:8]C)=[O:7])(=[O:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O.O>[C:1]([NH:4][C@@H:5]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:18]3[C:23]([CH:24]=[C:25]4[C:30]=2[CH:29]=[CH:28][CH:27]=[CH:26]4)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c3ccccc3cc3ccccc23)cc1)NC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](Cc1ccc(-c2c3ccccc3cc3ccccc23)cc1)C(=O)O
Reaction time: 16 h
Yield: 90 %

Procedure:
To a solution of 96 (80 mg, 0.20 mmol) in THF/water, 2:1 (3 mL) was added lithium hydroxide monohydrate (17 mg, 0.40 mmol) and the resulting suspension was allowed to stir for 16 h. The reaction mixture was diluted with water (30 mL) and the THF was removed by evaporation. The aqueous layer was washed with DCM (40 mL) to remove unreacted starting material. The aqueous phase was acidified with 10% HCl and the resulting precipitate was extracted with DCM (3×40 mL). The combined organics were dried and evaporated to yield the title compound (69 mg, 0.18 mmol, 90%) as a white solid. Mp 76° C. [α]D20 +29.7 (c. 0.1, EtOH). 1H NMR (CDCl3, 300 MHz): δ 8.47 (s, 1H, ArH10″); 8.02 (d, J=8.4 Hz, 2H, ArH3″ and ArH6″); 7.59 (d, J=8.7 Hz, 2H, ArH8″ and ArH1″); 7.45 (m, 2H, ArH4″ and ArH5″); 7.35 (m, 6H, ArH2″ and ArH7″, 4×ArH″); 6.27 (d, J=6.6 Hz, 1H, NH); 5.00 (m, 1H, H2); 3.39 (dd, J=4.8, 12.9 Hz, 1H, H3a); 3.26 (dd, J=6.3, 14.4 Hz, 1H, H3b); 2.07 (s, 3H, COCH3). Mass Spectrum (ES, +ve) m/z 383 (70%) [MH+]. HRMS calcd for C25H22NO3 384.1600, found 384.1610.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([OH:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[N:9]2)=[CH:4][CH:3]=1.[C:23](Cl)(=[O:27])[CH2:24][CH2:25][CH3:26]>C(Cl)Cl.N1C=CC=CC=1>[C:23]([O:22][CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:21])[N:12]1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[N:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1)(=[O:27])[CH2:24][CH2:25][CH3:26]
Reactant: CCCC(=O)Cl
Reactant: O=C1c2ccccc2C(O)N1c1ccc2ccc(Cl)nc2n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 43.4 %

Procedure:
The procedure is as in Example 30, but starting with 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (6.4 g) in methylene chloride (320 cc), pyridine (48 cc) and butyryl chloride (12.8 g). After one recrystallization in isopropyl ether followed by two recrystallizations in acetonitrile, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl butyrate (3.4 g), m.p. 140° C., is obtained.