Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][CH:10]3[CH2:18][O:17][CH2:16][CH2:15][N:11]3[CH2:12][C:13]=2[CH:14]=1)([O-])=O.Cl.[H][H]>CO>[ClH:1].[ClH:1].[CH2:18]1[CH:10]2[N:11]([CH2:12][C:13]3[CH:14]=[C:5]([NH2:2])[CH:6]=[CH:7][C:8]=3[CH2:9]2)[CH2:15][CH2:16][O:17]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(c1)CN1CCOCC1C2
Agent: Cl
Solvent: CO
Product: Nc1ccc2c(c1)CN1CCOCC1C2
Yield: 235.6 %

Procedure:
To 8-nitro-3,4,5,6,11,11a-hexahydro-1H-[1,4]oxazino[4,3-b]isoquinoline hydrochloride (0.4 g) in methanol (50 ml) was added 6N hydrochloric acid (0.3 ml) and 5% Pd--C (100 mg). The mixture was treated with hydrogen at 50 psi on a Parr Hydrogenator. Hydrogen uptake was complete in 2.0 h. The catalyst was filtered off and the solvent removed under reduced pressure to yield the title product as a solid (0.4824 g).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11]O)[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3].C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][Br:14])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cccc(CO)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCOc1cccc(CBr)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
To a solution of (3-allyloxy-phenyl)-methanol (Tetrahedron, 2000, 56(13), 1873-1882) (1.07 g, 6.49 mmol) in THF (7 mls) at 3° C. was added carbon tetrabromide (2.69 g, 8.11 mmol) then triphenylphosphine (2.13 g, 8.11 mmol) in THF (2 mls). The reaction mixture was stirred at 5° C. for 1 hour. The reaction mixture was filtered and concentrated in vacuo. The residue was washed with pentane to give a yellow solid which was purified by column chromatography on silica gel, eluting with pentane:ethyl acetate, 100:0, to 95:5 to afford the title compound as a pale yellow oil in 24% yield, 350 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][CH3:12])[C:3]=1[C:13]([F:16])([F:15])[F:14].O.O.[Sn](Cl)(Cl)(Cl)Cl>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:11][CH3:12])[C:3]=1[C:13]([F:14])([F:15])[F:16]
Reactant: COc1c([N+](=O)[O-])ccc(Cl)c1C(F)(F)F
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(N)ccc(Cl)c1C(F)(F)F

Procedure:
To a solution of 1-chloro-3-methoxy-4-nitro-2-(trifluoromethyl)benzene (1.73 g, 6.74 mmol) in EtOAc (40 mL) was added tin chloride dihydrate (3.04 g, 13.5 mmol). The reaction mixture was heated at reflux for 3 h. The crude reaction mixture was purified by column chromatography (SiO2, EtOAc in hexanes) to give the title compound. LCMS: (FA) ES+ 226.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[CH:5][CH:4]=1.[Li]CCCC.[CH2:20]([CH:22]([CH2:25][CH3:26])[CH:23]=[O:24])[CH3:21]>C1COCC1>[CH2:20]([CH:22]([CH2:25][CH3:26])[CH:23]([C:12]1[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][CH:13]=2)[N:9]=[CH:10][CH:11]=1)[OH:24])[CH3:21]
Reactant: CCC(C=O)CC
Reactant: COc1ccc(Cn2cccn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)C(O)c1ccnn1Cc1ccc(OC)cc1
Reaction time: 1.25 h
Yield: 44.8 %

Procedure:
To 1-(4-methoxybenzyl)-1H-pyrazole (Synthetic Comm. 25(5), 761-774 (1995)) (2.43 g, 12.9 mmol) in THF (100 mL) at −78° C. was added a solution of n-BuLi (2 M in cyclohexane, 7.1 mL, 14.2 mmol) dropwise. After 75 min, 2-ethylbutyraldehyde (1.3 mL, 10.6 mmol) was added. After 45 min the reaction mixture was quenched with saturated aqueous ammonium chloride (50 mL), extracted with EtOAc (3×100 mL), dried (Na2SO4) and concentrated. Column chromatography (EtOAc/hexanes, 1:4) provided 1.37 g (37%) of 2-ethyl-1-[1-(4-methoxybenzyl)-1H-pyrazol-5-yl]butan-1-ol as an oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[OH:8][C:9]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:19][CH2:20][N+:15]([CH2:21][CH2:22][CH2:23][NH:24]C(NC3C=CC=CC=3)=O)([CH2:16][CH2:17]2)[CH2:14]1)=[O:11].[CH2:46]([C:50]1[CH:55]=[CH:54][C:53]([N:56]=[C:57]=[O:58])=[C:52]([CH3:59])[CH:51]=1)[CH2:47][CH2:48][CH3:49]>>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[CH2:46]([C:50]1[CH:55]=[CH:54][C:53]([NH:56][C:57](=[O:58])[NH:24][CH2:23][CH2:22][CH2:21][N+:15]23[CH2:16][CH2:17][CH:18]([CH2:19][CH2:20]2)[C@@H:13]([O:12][C:10](=[O:11])[C:9]([OH:8])([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:14]3)=[C:52]([CH3:59])[CH:51]=1)[CH2:47][CH2:48][CH3:49]
Reactant: CCCCc1ccc(N=C=O)c(C)c1
Reactant: O=C(NCCC[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)c1ccccc1)C2)Nc1ccccc1
Agent: O=C([O-])C(F)(F)F
Product: CCCCc1ccc(NC(=O)NCCC[N+]23CCC(CC2)[C@@H](OC(=O)C(O)(c2ccccc2)c2ccccc2)C3)c(C)c1

Procedure:
This compound is made via an analogous procedure to (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(3-phenyl-ureido)-propyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate (Example 47) by replacing phenyl isocyanate with 4-butyl-1-isocyanato-2-methyl-benzene.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH2:16]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:19]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH2:16][Br:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cc(Br)ccc1OCc1ccccc1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: BrCc1cc(Br)ccc1OCc1ccccc1
Reaction time: 0.25 h

Procedure:
To a solution of (2-benzyloxy-5-bromo-phenyl)-methanol (4.36 g, 14.87 mmol) in DCM (200 ml) cooled with ice-bath under N2 atmosphere a 1M solution of PBr3 in DCM (14.87 ml, 14.87 mmol) was added. The mixture was stirred at that temperature for 15 min and then at RT overnight. The reaction was quenched with sat. NaHCO3 solution. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated to dryness.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[CH3:16][N:17]([CH3:30])[CH2:18][CH2:19][C@@H:20]([NH2:29])[CH2:21][S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:30][N:17]([CH3:16])[CH2:18][CH2:19][C@@H:20]([NH:29][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13])[CH2:21][S:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CN(C)CC[C@@H](N)CSc1ccccc1
Reactant: NS(=O)(=O)c1ccc(F)c(C(F)(F)F)c1
Product: CN(C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1C(F)(F)F

Procedure:
The title compound was prepared from 4-fluoro-3-(trifluoromethyl)-benzenesulfonamide and (R)—N1,N1-dimethyl-4-phenylsulfanyl-butane-1,3-diamine using the procedure described for Intermediate 4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[C:11]([OH:14])[CH:10]=1.[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24]O)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][O:14][C:11]1[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[O:13][N:12]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Oc1cc(-c2ccc(F)cc2F)on1
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(F)cc2F)on1
Yield: 85 %

Procedure:
5-(2,4-difluorophenyl)-3-hydroxyisoxazole (0.3 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.27 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.44 g, 85%) as a colorless powder.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[CH3:9][C:10]1[C:11]([S:16](Cl)(=[O:18])=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=1>>[C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][S:16]([C:11]2[C:10]([CH3:9])=[CH:15][CH:14]=[CH:13][N:12]=2)(=[O:18])=[O:17])[CH:2]=1
Reactant: Cc1cccc(N)c1
Reactant: Cc1cccnc1S(=O)(=O)Cl
Product: Cc1cccc(NS(=O)(=O)c2ncccc2C)c1

Procedure:
prepared by reaction of m-tolylamine with 3-methyl-pyridine-2-sulfonyl chloride
Reaction SMILES: [Li]CCCC.CCCCCC.[Cl:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]=[CH:20][S:21][C:14]=12.[C:22](Cl)(=[O:25])[CH2:23][CH3:24]>C1COCC1>[Cl:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]=[C:20]([C:22](=[O:25])[CH2:23][CH3:24])[S:21][C:14]=12
Reactant: CCC(=O)Cl
Reactant: Clc1ccnc2ccsc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(=O)c1cc2nccc(Cl)c2s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2.5 M nBuLi in hexane (0.619 ml, 1.55 mmole) was added to a solution of 7-chlorothieno[3,2-b]pyridine (0.250 g, 1.47 mmole) in THF (5 ml) at −78° C. The reaction mixture was stirred at −78° C. for 30 min, and then propanoyl chloride (0.162 ml, 1.76 mmole) was added. The reaction mixture stirred at −78° C. and slowly warmed to 0° C. and quenched with H2O (10 ml), extracted with EtOAc (2×10 ml). The organic layer was dried over MgSO4 and concentrated. The residue was purified by flash column chromatography eluting with 10–70% EtOAc in hexane to a off-white solid (0.084 g, 25%). 1H NMR (300 MHz, CDCl3) δ 8.66 (1H, d, J=4.9 Hz), 8.12 (1H, s), 7.38 (1H, d, J=4.9 Hz), 3.09 (2H, q, J=7.3 Hz), 1.29 (3H, t, J=7.3 Hz,); ESIMS (MH+): 225.95.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.[Li].C([Li])CCC.[CH:13](=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16]>>[CH2:14]([CH:13]([C:4]1[S:5][CH:6]=[C:2]([CH3:1])[N:3]=1)[OH:18])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)CC=O
Reactant: Cc1cscn1
Agent: [Li]
Agent: [Li]CCCC
Product: Cc1csc(C(O)CC(C)C)n1

Procedure:
d. Isobutyl (4-methyl-2-thiazolyl) carbinol was prepared by starting from 4-methyl-thiazole and substituting the hydrogen atom in the 2-position by lithium by reaction with butyl-lithium. The resulting metal-organic compound was reacted with isovaleraldehyde [cf. J.A.C.S. 74, 6260 (1952)]. The resulting product had a b.p. of 94° C./0.1 mm. Hg.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:10]=1)[C:8]#[N:9])#[CH:2].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](I)[CH:13]=1.C(N(CC)CC)C>C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:11][C:12]1[CH:13]=[C:14]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([CH:10]=2)[C:8]#[N:9])[CH:15]=[CH:16][CH:17]=1
Reactant: Fc1cccc(I)c1
Reactant: C#Cc1cncc(C#N)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: N#Cc1cncc(C#Cc2cccc(F)c2)c1
Temperature: 80 °C
Yield: 73 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (390 mg, 0.56 mmol), copper (I) iodide (211 mg, 1.11 mmol), and 5-ethynylnicotinonitrile (1.50 g, 11.7 mmol), (prepared essentially as described in PREPARATION 4), to a solution of 1-fluoro-3-iodobenzene (1.31 mL, 11.1 mmol) in triethylamine (21.6 mL, 155 mmol) and heat to 80° C. in a sealed tube for 1.5 h. Cool to room temperature and dilute with ethyl acetate. Wash with a 50% saturated aqueous solution of sodium bicarbonate. Back-extract the aqueous layer three times with dichloromethane and twice with ethyl acetate until the aqueous layer is no longer an emulsion. Combine all organic layers and wash with a saturated aqueous solution of sodium chloride, dry (sodium sulfate), filter and concentrate. Dissolve the residue in ethyl acetate and filter through diatomaceous earth then purify by silica gel chromatography, eluting with a gradient from 95:5 to 80:20 (90:10 hexanes:ethyl acetate):dichloromethane. Further purify by silica gel chromatography, eluting with dichloromethane then 95:5 dichloromethane:ethyl acetate, to give the title compound as a white crystalline solid (1.8 g, 71%).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[N:12]1([C:18]([O:20][CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)=[O:19])[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13]1>C(Cl)Cl>[CH:14]12[O:9][CH:15]1[CH2:16][CH2:17][N:12]([C:18]([O:20][CH2:21][C:22]1[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=1)=[O:19])[CH2:13]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(OCc1ccc2ccccc2c1)N1CC=CCC1
Solvent: ClCCl
Product: O=C(OCc1ccc2ccccc2c1)N1CCC2OC2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of mCPBA (13.02 g, 58.13 mmol) dissolved in methylene chloride (50 mL) was added dropwise to a cooled (0° C.) solution of naphthalen-2-ylmethyl 5,6-dihydropyridine-1(2H)-carboxylate (11 g, 41.5 mmol) dissolved in methylene chloride (33 mL). The solution was allowed to warm to ambient temperature and stirred overnight. The reaction was quenched with 5% K2CO3 and then the layers were separated. The organic phase was washed with 5% K2CO3, saturated NaCl, dried over Na2SO4and concentrated in vacuo (9.5 g).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20](=[O:22])[CH3:21])[N:12]=1.C1COCC1.[OH-].[Na+]>CCO>[C:20]([NH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]1[N:12]=[C:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:23])=[O:2])[O:9][CH:10]=1)(=[O:22])[CH3:21]
Reactant: COC(=O)CCCCc1nc(-c2ccccc2NC(C)=O)co1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)Nc1ccccc1-c1coc(CCCCC(=O)O)n1

Procedure:
Combine 5-[4-(2-acetylamino-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (3.26 g, 10.3 mmol) with THF (3 mL), EtOH (3 mL) and 1 N NaOH (40 mL) and stir at room temperature until hydrolysis is complete. Concentrate the mixture and dilute the residue with water before adjusting to pH 3.5-4.0 with aq HCl. Extract the mixture with 1-2% MeOH/EtOAc and concentrate the combined extracts in vacuo. Chromatograph the resulting residue over silica gel (MeOH/CH2Cl2) which allows for isolation of 5-[4-(2-acetylamino-phenyl)-oxazol-2-yl]-pentanoic acid (2.76 g, 89%). MS (ES): (M−1)− 301.2, 302.3.
Reaction SMILES: [ClH:1].C(OC([NH:9][C@@H:10]([CH2:32][CH2:33][S:34][CH3:35])[C:11]([NH:13][C@@:14]1([C:29]([OH:31])=[O:30])[CH2:19][C@@H:18]([S:20][C:21]2[NH:25][CH:24]=[N:23][N:22]=2)[C@@H:17]2[C@H:15]1[C@H:16]2[C:26]([OH:28])=[O:27])=[O:12])=O)(C)(C)C.COC(C)(C)C>O1CCOCC1>[ClH:1].[NH2:9][C@@H:10]([CH2:32][CH2:33][S:34][CH3:35])[C:11]([NH:13][C@@:14]1([C:29]([OH:31])=[O:30])[CH2:19][C@@H:18]([S:20][C:21]2[NH:25][CH:24]=[N:23][N:22]=2)[C@@H:17]2[C@H:15]1[C@H:16]2[C:26]([OH:28])=[O:27])=[O:12]
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@]1(C(=O)O)C[C@@H](Sc2nnc[nH]2)[C@H]2[C@H](C(=O)O)[C@H]21
Agent: Cl
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Product: CSCC[C@H](N)C(=O)N[C@@]1(C(=O)O)C[C@@H](Sc2nnc[nH]2)[C@H]2[C@H](C(=O)O)[C@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add 4M hydrogen chloride in 1,4-dioxane (19.35 mL, 77.38 mmol) dropwise to a solution of (1R,2S,4R,5R,6R)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4-methylsulfanyl-butanoyl]amino]-4-(4H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (2.66 g, 5.16 mmol) in 1,4-dioxane (26.6 mL) at room temperature in a water bath, and maintain stirring overnight at room temperature. Add methyl-t-butyl ether (200 mL) and stir the mixture for 2 hours. Filter the solid and dry in vacuo overnight. Redissolve the material in water and freeze-dry overnight. Triturate the solid in acetone (10 volumes) at reflux, filter and dry in vacuo under nitrogen for 48 hours to give the title compound (2.33 g, 5.16 mmol) as a white solid. MS (m/z): 416 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:11](=[O:12])[C:10]2[NH:9][C:8]([C:13]3[CH:18]=[CH:17][C:16]([S:19](O)(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[N:7][C:6]=2[N:5]([CH2:23][CH3:24])[C:4]1=[O:25])[CH3:2].S(Cl)(Cl)=O.[NH3:30]>CN(C)C=O>[CH2:1]([N:3]1[C:11](=[O:12])[C:10]2[NH:9][C:8]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:30])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[N:7][C:6]=2[N:5]([CH2:23][CH3:24])[C:4]1=[O:25])[CH3:2]
Reactant: N
Reactant: CCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)O)cc3)nc2n(CC)c1=O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCn1c(=O)c2[nH]c(-c3ccc(S(N)(=O)=O)cc3)nc2n(CC)c1=O
Temperature: 25 °C

Procedure:
A mixture of 4-(1,3-diethyl-2,3,6,7-tetrahydro-2,6dioxo-1H-purin-8-yl)benzenesulfonic acid (5.0 g, 0.014 moles) and N,N-dimethylformamide (150 ml) is cooled to 0° and treated with thionyl chloride (3.3 g, 0.027 moles). When the addition is complete, the reaction mixture is permitted to warm to ambient temperature and stirred vigorously until a thick slurry results. To this slurry is added N,N-dimethylformamide saturated with ammonia (100 ml). The resulting mixture is then saturated with gaseous ammonia and concentrated on a rotary evaporator. The residue is taken up in water, filtered, triturated with ethanol and dried at 68° C. to yield 2.9 grams of 4-(1,3-diethyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)benzenesulfonamide, mp 350°-353° C.(d).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].[ClH:8].[NH2:9][CH2:10][C:11](=[O:17])[CH2:12][CH2:13][C:14](O)=[O:15]>>[ClH:8].[NH2:9][CH2:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([O:5][CH2:4][CH2:3][C:2]([CH3:7])([CH3:6])[CH3:1])=[O:15]
Reactant: NCC(=O)CCC(=O)O
Reactant: CC(C)(C)CCO
Agent: Cl
Product: CC(C)(C)CCOC(=O)CCC(=O)CN
Reaction time: 4 h

Procedure:
From 3,3-dimethyl-1-butanol (5.0 g; 49 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol) at 70° C. The reaction was complete after 4 h. The yield was 0.91 g (60%), mp146-148°.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][NH:6][C:7](=[O:31])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25](Br)=[C:24]([CH3:30])[CH:23]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[C:36]([CH3:43])[CH:35]=1>>[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:25]2[C:26]([CH3:28])=[CH:27][C:22]([O:21][CH:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:32])=[O:31])=[CH:13][CH:12]=3)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:23][C:24]=2[CH3:30])=[C:36]([CH3:43])[CH:35]=1
Reactant: CCCCCCC(Oc1cc(C)c(Br)c(C)c1)c1ccc(C(=O)NCCC(=O)OC)cc1
Reactant: Cc1cc(F)ccc1B(O)O
Product: CCCCCCC(Oc1cc(C)c(-c2ccc(F)cc2C)c(C)c1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
This compound is made in a manner substantially similar to Example 117 using isomer 1 of 3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-heptyl]-benzoylamino}-propionic acid methyl ester and 4-fluoro-2-methyl-phenylboronic acid as starting materials in step D. MS (ES): 520.2 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:38](=[O:37])[CH2:39][OH:40])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)CO)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f5) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24](F)[C:3]=1[C:4]([NH:6][C@H:7]([C:21]([OH:23])=[O:22])[CH2:8][NH:9][C:10](=[O:20])[CH2:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])=[O:5].[Cl:29]C1C=CC=C(Cl)C=1C(N[C@H](C(O)=O)CNC([C@@H]1CCC(=O)O1)=O)=O>>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:29])[C:3]=1[C:4]([NH:6][C@H:7]([C:21]([OH:23])=[O:22])[CH2:8][NH:9][C:10](=[O:20])[CH2:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])=[O:5]
Reactant: CC(CC(=O)NC[C@H](NC(=O)c1c(F)cccc1Cl)C(=O)O)c1ccccc1
Reactant: O=C1CC[C@@H](C(=O)NC[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)O)O1
Product: CC(CC(=O)NC[C@H](NC(=O)c1c(Cl)cccc1Cl)C(=O)O)c1ccccc1

Procedure:
N-(2-chloro-6-fluorobenzoyl)-3-[(3RS)-3-phenylbutanoyl]amino-L-alanine) or k is 0 (for example N-(2,6-dichlorobenzoyl)-3-[(2S)-5-oxotetrahydrofuran-2-carbonyl]amino-L-alanine;
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH2:5][NH:6][CH2:7][CH2:8][C:9]=2[N:10]=1.Br[CH2:12][B-:13]([F:16])([F:15])[F:14].[K+:17]>O1CCCC1>[CH3:1][C:2]1[S:3][C:4]2[CH2:5][N:6]([CH2:12][B-:13]([F:16])([F:15])[F:14])[CH2:7][CH2:8][C:9]=2[N:10]=1.[K+:17]
Reactant: F[B-](F)(F)CBr
Reactant: Cc1nc2c(s1)CNCC2
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1nc2c(s1)CN(C[B-](F)(F)F)CC2
Temperature: 25 °C

Procedure:
A mixture of 2-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine (3.00 g), potassium bromomethyltrifluoroborate (3.91 g), KHCO3 (1.95 g), KI (0.32 g), and tetrahydrofuran (25 mL) is stirred at reflux temperature for 4 h. After cooling to room temperature, the solvent is evaporated and the residue is suspended in acetone. The insoluble salts are separated by filtration and the filtrate is treated with diethyl ether. The precipitate is separated by filtration and dried to give the title compound (alternatively, the crude product is purified by chromatography on silica gel using dichloromethane and methanol as eluent). Mass spectrum (ESI−): m/z=235 [M]−.
Reaction SMILES: CC([O:4][CH2:5][CH2:6][N:7]1[C:20]2[C:15](=[CH:16][C:17]([CH2:21][CH:22]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:18][CH:19]=2)[C:9]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:8]1=[O:30])=O.C[O-].[Na+]>CO>[OH:4][CH2:5][CH2:6][N:7]1[C:20]2[C:15](=[CH:16][C:17]([CH2:21][CH:22]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:18][CH:19]=2)[C:9]2([CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[C:8]1=[O:30]
Reactant: CC(=O)OCCN1C(=O)C2(CCNCC2)c2cc(CC3CCCCCCC3)ccc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1N(CCO)c2ccc(CC3CCCCCCC3)cc2C12CCNCC2
Reaction time: 0.5 h

Procedure:
1-(methylcarbonyloxy-ethyl)-5(cyclooctyl-methyl)-spiro[indoline-3,4′-piperidin]-2-one (0.012 g, 0.028 mmol) was dissolved in methanol (1.5 mL). To the reaction mixture was then added at room temperature a 25% solution of sodium methoxide in methanol (50 μL) and the reaction mixture was stirred for 30 minutes. The solvent was evaporated in vacuo to yield an oil which was then partitioned with aqueous 0.1N HCl and dichloromethane. The organic layer was washed with brine, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (35% ethyl acetate/hexanes) to yield the title compound as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[C:14]([OH:16])[C:13]([Cl:17])=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28](O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([O:16][C:14]2[C:13]([Cl:17])=[CH:12][C:9]3[C:10]([CH3:11])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[O:7][C:8]=3[CH:15]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)c1oc2cc(O)c(Cl)cc2c1C
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1oc2cc(OC3CCN(C(=O)OC(C)(C)C)CC3)c(Cl)cc2c1C
Reaction time: 3 h
Yield: 94.4 %

Procedure:
The above prepared 5-chloro-6-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (0.900 g, 3.53 mmol) was dissolved in 15 mL of THF and treated successively at −10° C. with 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.996 g, 1.4 eq.), triphenylphosphine (1.298 g, 1.4 eq.) and DIAD (0.971 mL, 1.4 eq.), and the mixture then kept at ambient temperature for another 3 h. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=85/15), gave 1.459 g of the title compound as colorless gum.