Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[NH:6][C@@H:5]([C:7]2[CH:16]=[CH:15][C:10]([NH:11]C(=O)C)=[CH:9][CH:8]=2)[CH2:4][C@@H:3]1[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[OH-].[K+].[ClH:26]>C(O)C>[ClH:26].[ClH:26].[ClH:26].[NH2:11][C:10]1[CH:15]=[CH:16][C:7]([C@@H:5]2[NH:6][C:2]([CH3:23])([CH3:1])[C@@H:3]([C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)[CH2:4]2)=[CH:8][CH:9]=1
Reactant: CC(=O)Nc1ccc([C@H]2C[C@H](c3ccncc3)C(C)(C)N2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)N[C@@H](c2ccc(N)cc2)C[C@@H]1c1ccncc1

Procedure:
0.18 G. of 4'-[trans-5,5-dimethyl-4-(4-pyridyl)-2-pyrrolidinyl]-acetanilide are treated with a solution of 0.18 g. of potassium hydroxide in 1.8 ml. of ethanol and boiled under reflux for 48 hours. The resulting reaction mixture is then evaporated under reduced pressure and the residue is treated with water and extracted three times with methylene chloride. The organic phase is dried over sodium sulfate and evaporated under reduced pressure. The residue which results is treated with ethereal HCl and crystallized with ethanol/ether to yield 4-[trans-5-(p-aminophenyl)-2,2-dimethyl-3-pyrrolidinyl]-pyridine trihydrochloride of melting point 240°-242° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:25]([NH:26][CH:27]3[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][N:35]=[C:36]=[S:37])[CH2:29][CH2:28]3)=[N:24][C:23]3[C:18]2=[N:19][CH:20]=[N:21][CH:22]=3)=[CH:12][CH:11]=1>O1CCCC1>[NH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][C:3]=1[NH:8][C:36]([NH:35][CH2:34][CH2:33][N:30]1[CH2:31][CH2:32][CH:27]([NH:26][C:25]2[N:17]([CH2:16][C:13]3[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=3)[C:18]3[C:23]([N:24]=2)=[CH:22][N:21]=[CH:20][N:19]=3)[CH2:28][CH2:29]1)=[S:37]
Reactant: Fc1ccc(Cn2c(NC3CCN(CCN=C=S)CC3)nc3cncnc32)cc1
Reactant: Nc1ccncc1N
Solvent: C1CCOC1
Product: Nc1ccncc1NC(=S)NCCN1CCC(Nc2nc3cncnc3n2Cc2ccc(F)cc2)CC1

Procedure:
A mixture of 2.95 parts of 3,4-pyridinediamine, 16 parts of 9-[(4-fluorophenyl)methyl]-N-[1-(2-isothiocyanatoethyl)-4-piperidinyl]-9H-purin-8-amine, and 90 parts of tetrahydrofuran was stirred and refluxed overnight. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95/5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 10.5 parts of N-(4-amino-3-pyridinyl)-N'-[2-[4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]amino]-1-piperidinyl]ethyl]thiourea (compound 182).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH:25]=O)[CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:27][C:28]1[S:29][CH2:30][C:31](=[O:33])[N:32]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22](/[CH:25]=[C:30]4/[C:31](=[O:33])[N:32]=[C:28]([NH2:27])[S:29]/4)[CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccnc3ccc(C=O)cc23)CC1
Reactant: NC1=NC(=O)CS1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccnc3ccc(/C=C4\SC(N)=NC4=O)cc23)CC1

Procedure:
The similar procedure as described in example 35 was used, starting from 4-(6-formyl-quinolin-4-yloxy)-piperidine-1-carboxylic acid tert-butyl ester, 2-Amino-thiazol-4-one (example 48b), sodium acetate and acetic acid to obtain 4-{6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinolin-4-yloxy}-piperidine-1-carboxylic acid tert-butyl ester as a yellow solid. Purification was performed with flash chromatography (Merck silica gel 60, 230-400 mesh, 1%-5% methanol in dichloromethane for 30 min. LC-MS m/e 455.5 (MH+).
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:11](O)[CH2:12][CH2:13][CH3:14].C1C=CC=CC=1.S(=O)(=O)(O)O>O>[SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:11][CH2:12][CH2:13][CH3:14])=[O:5]
Reactant: CCCCO
Reactant: O=C(O)c1ccccc1S
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: CCCCOC(=O)c1ccccc1S
Yield: 68.6 %

Procedure:
Using a procedure similar to that of Example IV, a mixture of 50 g (0.32 mole) of 2-mercaptobenzoic acid, 50 g (0.7 mole) of n-butanol, 200 ml of benzene and 1.1 g of sulfuric acid (93%) was heated at reflux for 24 hours during which time 5.9 ml of water was collected in the water separator. The mixture was cooled, washed, concentrated and the residual oil distilled to give n-butyl 2-mercaptobenzoate: 46.1 g (68.6% yield); bp 127°-128°C/ 1.0 mm; mol wt 210:
Reaction SMILES: CO.[Li+].[BH4-].C([O:7][C:8]([C:10]1[CH:18]=[C:13]2[CH2:14][CH2:15][CH2:16][CH2:17][N:12]2[N:11]=1)=O)C>C1COCC1>[N:11]1[N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]2=[CH:18][C:10]=1[CH2:8][OH:7]
Reactant: CCOC(=O)c1cc2n(n1)CCCC2
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cc2n(n1)CCCC2
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 102.3 %

Procedure:
MeOH (0.29 mL) was added to the THF (19 mL) solution of LiBH4 (cont. 90%) (174 mg) under a nitrogen atmosphere at room temperature, then 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylic acid ethyl ester (862 mg) was added to the suspension and stirred for 1 h at room temperature and 1.5 h at 40° C. The mixture was quenched with 1 mol/L HCl at pH 1 and stirred for 1 h at room temperature. Solid K2CO3 was added to the solution to adjust pH to 8 and the mixture was extracted with AcOEt. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to afford titled compound as pale yellow oil (691 mg, 95%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[OH:15])=[O:6].Br[CH2:21][CH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:27]([O:26][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][O:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=1[NH:7][C:5](=[O:6])[C:4]1[CH:16]=[CH:17][C:18]([Cl:19])=[C:2]([Br:1])[CH:3]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)CCCBr
Reactant: Cc1cccc(O)c1NC(=O)c1ccc(Cl)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(OCCCC(=O)OC(C)(C)C)c1NC(=O)c1ccc(Cl)c(Br)c1
Yield: 63.6 %

Procedure:
A mixture of 3-bromo-4-chloro-N-(2-hydroxy-6-methyl-phenyl)-benzamide (11.3 g, 33.2 mmol), t-butyl 4-bromobutyrate (8.2 g, 36.6 mmol) and K2CO3 (9.2 g, 66.5 mmol) was heated in DMF (100 mL) at 60° C. for 14 hrs. The mixture was then concentrated to remove DMF and partitioned between ethyl acetate and water. The organic layer was separated and washed with water and brine, dried over MgSO4, then purified by silica gel column chromatography eluting with ethyl acetate/hexane (1/4) to yield a red solid, which was further washed with ether to produce a white powder as 4-[2-(3-bromo-4-chloro-benzoylamino)-3-methyl-phenoxy]-butyric acid tert-butyl ester (10.2 g). MS [M-(t-Bu)+H]+: 425.8/427.8; tR=2.79 min. (method 1)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]=[C:9]=[S:10])=[O:7].[CH2:11]([O:13][CH2:14][C:15]1[N:16]([CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[C:17]2[C:22]([CH3:23])=[C:21]([CH3:24])[N:20]=[C:19]([NH2:25])[C:18]=2[N:26]=1)[CH3:12]>>[NH2:25][C:19]1[C:18]2[N:26]=[C:15]([CH2:14][O:13][CH2:11][CH3:12])[N:16]([CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][N:32]([C:9]([NH:8][C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)=[O:7])=[S:10])[CH2:31][CH2:30]3)[C:17]=2[C:22]([CH3:23])=[C:21]([CH3:24])[N:20]=1
Reactant: O=C(N=C=S)c1ccco1
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCNCC1
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCN(C(=S)NC(=O)c2ccco2)CC1

Procedure:
Using the method of Examples 54-65, 2-furoylisothiocyanate was reacted with 2-(ethoxymethyl)-6,7-dimethyl-1-(2-piperidin-4-ylethyl)-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 485.2357.
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].C([O:15][C:16]([C:18]1[N:19]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2)=O)C.[OH-].[Na+]>C1COCC1>[OH:15][CH2:16][C:18]1[N:19]([S:27]([C:30]2[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=2)(=[O:29])=[O:28])[C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2
Reactant: CCOC(=O)c1cc2ccccc2n1S(=O)(=O)c1ccc(C)cc1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(CO)cc3ccccc32)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To stirred solution of Red-Al (sodium dihydrobis(2-methoxyethoxy)aluminate ≈70% in toluene) (30 mL) in dry THF (100 mL) cooled at 5° C. and under nitrogen was added dropwise and at this temperature a solution of compound of step 1 (26,8 g, 78 mmol) in dry THF (75 mL). After stirring one hour at 5° C. and then one hour at room temperature the mixture was cooled at 10° C. and treated dropwise with 2N NaOH, to effect hydrolysis of the intermediate complex. The organic phase was separated and the solvent in vacuo evaporated. The residue was solved in ethyl ether, the solution washed with water, dried over MgSO4 and evaporated to give the required alcohol (23.3 g, 98%) as a yellow oil; IR (film) 3500, 1597 cm-1.
Reaction SMILES: I[CH3:2].[H-].[Na+].[Br:5][C:6]1[CH:7]=[C:8]([C:23]([F:26])=[CH:24][CH:25]=1)[CH2:9][C@@H:10]([C:19]([O:21][CH3:22])=[O:20])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].O>O1CCCC1.C(OCC)(=O)C>[Br:5][C:6]1[CH:7]=[C:8]([C:23]([F:26])=[CH:24][CH:25]=1)[CH2:9][C@@H:10]([C:19]([O:21][CH3:22])=[O:20])[N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH3:2]
Reactant: COC(=O)[C@H](Cc1cc(Br)ccc1F)NC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H](Cc1cc(Br)ccc1F)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
49.8 g (350.86 mmol) of iodomethane and 2.28 g (57.01 mmol) of sodium hydride are added to a solution of 16.5 g (43.86 mmol) of methyl 3-bromo-N-(tert-butoxycarbonyl)-6-fluoro-L-phenylalaninate (Example 5O) in 220 ml of anhydrous tetrahydrofuran. The reaction mixture is stirred at RT overnight. 1000 ml of water and 1000 ml of ethyl acetate are added to the mixture. The organic phase is washed successively with water and a saturated sodium chloride solution, dried over sodium sulfate and concentrated. The crude product is purified by column chromatography on silica gel (mobile phase: cyclohexane:ethyl acetate 3:1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:26]([O:28]CC2C=CC=CC=2)=[O:27])[C:12]2[CH:17]=[CH:16][C:15]([O:18]CC3C=CC=CC=3)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.CCOC(C)=O>CCO.[Pd]>[CH3:1][O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:26]([OH:28])=[O:27])[C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CC(C(=O)OCc2ccccc2)c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CC(C(=O)O)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 80 %

Procedure:
To a stirred solution of 4-[2-benzyloxycarbonyl-2-(4-benzyloxy-phenyl)-ethyl]-benzoic acid methyl ester (Step C, 3.0 g, 6.66 mmol) in EtOH:EtOAc (50 mL, 1:1 ratio) at rt, was added 10% palladium on carbon (0.3 g), hydrogenated at 1 atm. H2 (gas) and the reaction mixture was stirred at rt for 14 h. The reaction mixture was filtered through celite plug and washed with ethyl acetate (50 mL) and concentrated under reduced pressure. The crude product was dried under vacuum for 3 h to afford 4-[2-carboxy-2-(4-hydroxy-phenyl)-ethyl]-benzoic acid methyl ester as a white solid (1.6 g, 86%): 1H NMR (300 MHz, CDCl3): δ 7.83 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 7.08 (dd, J=4.62, 12.5 Hz, 2H), 6.66 (dd, J=6.6, 12.5 Hz, 2H), 3.79 (s, 3H), 3.75 (t, J=8.1 Hz, 1H), 3.22 (dd, J=8.4, 13.5 Hz, 1H), 2.93 (dd, J=7.2, 13.8 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][CH:5]([N:10]1[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11]1)[CH2:6]2.[C:23]1([Mg]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[OH:1][C:2]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][CH:5]([N:10]1[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH2:11]1)[CH2:6]2
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C2CC3CCC(C2)C3=O)C1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C2CC3CCC(C2)C3(O)c2ccccc2)C1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of the ketone obtained in Step B (65 mg, 0.21 mmol) in THF (2 mL) cooled in an ice bath was added a 1 M solution of phenyl magnesium bromide in THF (0.25 mL). After being stirred at −78° C. for 3 hours, the reaction was quenched with aqueous ammonium chloride. The resulting solution was extracted with EtOAc 3 times. The combined EtOAc layers were dried over MgSO4 and concentrated. Flash chromatography on silica gel eluting with 5%, 10% and 50% MeOH(CH2Cl2 provided 27 mg of the title compound as a mixture of two isomers (7:3). MS calculated (M+H)+ 387, found 387.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)C.C1COCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COc1cc([N+](=O)[O-])ccc1N1CCCCC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(N)ccc1N1CCCCC1

Procedure:
1-(2-Methoxy-4-nitro-phenyl)-piperidine (Stage 85.2; 4.0 g, 17 mmol) in ethanol/THF 5:1 (90 ml) is hydrogenated in the presence of Pd/C 10 % (“Engelhard 4505”; 0.4 g). Then the catalyst is filtered off and the filtrate is concentrated yielding the title compound: 1H-NMR (DMSO-d6): 6.58 (d, 1H), 6.19 (d, 1H), 6.04 (dd, 1H), 4.66 (s, H2N), 3.65 (s, H3CO), 2.70 (m, 4H), 1.56 (m, 4H), 1.43 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C[Mg]Br.Cl[CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[CH:5][NH:6]2
Reactant: Brc1cccc2[nH]ccc12
Reactant: ClCc1cccnc1
Agent: C[Mg]Br
Solvent: ClCCl
Product: Brc1cccc2[nH]cc(Cc3cccnc3)c12
Yield: 31.4 %

Procedure:
Treatment of 4-bromo-1H-indole (J.Org.Chem., 48 2066(1983)) (16.95 g) with methyl magnesium bromide (34.6 ml of 3M solution in ether) followed by a dichloromethane solution of 3-(chloromethyl)pyridine (prepared from 17.02 g of 3-(chloromethyl)pyridine hydrochloride) according to the method of Preparation 6 gave the title compound (7.80 g), m.p. 173°-174° C. Found: C,58.90; H,3.88; N,9.80. C,14 H11BrN2 requires: C,58.55; H,3.86; N,9.76%.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:26]([O:28]C)=[O:27])([CH3:25])[CH3:24])[CH:17]=1)[C:10]([CH3:31])([CH3:30])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[C:26]([C:23]([NH:22][C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:30])([CH3:31])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[CH:20][CH:19]=1)([CH3:25])[CH3:24])([OH:28])=[O:27]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)OC)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(Nc1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1)C(=O)O
Temperature: 60 °C
Reaction time: 12 h
Yield: 4.9 %

Procedure:
A mixture of 2-[3-(1-methoxycarbonyl-1-methyl-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (678 mg, 1.6 mmol) in methanol (10 mL) and tetrahydrofuran (30 mL), 30% sodium hydroxide in water (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(1-carboxy-1-methyl-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (30 mg, 4%) as a white solid: LC/MS m/e calcd for C22H26N2O4 (M+H)+: 383.46, observed: 383.1.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:27]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:27][C:14]1[S:13][C:12]([NH:11][C:9](=[O:10])[CH:8]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:16][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Nc1ncc(Br)s1)C(CC1CCCCC1)N1Cc2ccccc2C1=O
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 55.8 %

Procedure:
To a suspension of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (Prepared in Example 1; 21 mg; 0.06 mmol) and N-bromosuccinimide (11 mg; 0.06 mmol) in anhydrous carbon tetrachloride (1.0 mL) was added benzoyl peroxide (1 mg; 0.004 mmol). The mixture was stirred at 95° C. in a sealed tube. After 1.5 h, N-bromosuccinimide (2 mg) and benzoyl peroxide (1 mg) were added and the mixture stirred for 30 min. further. The mixture was allowed to cool to room temperature and the solvent removed in vacuo. The residue was taken up into ethyl acetate and washed with water. The organic extract was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (Biotage 12S, eluent: 20% ethyl acetate/hexanes to give 15 mg (58%) of N-(5-Bromo-thiazol-2-yl)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide as a grey foam: EI-HRMS m/e calcd for C20H23BrN3O2S (M+) 447.0616, found 447.0623.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:27])=[C:6]([C:9]1[C:18]([O:19][CH2:20][O:21][CH3:22])=[CH:17][C:16]2[C:15]([CH3:24])([CH3:23])[CH2:14][CH2:13][C:12]([CH3:26])([CH3:25])[C:11]=2[CH:10]=1)[CH2:7][CH3:8])C.C(OC(=O)/C(/F)=C(\C1C(OCOC)=CC2C(C)(C)CCC(C)(C)C=2C=1)/CC)C.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[F:27]/[C:5](=[C:6](/[C:9]1[C:18]([O:19][CH2:20][O:21][CH3:22])=[CH:17][C:16]2[C:15]([CH3:24])([CH3:23])[CH2:14][CH2:13][C:12]([CH3:25])([CH3:26])[C:11]=2[CH:10]=1)\[CH2:7][CH3:8])/[CH2:4][OH:3]
Reactant: CCOC(=O)C(F)=C(CC)c1cc2c(cc1OCOC)C(C)(C)CCC2(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: CCOC(=O)/C(F)=C(/CC)c1cc2c(cc1OCOC)C(C)(C)CCC2(C)C
Solvent: ClCCl
Product: CC/C(=C(\F)CO)c1cc2c(cc1OCOC)C(C)(C)CCC2(C)C

Procedure:
Following General Procedure C and using (E) 2-fluoro-3-(3-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-pent-2-enoic acid ethyl ester (Intermediate 15, 3.3 g, 8.4 mmol), CH2Cl2 (50 mL), and DIBAL-H (33.6 mL, 1.0 M in THF, 33.6 mmol) followed by flash column chromatography on silica gel (10%→20% EtOAc-hexane), the title compound was obtained as a white solid (2.4 g, 75% over 2 steps).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([SH:23])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:24][CH3:25].[Si:26]([O:33][CH2:34][CH2:35][O:36][C:37]1[CH:42]=[C:41]([F:43])[C:40]([CH2:44]O)=[C:39]([F:46])[CH:38]=1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].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>[Si:26]([O:33][CH2:34][CH2:35][O:36][C:37]1[CH:38]=[C:39]([F:46])[C:40]([CH2:44][S:23][C:14]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:24][CH3:25])[CH:4]=3)([CH3:10])[CH3:9])=[CH:12][N:13]=2)=[C:41]([F:43])[CH:42]=1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: COc1cc(C(C)(C)c2cnc(S)n2-c2ccc(F)cc2)ccc1Cl
Reactant: CC(C)(C)[Si](C)(C)OCCOc1cc(F)c(CO)c(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCO[Si](C)(C)C(C)(C)C)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 16 h
Yield: 66 %

Procedure:
To a mixture of 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-thiol (136 mg, 0.36 mmol, 1.0 eq), (4-(2-(tert-butyldimethylsilyloxy)ethoxy)-2,6-difluorophenyl)methanol (115 mg, 0.36 mmol, 1.0 eq) and triphenylphosphine (140 mg, 0.54 mmol, 1.5 eq) in dry THF (2 mL) was added diisopropylazodicarboxylate (0.1 mL). After stirring 16 h, the reaction mixture was concentrated and purified by chromatography (silica, 0-50% EtOAc/Hex) to afford 2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-2,6-difluorobenzylthio)-5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (161 mg, 66%). 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.11 (d, J=7.9 Hz, 1H), 6.76 (dd, J=8.9, 7.8 Hz, 2H), 6.39-6.23 (m, 6H), 4.61 (s, 2H), 3.94-3.80 (m, 4H), 3.69 (s, 3H), 1.45 (s, 6H), 1.26-1.15 (m, 3H), 0.81 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[NH:6][C@@H:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([O-])=O.C([O-])=O.[NH4+]>C(O)C.O.[Pd]>[NH2:1][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[NH:6][C@@H:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)C[C@@H](Nc1ccccc1[N+](=O)[O-])c1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)C[C@@H](Nc1ccccc1N)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl (3R)-3-(2-nitroanilino)-3-phenylpropanoate (100 mg, 292 μmol) in a mixture of ethanol and water (4 mL, 3:1), was added palladium on carbon (20 mg, 10% w/w Pd) and ammonium formate (191 mg, 3.03 mmol). The suspension was heated to reflux for 10 minutes, and was then cooled to room temperature, filtered through a pad of Celite®, and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (98:2) to afford the title compound, 1H NMR: (CD3OD) 7.41 (d, J=7.3, 1H), 7.33-7.31 (m, 2H), 7.25-7.21 (m, 1H), 6.75-6.73 (m, 1H), 6.72-6.52 (m, 2H), 6.47-6.45 (m, 1H), 4.82 (obs., 1H), 2.87 (dd, J=14.6, 7.7, 1H), 2.74 (dd, J=14.6, 6.2, 1H), 1.41 (s, 9H).