Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20](F)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(O[C:34](=[O:39])[NH:35][CH2:36][CH2:37][NH2:38])C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([N:38]4[CH2:37][CH2:36][NH:35][C:34]4=[O:39])=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(N4CCNC4=O)ccc23)CC1
Temperature: 115 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
To a mixture of 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (458 mg, 1.38 mmol), which was prepared as described in Example 65b, and (2-amino-ethyl)-carbamic acid benzyl ester hydrochloride (446 mg, 1.93 mmol) in DMSO (1.0 mL) was added K2CO3 (1.52 g, 11.04 mmol). The mixture was stirred at 115° C. overnight and subsequently partitioned between EtOAc and water. The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography on silica gel (EtOAc as eluent) to afford the desired product as a white solid (400 mg, 73%). 1H NMR (CDCl3) δ 9.13 (s, 1H), 8.69 (dd, J=9.40 and 2.35 Hz, 1H), 8.08 (d, J=9.53 Hz, 1H), 7.42 (d, J=2.33 Hz, 1H), 5.25 (br, 1H), 4.31 (m, 2H), 4.09 (t, J=8.21 Hz, 2H), 3.69 (t, J=8.14 Hz, 2H), 3.63 (m, 1H), 2.95 (m, 2H), 1.77-2.04 (4H), 1.48 (s, 9H). Calcd for C21H28N5O3 (MH+) 398.3, found 398.3.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33]Cl)[CH:26]=4)=[CH:19][CH:20]=3)[CH:15]=2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33][N:46]5[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]5)[CH:26]=4)=[CH:19][CH:20]=3)[CH:15]=2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc3ccc(Oc4ccnc(NC(=O)CCl)c4)cc3c2)c1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(CC(=O)Nc2cc(Oc3ccc4ccc(C(=O)Nc5cccc(C(C)(C)C)c5)cc4c3)ccn2)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a suspension of N-(3-tert-butylphenyl)-7-({2-[(chloroacetyl)amino]pyridin-4-yl}oxy)-2-naphthamide (65.0 mg, 0.133 mmol) and potassium carbonate (36.8 mg, 0.266 mmol) in DMF (2 mL) was added 1-methylpiperazine (0.177 mL, 0.160 mmol). The reaction mixture was allowed to stir at 60° C. for 2 h. and then concentrated. EtOAc and water were added and the organic and aqueous solutions were separated. The organic solution was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give N-(3-tert-butylphenyl)-7-[(2-{[(4-methylpiperazin-1-yl)acetyl]-amino}pyridin-4-yl)oxy]-2-naphthamide I-264 ( ) (33 mg, 37%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][O:4][CH2:5][CH2:6]OS(C)(=O)=O.[NH:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[NH:23][CH:24]1[CH2:29][CH2:28][N:27](C(OCC)=O)[CH2:26][CH2:25]1>>[F:1][C:2]([F:13])([F:12])[CH2:3][O:4][CH2:5][CH2:6][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[NH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Reactant: CS(=O)(=O)OCCOCC(F)(F)F
Product: FC(F)(F)COCCn1c(NC2CCNCC2)nc2ccccc21

Procedure:
Prepare by the method of Preparation 14 using 2-methanesulfonyloxyethyl 2,2,2-trifluoroethyl ether and (1H-benzimidazol-2-yl)(1-ethoxycarbonylpiperidin-4-yl)amine to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[C:13]([C:15]#[C:16][CH3:17])[CH:14]=2)=[CH:4][C:3]=1[C@:18]12[O:26][CH2:25][CH2:24][C@H:23]1[CH2:22][S:21][C:20]([NH:27]C(=O)OC(C)(C)C)=[N:19]2.C(O)(C(F)(F)F)=O>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[C:13]([C:15]#[C:16][CH3:17])[CH:14]=2)=[CH:4][C:3]=1[C@:18]12[O:26][CH2:25][CH2:24][C@H:23]1[CH2:22][S:21][C:20]([NH2:27])=[N:19]2
Reactant: CC#Cc1cncc(-c2cc([C@@]34N=C(NC(=O)OC(C)(C)C)SC[C@@H]3CCO4)c(F)cc2F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC#Cc1cncc(-c2cc([C@@]34N=C(N)SC[C@@H]3CCO4)c(F)cc2F)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 68.7 %

Procedure:
To a solution of (±)-tert-butyl (4aR,7aR)-7a-(2,4-difluoro-5-(5-(prop-1-ynyl)pyridin-3-yl)phenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-ylcarbamate (Preparation 6, 22 mg) in dichloromethane (300 μL) was added TFA (35 μL, 0.508 mmol) at rt, and the reaction mixture was stirred at rt for 2.5 h. The crude product was directly purified by prep TLC eluting with 90% CH2Cl2/9% MeOH/1% NH4OH to give the title compound (12 mg) a colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.66-8.61 (m, 2H), 7.86-7.83 (m, 1H), 7.71 (t, J=8.8 Hz, 1H), 6.98-6.91 (m, 1H), 4.15-4.03 (m, 2H), 3.15 (dd, J=13.1, 4.0 Hz, 1H), 3.00 (ddd, J=13.1, 7.5, 2.0 Hz, 1H), 2.80-2.73 (m, 1H), 2.24-2.09 (m, 5H). MS (M−1): 364.2.
Reaction SMILES: C(O[C:6](=[O:24])[N:7]([CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)(C)(C)C.[CH2:25]([O:27][C:28](=[O:40])[CH:29](C(OCC)=O)[C:30](OCC)=[O:31])[CH3:26]>>[CH2:25]([O:27][C:28]([C:29]1[C:6](=[O:24])[N:7]([CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[C:30]=1[OH:31])=[O:40])[CH3:26]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2ccccc2c1)n1cccc1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1c(O)c2cccn2n(Cc2ccc3ccccc3c2)c1=O

Procedure:
Prepared according to the thermal cyclization condition used in Example 1 step c) from naphthalen-2-ylmethyl-pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.) and 2-ethoxycarbonyl-malonic acid diethyl ester (3.0 eq.). ESI (m/z): 363 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:20]([NH:22][C@H:23]([C:28]([NH:30][C@H:31]([C:36]([NH:38][CH:39]([C:44]([NH2:46])=[O:45])[CH2:40][CH2:41][CH2:42][CH3:43])=[O:37])[CH2:32][C:33](=[O:35])[OH:34])=[O:29])[CH2:24][CH2:25][S:26][CH3:27])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=O)(C)(C)C.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]>O1CCOCC1>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[NH2:8][C@H:9]([C:20]([NH:22][C@H:23]([C:28]([NH:30][C@H:31]([C:36]([NH:38][CH:39]([C:44]([NH2:46])=[O:45])[CH2:40][CH2:41][CH2:42][CH3:43])=[O:37])[CH2:32][C:33](=[O:34])[OH:35])=[O:29])[CH2:24][CH2:25][S:26][CH3:27])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1
Reactant: CCCCC(NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(N)=O
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCCCC(NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(N)=O

Procedure:
the reaction of N-t-butoxycarbonyl-L-tryptophanyl-L-methionyl-L-aspartyl-DL-norleucine amide according to the procedure of Example 7 using trifluoroacetic acid instead of hydrochloric acid in dioxane affords L-tryptophanyl-L-methionyl-L-aspartyl-DL-norleucine amide trifluoroacetate. This compound is represented by the following formula.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[C:15]=2[OH:18])[CH2:10]1.C([O-])(=O)C.[Na+]>O>[C:1]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[C:15]=2[OH:18])[CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: NC1Cc2ccc(O)c(O)c2C1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)NC1Cc2ccc(O)c(O)c2C1
Reaction time: 4 h

Procedure:
Acetic anhydride is added to a mixture of 2-amino-4,5-dihydroxyindane Cannon, J. G., et al., J. Med. Chem.,27, 922(1984)! in water containing sodium acetate. The mixture is chilled and stirred in ice for 4 hours followed by filtration to give N-acetyl-2-amino-4,5-dihydroxyindane. Benzylbromide, powdered potassium carbonate and acetone is added to the isolated N-acetyl-2-amino-4,5-dihydroxyindane and the mixture is stirred for 18 hours. The reaction mixture is poured into water, extracted and evaporated in vacuo to give N-acetyl-2-amino-4,5-dibenzyloxyindane. Hydrolysis with ethanolic sodium hydroxide gives 2-amino-4,5-dibenzyloxyindane.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[OH:20][CH2:21][C@H:22]([NH2:25])[CH2:23][CH3:24].CCN(C(C)C)C(C)C>>[OH:20][CH2:21][C@H:22]([NH:25][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1)[CH2:23][CH3:24]
Reactant: CC[C@@H](N)CO
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](CO)NC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (R)-1-hydroxymethyl-propylamine and DIEA to give 2-((R)-1-hydroxymethyl-propylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 328 (MH+).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][C:8]1[C:9](=[O:19])[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([OH:18])=[CH:13][CH:12]=2)[C:4]([OH:6])=[O:5].[Cl:20][C:21]1[CH:38]=[CH:37][C:24]([C:25](N2C3C=CC=CC=3OC2=S)=[O:26])=[CH:23][CH:22]=1>CN1CCCC1=O>[Cl:20][C:21]1[CH:38]=[CH:37][C:24]([C:25]([NH:2][CH:3]([CH2:7][C:8]2[C:9](=[O:19])[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([OH:18])=[CH:13][CH:12]=3)[C:4]([OH:6])=[O:5])=[O:26])=[CH:23][CH:22]=1
Reactant: NC(Cc1cc2cc(O)ccc2[nH]c1=O)C(=O)O
Reactant: O=C(c1ccc(Cl)cc1)n1c(=S)oc2ccccc21
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=C(NC(Cc1cc2cc(O)ccc2[nH]c1=O)C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2 Grams of 2-amino-3-(6-hydroxy-2-quinolon-3-yl)propionic acid hydrochloride was suspended in 50 ml of 1-methyl-2-pyrrolidone, then 2.2 g of 3-(4-chlorobenzoyl)benzoxazoline-2-thione was added thereto and stirred at a room temperature for 3 days. The reaction mixture was poured in ice-water and the crystals precipitated were collected by filtration. The crystals were dissolved in 1N-sodium hydroxide aqueous solution, and acidified with 10%-hydrochloric acid, then the crystals precipitated were collected by filtration. The crystals were dried and washed with chloroform. Recrystallized from methanol-water to obtain 1.5 g of 2-(4-chlorobenzoylamino)-3-(6-hydroxy-2-quinolon-3-yl)propionic acid in the form of light yellowish powdery product.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:11]=[C:12]([C:16]2[N:20]([CH3:21])[N:19]=[C:18]([C:22]([N:24]3[CH2:28][CH2:27][CH:26]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:25]3)=[O:23])[C:17]=2[CH3:34])[CH:13]=[CH:14][CH:15]=1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[N:20]([CH3:21])[N:19]=[C:18]([C:22]([N:24]4[CH2:28][CH2:27][CH:26]([N:29]([CH2:30][CH3:31])[CH2:32][CH3:33])[CH2:25]4)=[O:23])[C:17]=3[CH3:34])[CH:11]=2)=[CH:38][CH:37]=1
Reactant: CCN(CC)C1CCN(C(=O)c2nn(C)c(-c3cccc(Br)c3)c2C)C1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCN(CC)C1CCN(C(=O)c2nn(C)c(-c3cccc(-c4ccc(Cl)cc4)c3)c2C)C1
Yield: 39 %

Procedure:
In analogy to the procedure described in example 14C] but with 2.8 eq of K3PO4, [5-(3-bromo-phenyl)-1,4-dimethyl-1H-pyrazol-3-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone and 4-chlorophenylboronic acid gave [5-(4′-chloro-biphenyl-3-yl)-1,4-dimethyl-1H-pyrazol-3-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone in 39% yield as light brown foam. MS: 451.3 (MH+, 1 Cl).
Reaction SMILES: [N:1]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH2:10][CH2:9][C@H:8]([CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[O:7]3)[CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][NH:40][CH2:41][CH:42]=1.C(Cl)(Cl)Cl>CS(C)=O>[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][N:40]([CH2:15][C@H:8]2[CH2:9][CH2:10][C:11]3[C:6](=[C:5]4[C:14](=[CH:13][CH:12]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[O:7]2)[CH2:41][CH:42]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3ccc4ncccc4c3O2)cc1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: Fc1ccc2[nH]cc(C3=CCN(C[C@H]4CCc5ccc6ncccc6c5O4)CC3)c2c1
Yield: 56.6 %

Procedure:
A solution of (6R)-toluene-4-sulfonic acid 7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-ylmethyl ester (0.17 g, 0.47 mmole) and 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.20 g, 0.94 mmole) in anhydrous DMSO (25 mL) was stirred at 80° C. for 2 hours. The reaction mixture was then poured into chloroform (100 mL) and washed with water (3×40 mL). The organic layer was dried over sodium sulfate and filtered, and the solvent was removed under vacuum. Column chromatography on silica gel (5% methanol/ethyl acetate) afforded 0.11 g (55%) of the title compound. The fumarate salt was prepared in ethyl acetate and isopropyl alcohol and had mp 210° C. and [α]25D=−60.03° (c=4.5, DMSO).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4](=[O:16])[CH2:5]/[C:6]/2=[CH:12]\[C:13]([NH2:15])=[O:14].[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]([OH:16])[CH2:5]/[C:6]/2=[CH:12]\[C:13]([NH2:15])=[O:14]
Reactant: NC(=O)/C=C1\CC(=O)c2c(F)cc(F)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)/C=C1\CC(O)c2c(F)cc(F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.4 %

Procedure:
A suspension of (E)-2-(4,6-difluoro-3-oxo-1-indanylidene)acetamide (0.100 g, 0.45 mmol) and sodium borohydride (0.017 g, 0.45 mmol) in 95% ethanol was stirred at ambient temperature for 2 hours. The mixture was cooled in an ice bath and quenched with 0.1N hydrochloric acid (3 mL). The ethanol was evaporated in vacuo, and the residue was dissolved in ethyl acetate (50 mL), washed successively with water (2×3 mL) and brine (30 mL), dried over sodium sulfate, filtered, and evaporated in vacuo. The resudue was washed successively with cold ethyl acetate, hexane, and diethyl ether to give 0.046 g (45%) of (E)-2-(4,6difluoro-3-hydroxy-1-indanylidene)acetamide as a white solid; mp 232°-237° C. (dec.) 1H-NMR (DMSO-d6): δ7.06-7.42 (m, 4H), 6.49 (s, 1H), 5.52 (d, 1H), 5.30 (m,1H), 3.44 (m,1H), 3.03 (d, 1H).
Reaction SMILES: [OH-].[Na+].CO.[Cl:5][C:6]1[N:7]=[C:8]([CH3:33])[N:9]([CH2:12][C:13]2[S:28][C:16]3[N:17]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:18](=[O:23])[N:19]([CH3:22])[C:20](=[O:21])[C:15]=3[C:14]=2[C:29]([O:31]C)=[O:30])[C:10]=1[Cl:11]>O1CCCC1>[Cl:5][C:6]1[N:7]=[C:8]([CH3:33])[N:9]([CH2:12][C:13]2[S:28][C:16]3[N:17]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:18](=[O:23])[N:19]([CH3:22])[C:20](=[O:21])[C:15]=3[C:14]=2[C:29]([OH:31])=[O:30])[C:10]=1[Cl:11]
Reactant: COC(=O)c1c(Cn2c(C)nc(Cl)c2Cl)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(Cl)c(Cl)n1Cc1sc2c(c1C(=O)O)c(=O)n(C)c(=O)n2CC(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium hydroxide (7.3 ml of 1M aqueous solution) followed by methanol (4 ml) were added to a solution of the product of step c) (2.28 g) in tetrahydrofuran (50 ml) and stirred at room temperature for 3 h. The solution was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash silica chromatography eluting with a gradient of 2-5% ethanol in dichloromethane to give the sub-title compound as a white solid (1.68 g). MS (APCI) 445/447 [M+H]+. δ 1HCDCl3 0.96 (6H,d), 2.22 (1H, septet), 2.37 (3H,s), 3.51 (3H,s), 3.78 (2H,d), 5.78 (2H,s), 15.51 (1H,br.s).
Reaction SMILES: [OH:1][CH:2]([CH2:16][CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:14][CH2:13][CH:12]2[CH:8]1[CH2:9][C:10](=[O:15])[CH2:11]2.[C:18](O)(=[O:20])[CH3:19]>>[C:18]([O:1][CH:2]([CH2:16][CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:14][CH2:13][CH:12]2[CH:8]1[CH2:9][C:10](=[O:15])[CH2:11]2)(=[O:20])[CH3:19]
Reactant: CCC(O)CCCCC1CCC2CC(=O)CC12
Reactant: CC(=O)O
Product: CCC(CCCCC1CCC2CC(=O)CC12)OC(C)=O
Temperature: 70 °C
Reaction time: 4 h

Procedure:
The starting material from Example 3, 2-(5-hydroxyhept-1-yl)bicyclo[3.3.0]octan-7-one }hexahydro-4-(5-hydroxyheptyl)-2(1H)-pentalenone} (2.5 g, 10.5 mmoles) is diluted with glacial acetic acid (10 ml) and stirred in a 70° C. water bath for 4 hours. The reaction is cooled to room temperature and partitioned between ether (50 ml) and water (50 ml). The ether layer is separated and the aqueous phase extracted with ether (2×50 ml). The organic layers are combined, neutralized with a solution of saturated sodium bicarbonate, and dried over anhydrous sodium sulfate. The solvent is removed under vacuum leaving a clear yellow oil. The crude product is chromatographed on silica gel and subsequently kugelrohred under vacuum leaving a clear, colorless oil (2.1 g, 7.4 mmoles).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[S:31]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32]1>>[CH2:21]([CH:18]([N:13]1[C:12]([C:33]2[CH:34]=[CH:35][S:31][CH:32]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH2:19][CH3:20])[CH3:22]
Reactant: CCC(CC)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: OB(O)c1ccsc1
Product: CCC(CC)n1nc2c(c1-c1ccsc1)CCNCC2
Yield: 99.7 %

Procedure:
The title compound (95 mg) was prepared as in Example 177, Steps C and D, using 150 mg of 2-(1-ethyl-propyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 183, Step A) and 126 mg of 3-thiopheneboronic acid. MS (ESI): exact mass calculated for C16H23N3S, 289.16; found, m/z 290.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.68-7.64 (m, 1H), 7.52-7.48 (m, 1H), 7.12-7.07 (m, 1H), 3.93-3.86 (m, 1H), 3.44-3.39 (m, 2H), 3.34-3.28 (m, 2H), 3.22-3.17 (m, 2H), 2.85-2.79 (m, 2H), 1.95-1.84 (m, 2H), 1.79-1.69 (m, 2H), 0.71 (t, J=7.4 Hz, 3H).
Reaction SMILES: C(O)C(N)(CO)CO.Cl.N[C@H:11]([C:19]([OH:21])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:19]([OH:21])(=[O:20])[CH:11]=[CH:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: NC(CO)(CO)CO
Product: O=C(O)C=Cc1ccccc1
Reaction time: 0.33 h

Procedure:
First, cells were recovered from the culture by centrifugation. The collection cells were washed by suspending them in a 0.85% sodium chloride solution and recovered by centrifugation. The washed cells were then suspended in a 25 mM Tris-HCl buffer solution (pH 8.8) to give a cell concentration of about 1% by wet weight. The suspension was added to an enzymatic reaction medium comprising a 25 mM Tris-HCl buffer solution (pH 8.8) supplemented with 25 mM L-phenylalanine and 0.005% cetyl pyridium hydrochloride. The resultant reaction medium was incubated at 30° C. for 20 minutes. After the reaction was terminated by addition of 1N HCl, cinnamic acid formed in the reaction mixture was analyzed by liquid chromatography to estimate the PAL activity. One unit (U) as defined herein corresponds to the amount of enzyme to produce one micromole of cinnamic acid per minute.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11]>O1CCCC1>[CH3:9][C:4]1[N:3]=[C:2]2[NH:1][C:10](=[O:11])[O:8][C:7]2=[CH:6][CH:5]=1
Reactant: Cc1ccc(O)c(N)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1ccc2oc(=O)[nH]c2n1

Procedure:
1.24 g (10 mmol) of 2-amino-3-hydroxy-6-methylpyridine are introduced into a three-necked round-bottomed flask. The system is placed under argon. 20 ml of anhydrous tetrahydrofuran and then 2.43 g (15 mmol) of 1,1'-carbonyldimidazole are added. The mixture is heated to reflux for 6 hours. The reaction medium is evaporated. The crystals obtained are washed with water, filtered off and redissolved in hot methanol. The solution is filtered and re-evaporated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:12]=O)[CH2:11][CH2:10]1.C(OC(=O)C)(=O)C.Cl[C:22](Cl)([F:27])[C:23]([O:25][CH3:26])=[O:24]>[Zn].[Cu]Cl.O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:12]=[C:22]([F:27])[C:23]([O:25][CH3:26])=[O:24])[CH2:10][CH2:11]1
Reactant: COC(=O)C(F)(Cl)Cl
Reactant: O=CC1(c2ccc(F)cc2F)CC1
Agent: Cl[Cu]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C(F)=CC1(c2ccc(F)cc2F)CC1
Yield: 38.8 %

Procedure:
The method of Example 1 was repeated using zinc powder (1 g), copper (I) chloride (0.12 g), molecular sieve 4A (1 g), tetrahydrofuran (18 ml), 1-(2,4-difluorophenyl)-1-formylcyclopropane (0.44 g), acetic anhydride (0.4 ml) and methyl dichlorofluoroacetate (0.62 g) to yield the title compound (0.24 g, 39%).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:14]1([NH:13][CH2:1][C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Nc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CNc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 55.3 %

Procedure:
Methyl 4-formylbenzoate (1 g, 6 mmol) and aniline (837 mg, 9 mmol) were dissolved in methanol (30 mL). The mixture was heated to 50° C., and acetic acid (two or three drop) was added to the reaction mixture. The resultant mixture was stirred at 50° C. for 1 hour. After the mixture was cooled to room temperature, sodium cyanoborohydride (1.13 g, 18 mmol) was added. The mixture was stirred at room temperature for 18 hours. The reaction was quenched with water (10 mL) and the mixture was extracted with dichloromethane (10 mL×3). The combined organic phase was separated, dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=8:1) to give methyl 4-((phenylamino)methyl)benzoate (0.8 g, 55%). LRMS (M+H+) m/z: cald. 241.08. found 241. LRMS (M+H+) m/z: calcd 241.08. found 241. 1H NMR (300 MHz, CD3OD): δ 7.95 (dd, J=7.2 Hz, J=2.1 Hz, 2H), 7.44 (d, J=7.8 Hz, 2H), 7.05 (t, J=6.0 Hz, 2H), 6.60-6.56 (m, 3H), 4.37 (s, 2H), 3.86 (s, 3H).
Reaction SMILES: Cl.CN([CH:5]([CH3:15])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)=[O:7])C.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23]>C(O)C>[ClH:14].[OH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[NH:16][CH2:15][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)=[O:7]
Reactant: Nc1ccccc1O
Reactant: CC(C(=O)c1cccc(Cl)c1)N(C)C
Agent: Cl
Solvent: CCO
Product: O=C(CCNc1ccccc1O)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
Dimethylamino-m-chloropropiophenone hydrochloride (74.9 g, 0.30 mol) was dissolved in 50% aqueous ethanol (700 ml) at reflux. 2-Aminophenol (32.9 g, 0.30 mol) was then added and the resulting red solution was refluxed for a further 2 hours. The reaction mixture was allowed to cool to room temperature and then extracted twice with ethyl acetate (2×100 ml). Note that brine was also added at this point to allow the two layers to separate effectively). The organic extracts were combined and an excess of concentrated hydrochloric acid (47 ml) was added. The solution was concentrated in vacuo and then allowed to cool. The precipitate that formed was filtered of, washed with diethyl ether and dried in vacuo to yield a cream powder (38.1 g, 40%).