Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([Cl:21])[CH:15]=1.[NH2-].[Li+].Cl>C(#N)C>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[C:16]([Cl:21])[CH:15]=1
Reactant: Nc1ccc(Br)cc1Cl
Reactant: O=C(O)c1ccc(F)c(F)c1F
Agent: Cl
Agent: [Li+]
Agent: [NH2-]
Solvent: CC#N
Product: O=C(O)c1ccc(F)c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 93.2 %

Procedure:
To a solution of 2,3,4-trifluorobenzoic acid (1 g, 5.68 mmol) and 4-bromo-2-chloroaniline (1.2 g, 5.68 mmol) in acetonitrile (10 mL) was added lithium amide (0.39 g, 17.04 mmol) and the reaction stirred at 60° C. for 1.5 hours. The mixture was cooled to room temperature and then to 0° C. and acidified with aq. hydrochloric acid. The obtained precipitate was collected by filtration and washed with cold water and dried in vacuo to afford 2-[(4-bromo-2-chlorophenyl)amino]-3,4-difluorobenzoic acid (1.92 g, 94% yield) as a beige solid. MS (EI) for C13H7BrClF2NO2: 363 (MH+).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:23]([N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39])[CH2:24][CH2:25][CH2:26][C:27]#[CH:28].C(N(CC)CC)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN1CCCC1=O>[CH3:22][N:19]1[CH2:20][CH2:21][CH:16]([O:15][CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:4]2[CH:3]=[C:2]([C:28]#[C:27][CH2:26][CH2:25][CH2:24][CH2:23][N:29]3[C:33](=[O:34])[C:32]4[C:31](=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:30]3=[O:39])[CH:7]=[CH:6][CH:5]=2)[CH2:17][CH2:18]1
Reactant: CN1CCC(OC(c2cccc(I)c2)c2ccccn2)CC1
Reactant: C#CCCCCN1C(=O)c2ccccc2C1=O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CN1CCC(OC(c2cccc(C#CCCCCN3C(=O)c4ccccc4C3=O)c2)c2ccccn2)CC1
Temperature: 90 °C
Reaction time: 14 h

Procedure:
A screw-cap tube is charged with 2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]pyridine (105 mg, example 37), tetrakis(triphenylphosphine)palladium (52 mg), copper(I) iodide (26 mg), N-5-hexynylphthalimide (186 mg), triethylamine (400 μL) and 1-methyl-2-pyrrolidinone (4 mL). The tube is evacuated, filled with argon and sealed. After stirring at 90° C. for 14 h, the mixture is diluted with water and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 98/2/0.5 to 95/5/0.5) to give 2-(6-{3-[(1-methylpiperidin-4-yloxy)-pyridin-2-ylmethyl]phenyl}hex-5-ynyl)isoindole-1,3-dione as an brown oil.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:34]=[CH:35][CH:36]=1)[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[N:21]=[CH:22][C:23]([NH:26]C(=O)OC(C)(C)C)=[N:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[NH2:26][C:23]1[CH:22]=[N:21][C:20]([C:18]([N:15]2[CH2:16][CH2:17][N:12]([CH2:11][C:10]3[CH:9]=[C:8]([CH:36]=[CH:35][CH:34]=3)[C:6]([NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:14]2)=[O:19])=[CH:25][N:24]=1
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3cnc(NC(=O)OC(C)(C)C)cn3)CC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3cnc(N)cn3)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
A mixture of tert-butyl 5-(1-(3-(tert-butylcarbamoyl)benzyl)piperazine-4-carbonyl)pyrazin-2-ylcarbamate (Example 30;120 mg, 0.242 mmol), dichloromethane (2 mL) and trifluoroacetic acid (2 mL) was stirred at room temperature for 3 hours and was then concentrated under vacuum. The residue was triturated with diethyl ether and then gravity filtered over fluted paper. The collected solid was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The aqueous layer was separated and extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum to afford the title compound (89 mg). MS (ESI) m/z 397.2 [M-+H]+
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH:32][CH:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1.[CH3:46][O:47][C:48]1[CH:53]=[C:52]([N+:54]([O-:56])=[O:55])[CH:51]=[CH:50][C:49]=1O>C1COCC1>[CH3:46][O:47][C:48]1[CH:53]=[C:52]([N+:54]([O-:56])=[O:55])[CH:51]=[CH:50][C:49]=1[O:32][CH:33]1[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COc1cc([N+](=O)[O-])ccc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.17 h
Yield: 81.6 %

Procedure:
To a mixture of triphenylphosphine (3.10 g, 11.8 mmol) and diethylazodicarboxylate (2.06 g, 11.8 mmol) under N2 in THF (40 mL) was added t-butyl 4-hydroxypiperidine-1-carboxylate (2.00 g, 9.94 mmol). After stirring 10 min, 2-methoxy-4-nitrophenol (1.00 g, 5.91 mmol) was added. The reaction was stirred for 16 h and the solvent was evaporated under reduced pressure to give orange oil. The crude product was purified by column chromatography on silica gel using 25% EtOAc/hexane yielding t-butyl 4-(2-methoxy-4-nitrophenoxy)piperidine-1-carboxylate as a beige solid (1.70 g, 82%). LC/MS (m/z): 353.2 (MH+), Rt 3.23 minutes
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[N:11]2[CH:12]3[CH2:17][CH2:16][N:15](C(OCC)=O)[CH2:14][CH:13]3[C:9]3[C:10]2=[C:5]([CH:6]=[CH:7][CH:8]=3)[N:4]([CH3:23])[CH2:3]1.[OH-].[K+]>C(O)CCC.O>[CH3:1][C:2]1([CH3:24])[N:11]2[CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH:13]3[C:9]3[C:10]2=[C:5]([CH:6]=[CH:7][CH:8]=3)[N:4]([CH3:23])[CH2:3]1
Reactant: CCOC(=O)N1CCC2C(C1)c1cccc3c1N2C(C)(C)CN3C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCCCO
Product: CN1CC(C)(C)N2c3c(cccc31)C1CNCCC12
Temperature: 120 °C
Reaction time: 20 h
Yield: 97.1 %

Procedure:
To a solution of ethyl 1,1,3-trimethyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (8 mg, 0.02 mmol) in n-butanol (5 mL) at rt was added KOH (50 mg, 0.89 mmol) and stirred at 120° C. for 20 hours. The solution was diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The combined extracts were dried over magnesium sulfate and concentrated to afford the title compound (5 mg, 81%). MS [M+H]+ 258.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[N:17][CH:18]=1>C(O)(=O)C>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][O:19][C:16]2[CH:15]=[CH:14][C:13]([N:12]3[C:1](=[O:11])[C:2]4[CH2:10][CH2:9][CH2:8][CH2:7][C:3]=4[C:4]3=[O:6])=[CH:18][N:17]=2)=[CH:23][CH:24]=1
Reactant: Nc1ccc(OCCc2ccc(Cl)cc2)nc1
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1ccc(OCCc2ccc(Cl)cc2)nc1
Reaction time: 1.5 h

Procedure:
A mixture of 3,4,5,6-tetrahydrophthalic anhydride (0.4 g), 5-amino-2-(4-chlorophenethoxy)pyridine (0.6 g) and acetic acid (20 ml) is heated to reflux. After about 1.5 hours, the reaction is cooled and concentrated to about one-half volume. On standing a crystalline solid precipitation which is collected by filtration and washed with 10% ethyl acetate/hexane to yield N-[2-(4-chlorophenethoxy)-5-pyridyl]-3,4,5,6-tetrahydrophthalimide.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:38]=[CH:37][CH:36]=[CH:35][C:7]=1[O:8][C:9]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:22][C:12]2[NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[N:15][C:11]=2[CH:10]=1)=O)C.[CH3:39][N:40](C)[C:41](=O)C1C=CC=CC=1O>>[CH3:39][N:40]([CH3:41])[C:4]([C:6]1[CH:38]=[CH:37][CH:36]=[CH:35][C:7]=1[O:8][C:9]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:22][C:12]2[NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[N:15][C:11]=2[CH:10]=1)=[O:3]
Reactant: CCOC(=O)c1ccccc1Oc1cc2nc(-c3ccccn3)[nH]c2cc1Oc1ccc(S(C)(=O)=O)cc1
Reactant: CN(C)C(=O)c1ccccc1O
Product: CN(C)C(=O)c1ccccc1Oc1cc2nc(-c3ccccn3)[nH]c2cc1Oc1ccc(S(C)(=O)=O)cc1

Procedure:
The entitled compound was obtained in the same method as in Example 14 or in accordance with the method or by combining it with an ordinary method but using 4-fluoro-5-(4-methanesulfonyl-phenoxy)-2-nitro-phenylamine obtained in Example 14 and 2-hydroxybenzoic acid dimethylamide in order.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]([O:14][CH:15]([C:18]1[CH:19]=[N:20][C:21]([CH3:24])=[N:22][CH:23]=1)[CH2:16][NH2:17])([CH3:13])[CH3:12]>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:17][CH2:16][CH:15]([O:14][CH:11]([CH3:13])[CH3:12])[C:18]1[CH:19]=[N:20][C:21]([CH3:24])=[N:22][CH:23]=1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: Cc1ncc(C(CN)OC(C)C)cn1
Product: Cc1ncc(C(CNC(=O)c2ccccc2Cl)OC(C)C)cn1

Procedure:
From 2-chlorobenzoic acid and 2-isopropoxy-2-(2-methylpyrimidin-5-yl)ethanamine. LCMS (MH+): m/z=334.0, tR (minutes, Method E)=0.52
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][C:10]2[CH:19]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[S:21][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[C:33]1(=O)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.P(=O)(O)(O)O>C(O)(=O)C>[CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([C:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]=2)[C:10]2[CH:19]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[S:21][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCCC1
Reactant: COC(=O)c1cc2cc(-c3ccccc3)n(Cc3ccccc3)c2s1
Agent: O=P(O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cc2c(C3=CCCCC3)c(-c3ccccc3)n(Cc3ccccc3)c2s1
Temperature: 80 °C
Yield: 95 %

Procedure:
A solution (0.2 M) of methyl 6-benzyl-5-phenyl-6H-thieno[2,3-b]pyrrole-2-carboxylate in acetic acid was treated with acetic anhydride (10 eq.), cyclohexanone (10 eq.) and 85% phosphoric acid (2.3 eq.). The mixture was heated at 80° C. for 3 h, then was poured into ice cold ammonium hydroxide. The product was extracted with AcOEt and the combined organic phase was washed sequentially with aqueous HCl (1 N), aqueous NaHCO3 (saturated solution) and brine then dried and concentrated. The crude was purified by flash chromatography on silica gel (1:30 acetone/toluene) affording the title compound (95%) as a solid.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH2:11][CH2:10]1)(C)(C)C.C1(C)C=CC=CC=1>O1CCOCC1>[ClH:1].[CH3:17][N:16]([CH3:18])[C:15]([CH:12]1[CH2:13][CH2:14][CH:9]([NH2:8])[CH2:10][CH2:11]1)=[O:19]
Reactant: CN(C)C(=O)C1CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CN(C)C(=O)C1CCC(N)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
HCl (concentrated, 7 mL) was added to a solution of (4-dimethylcarbamoyl-cyclohexyl)-carbamic acid tert-butyl ester (1.5 g) in 1,4-dioxane (20 mL), and the resulting mixture was stirred at RT for 5 h. Toluene was added and the reaction mixture was evaporated under reduced pressure. The oily residue was triturated with EtOAc to give 4-amino-cyclohexanecarboxylic acid dimethylamide hydrochloride salt (0.9 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:45])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2([CH3:44])[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]2)=[O:29])[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:44][C:31]1([NH:30][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:45])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NC2(C)CCN(C(=O)OC(C)(C)C)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NC2(C)CCNCC2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reaction time: 2.5 h

Procedure:
To a stirred solution of racemic tert-butyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-4-methylpiperidine-1-carboxylate (27.0 mg, 0.0407 mmol, example 386) in dichloromethane (3 mL) was added TRIFLUOROACETIC ACID (4.44 g, 3 mL) and the reaction mixture was stirred at 0˜5 C for 2.5 hrs. The solvent was removed in vacuum and residue was dissolved in CH2Cl2 (80 mL), washed with sat Na2CO3 (15 mL), water (2×15 mL) and evaporated to give rac-(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-methyl-piperidin-4-yl)-amide as a white solid. MS (ES+) m/z Calcd: [(M+H)+]: 563. found: 563.
Reaction SMILES: C([N:8]([CH2:13][CH:14]1[CH2:16][CH:15]1[CH3:17])[CH2:9][CH:10]([F:12])[F:11])C1C=CC=CC=1.Cl>O1CCOCC1.C(O)C.[OH-].[Pd+2].[OH-]>[F:11][CH:10]([F:12])[CH2:9][NH:8][CH2:13][CH:14]1[CH2:16][CH:15]1[CH3:17]
Reactant: CC1CC1CN(Cc1ccccc1)CC(F)F
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: CC1CC1CNCC(F)F
Reaction time: 1 h

Procedure:
A solution of N-benzyl-2,2-difluoro-N-[(2-methylcyclopropyl)methyl]ethanamine (1.25 g, 5.2 mmol) and hydrochloric acid (5.7 mmol, 1.44 mL of a 4M solution in dioxane) in ethanol (50 mL) was degassed with nitrogen and treated with palladium hydroxide (125 mg). The reaction was placed under a hydrogen atmosphere and stirred vigorously for 1 hour. The reaction was filtered through celite, washed with methanol and concentrated in vacuo to give (2,2-difluoroethyl)[(2-methylcyclopropyl)methyl]amine as a pale yellow oil: 1H NMR (400 MHz, CD3OD) δ 6.35 (tt, 48, 3 Hz, 1H), 3.56 (td, J=15.6, 3.1 Hz, 2H), 3.03 (m, 2H), 1.11 (d, J=5.9 Hz, 3H), 0.83 (m, 2H), 0.60 (m, 1H), 0.50 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[C:13]3[CH2:20][CH2:19][CH2:18][C:14]=3[S:15][C:16]=2[NH2:17])=O)=[CH:6][CH:5]=1.[CH:22]1([C:25](=[O:30])[CH2:26][C:27](=O)[CH3:28])[CH2:24][CH2:23]1>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:26]([C:25]([CH:22]3[CH2:24][CH2:23]3)=[O:30])=[C:27]([CH3:28])[N:17]=[C:16]3[S:15][C:14]4[CH2:18][CH2:19][CH2:20][C:13]=4[C:12]=23)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)c2c(N)sc3c2CCC3)cc1
Reactant: CC(=O)CC(=O)C1CC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2c(C(=O)C3CC3)c(C)nc3sc4c(c23)CCC4)cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 28.1 %

Procedure:
To a stirred solution of 60 mg (0.20 mmol) 4-(2-amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonyl)-benzoic acid methyl ester in 2 ml acetic acid was added 33 mg (0.26 mmol) of 1-cyclopropyl-butane-1,3-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 22 mg (28%) 4-(3-cyclopropanecarbonyl-2-methyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-4-yl)-benzoic acid methyl ester as a light brown oil. ES-MS m/e (%): 392 (M+H+, 100).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1.[CH3:18][NH:19][CH2:20][CH2:21][CH3:22]>CCO>[F:13][C:12]1[C:6]2[CH2:5][O:4][CH:3]([CH2:2][N:19]([CH3:18])[CH2:20][CH2:21][CH3:22])[O:8][C:7]=2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=1
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Reactant: CCCNC
Solvent: CCO
Product: CCCN(C)CC1OCc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 34 using 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (8.5 mg, 0.026 mmol), N-methylpropan-1-amine (0.50 ml) and EtOH (3 ml). MS m/z (rel. intensity, 70 eV) 317 (M+, 0.3), 95 (5), 87 (6), 86 (bp), 75 (5), 58 (15).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][N:7]([CH2:10][CH2:11][CH2:12][C@H:13]([NH:17][C:18](=[O:44])[C@H:19]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[CH:38]=2)[NH:20][C:21](=[O:35])[CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]([OH:16])=O)[N:6]=1)=[O:4].C[N:46]1CCOCC1.ClC(OCC(C)C)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][N:7]([CH2:10][CH2:11][CH2:12][C@H:13]([NH:17][C:18](=[O:44])[C@H:19]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[CH:38]=2)[NH:20][C:21](=[O:35])[CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:14]([NH2:46])=[O:16])[N:6]=1)=[O:4]
Reactant: COC(=O)c1ccn(CCC[C@H](NC(=O)[C@H](Cc2cccc(C)c2)NC(=O)C(c2ccccc2)c2ccccc2)C(=O)O)n1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1ccn(CCC[C@H](NC(=O)[C@H](Cc2cccc(C)c2)NC(=O)C(c2ccccc2)c2ccccc2)C(N)=O)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of N-[4-(3-methoxycarbonyl-1H-pyrazol-1-yl)-1(S)-carboxybutyl]-3-methyl-Nα-(2,2-diphenylacetyl)-L-phenylalaninamide (0.3 g, 0.5 mmol)) and N-methylmorpholine (0.17 mL, 1.5 mmol) in CH2Cl2 (50 mL) is cooled to −10° C., and isobutyl chloroformate (0.065 mL, 0.5 mmol) is added dropwise over 10 minutes. After stirring for 15 minutes, ammnonia gas is bubbled into the solution at a moderately vigorous rate for 15 minutes. The solution is then warmed to room temperature over 30 min. CH2Cl2 is evaporated, the residue is treated with water (30 mL). The suspension is adjusted to pH=7 with 1 N HCl, and filtered. The solid is washed with water (50 mL) and dried in vacuo to yield N-[4-(3-methoxycarbonyl-1H-pyrazol-1-yl)-1(S)-(aminocarbonyl)-butyl]-3-methyl-Nα-(2,2-diphenylacetyl)-L-phenylalaninamide.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:14])[F:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25]>CN(C)C=O>[Br:1][C:2]1[C:7]([O:8][CH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25])=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:13])[F:14])=[CH:4][CH:3]=1
Reactant: CC(C)(CO)CBr
Reactant: COc1c(OC(F)F)ccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(OC(F)F)ccc(Br)c1OCC(C)(C)CO
Temperature: 80 °C
Yield: 75.8 %

Procedure:
To a stirring solution of 6-bromo-3-(difluoromethoxy)-2-methoxyphenol (200 mg, 0.743 mmol) in dimethylformamide (10 mL) was added potassium carbonate (307 mg, 2.229 mmol) and 3-bromo-2,2-dimethylpropan-1-ol (248 mg, 1.486 mmol) and the resultant reaction mixture was heated to 80° C. for 2 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure to afford 200 mg of 3-(6-Bromo-3-(difluoromethoxy)-2-methoxyphenoxy)-2,2-dimethylpropan-1-ol as a solid.
Reaction SMILES: [OH:1][C@H:2]([CH3:24])[CH2:3][NH:4][C:5]([CH3:23])([CH3:22])[CH2:6][C:7]([NH:9][C@@H:10]1[CH2:16][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[NH:12][C:11]1=[O:21])=[O:8].C(N(CC)C(C)C)(C)C.FC(F)(F)S(O[Si:40]([CH2:45][CH3:46])([CH2:43][CH3:44])[CH2:41][CH3:42])(=O)=O>C(Cl)Cl>[CH2:41]([Si:40]([CH2:45][CH3:46])([CH2:43][CH3:44])[O:1][C@H:2]([CH3:24])[CH2:3][NH:4][C:5]([CH3:23])([CH3:22])[CH2:6][C:7]([NH:9][C@@H:10]1[CH2:16][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[NH:12][C:11]1=[O:21])=[O:8])[CH3:42]
Reactant: C[C@@H](O)CNC(C)(C)CC(=O)N[C@@H]1CCc2ccccc2NC1=O
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[Si](CC)(CC)O[C@H](C)CNC(C)(C)CC(=O)N[C@@H]1CCc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
To a stirred solution of 660 mg (1.48 mmol) of the intermediate obtained in Step B in 3 mL of methylene chloride at room temperature was added 1.1 mL of N,N-diisopropylethylamine (0.81 g, 4.2 eq.) followed by 0.71 mL of triethylsilyl trifluoromethanesulfonate (0.83 g, 2.1 eq.). The resulting mixture was stirred at room temperature for 2 hours then partitioned between ethyl acetate and saturated aqueous sodium chloride (buffered to pH 9 with 2 drops of ammonium hydroxide). The organic layer was separated, washed with buffered brine, dried over magnesium sulfate, filtered and solvents evaporated under vacuum. The residue was purified by preparative high pressure liquid chromatography on silica, eluting with ethyl acetate/0.1% ammonium hydroxide in methanol (85:15), to afford 480 mg (1.07 mmol, 72%) of product. 1H NMR (200 MHz,CD3OD): 0.63 (q,8 Hz,6H), 0.97 (t,8 Hz,9H), 1.14 (s,6H), 1.18 (d,6 Hz,3H), 2.05 (m,1H), 2.28 (d,2Hz,2H), 2.35-3.00 (m,5H), 4.01 (m,1H), 4.44 (dd;8,12 Hz;1H), 7.05 (d,8 Hz,1H), 7.10-7.35 (m,3H). FAB-MS: calculated for C24H41N3O3Si 447; found 448 (M+H, 100%).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=O)[N:4]=[CH:3]1.[NH2:11][C@@H:12]([CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)=[O:14]>>[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([NH:11][C@@H:12]([CH2:29][O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=2)=[O:14])=[O:10])[N:4]=[CH:3]1
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1cccc(Oc2ccccc2)c1
Agent: Cl
Product: O=C(Cc1c[nH]cn1)N[C@@H](COCc1ccccc1)C(=O)Nc1cccc(Oc2ccccc2)c1
Yield: 21 %

Procedure:
Proceeding as in Example 1, but substituting 1H-imidazol-4-ylacetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(3-phenoxyphenyl)propanamide, gave Compound 243, (S)-2-(2-(1H-imidazol-4-yl)acetamido)-3-(benzyloxy)-N-(3-phenoxyphenyl)propanamide (100 mg, 21%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 11.87 (br s, 1H), 10.28 (s, 1H), 8.42-8.41 (d, 1H), 7.54-7.43 (m, 10H), 7.18-7.14 (t, 1H), 7.05-7.03 (d, 2H), 6.95 (s, 1H), 6.75-6.67 (d, 1H), 4.69-4.62 (m, 1H), 4.49 (s, 1H), 3.69-3.60 (m, 2H), 3.51-3.40 (m, 2H). MS (EI) for C27H26N4O4. found 471.0 (MH+).
Reaction SMILES: O[CH:2]([C:13]1[CH:18]=[CH:17][C:16]2[O:19][CH2:20][O:21][C:15]=2[CH:14]=1)[CH2:3][CH2:4][CH:5]([CH3:12])[CH2:6][CH2:7][O:8][CH:9]([CH3:11])[CH3:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH:9]([O:8][CH2:7][CH2:6][CH:5]([CH3:12])[CH2:4][CH:3]=[CH:2][C:13]1[CH:18]=[CH:17][C:16]2[O:19][CH2:20][O:21][C:15]=2[CH:14]=1)([CH3:11])[CH3:10]
Reactant: CC(CCOC(C)C)CCC(O)c1ccc2c(c1)OCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(CC=Cc1ccc2c(c1)OCO2)CCOC(C)C
Temperature: 25 °C

Procedure:
6.50 g (0.022 mol) of 1-(1-hydroxy-6-isopropoxy-4-methyl-hexyl)-3,4-methylenedioxybenzene are boiled at reflux together with 0.30 g (0.0016 mol) of p-toluenesulphonic acid monohydrate in 500 cc of benzene over the course of 2 hours and using a Dean-Stark trap. After cooling to room temperature, the benzene solution is washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried with sodium sulphate and evaporated in a vacuum. After chromatography of the residue on silica gel wth hexane/ethyl acetate (98:2), pure 1-(6-isopropoxy-4-methyl-1-hexenyl)-3,4-methylenedioxybenzene is obtained as a colourless oil. nD20 = 1.5258.