Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH2:13]([N:16]([C@@H:32]([CH3:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@@H:17]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:14]=[CH2:15].CI>O1CCCC1>[CH3:1][C@@H:18]([C@@H:17]([N:16]([C@@H:32]([CH3:39])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:13][CH:14]=[CH2:15])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: CC(C)NC(C)C
Reactant: C=CCN([C@H](CC(=O)OC(C)(C)C)c1ccccc1)[C@@H](C)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: C=CCN([C@@H](C)c1ccccc1)[C@@H](c1ccccc1)[C@H](C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of diisopropylamine (0.691 ml, 4.93 mmol) in anhydrous tetrahydrofuran (10 ml) was cooled to -78° C. prior to the dropwise addition of 1.6M butyllithium (2.57 ml, 4.11 mmol) via a syringe. The solution was warmed to 0° C. and then immediately recooled to -78° C., whereupon a solution of compound (8) from Example 2 (600 mg, 1.64 mmol) in tetrahydrofuran (10 ml) was added dropwise via a cannula. Stirring was continued for 1 hour at -78° C. followed by the rapid injection of methyl iodide (0.512 ml, 8.22 mmol). The reaction mixture was allowed to warm slowly to room temperature overnight (16 hours) after which the solvent was evaporated. The residue was partitioned between ethyl acetate (50 ml) and brine (25 ml) and the organic layer was dried (magnesium sulphate), filtered and evaporated to yield a yellow oil. This was purified by flash chromatography on silica gel [ethyl acetate/petroleum ether (1:49)] affording the title compound (51) in 94% diastereoisomeric excess (Rf 0.25) as a colourless oil (406 mg, 65%). δH (300 MHz, CDCl3) 7.41-7.17 (10H, m, Ph), 5.93-5.79 (1H, m, NCH2CH=CH2), 5.11 (1H, app. dd, J=17.3 and 1.3, trans CH=CH2), 5.08 (1H, app. dd, J=10.1 and 1.1, cis CH=CH2), 4.18 (1H, d, J=11.4, PhCHCH3), 3.29 (1H, app. ddt, J=14.7, 5.0 and 1.9, NCH2), 3.19 (1H, dq, J=11.4 and 6.9, CHCHCH3), 3.10 (1H, dd, J=14.7 and 8.0, NCH2), 1.50 (9H, s, (CH3)3C), 0.94 (3H, d, J=6.7, PhCHCH3), 0.90 (3H, d, J=6.9, CHCHCH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](O)=[O:19])[CH2:11][CH2:10]1.C(N(CC)CC)C.O=C1N(N(N2CCOC2=O)P(Cl)(Cl)=O)CCO1.[CH2:51]([NH:54][CH2:55][C:56]#[CH:57])[CH2:52][CH3:53]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([N:54]([CH2:55][CH2:56][CH3:57])[CH2:51][C:52]#[CH:53])=[O:19])[CH2:13][CH2:14]1
Reactant: C#CCNCCC
Reactant: COc1ccccc1N1CCN(CCC(C(=O)O)c2ccccc2)CC1
Agent: O=C1OCCN1N(N1CCOC1=O)P(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCN(CCC)C(=O)C(CCN1CCN(c2ccccc2OC)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.5 %

Procedure:
A mixture of 4-[4-(2-methoxyphenyl)piperazin-1-yl]-2-phenylbutanoic acid (1.772 g, 5 mmole), triethylamine (1.518 g, 15 mmole), and N,N-bis(2-oxo-3-oxazolidinyl)phosphoramidic chloride (1.527 g, 6 mmole) was stirred in methylene chloride (80 mL) under exclusion of moisture at ambient temperature for 30 minutes, after which N-propylpropargylamine (0.804 g, 6 mmole) was added at once at 0° C. The reaction mixture was stirred at room temperature overnight, washed with water (2×100 mL), dried over magnesium sulfate, filtered, and evaporated to dryness in vacuo. Chromatography on silica gel with methanol/chloroform as eluant, followed by trituration from diethyl ether with addition of ethanolic hydrochloric acid gave 0.25 g of the title compound as the dihydrochloride sesquihydrate, m.p. 172°-4° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]=[CH:15][C:16]([O:18][C:19]3[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=3)=[O:17])[CH:5]=[CH:4][C:3]1=2.C1COCC1.CCCCCC.[BH4-].[Na+]>O>[CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH:14]=[CH:15][C:16]([O:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:23][OH:24])=[CH:25][CH:26]=3)=[O:17])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C=CC(=O)Oc3ccc(C=O)cc3)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(C)CCC(C)(C)c2cc(C=CC(=O)Oc3ccc(CO)cc3)ccc21
Reaction time: 3 h

Procedure:
3.1 g (8.5 mmol) of 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acryloyloxy]benzaldehyde and 50 ml of a mixture of THF and methanol (50/50) are introduced into a round-bottomed flask. 163 mg (4.25 mmol) of sodium borohydride is added portionwise and the mixture is stirred at [lacuna] temperature for three hours. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate, filtered and evaporated. The solid obtained is recrystallized from a mixture of diisopropyl ether and hexane. After filtration and drying, 1.6 g (53%) of 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acryloyloxy]benzenemethanol, with a melting point of 140-50° C., are collected.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([OH:8])[CH:7]=1.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:9][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[OH:8]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(F)cc1O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
A mixture of 5-fluoro-2-nitrophenol (500 mg, 3.18 mmol) and tin (II) chloride (1.76 g, 9.2 mmol) in ethanol (10 mL) was heated at 80° C. under argon. After 30 min, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH 7-8), by addition of 5% aqueous sodium bicarbonate, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. Evaporation of the solvent gave the title compound (335 mg, 83%). 1H NMR (CD3OD/CDCl3): d 6.6 (m, 1H), 6.38 (dd, 1H, J=8.3 Hz and J=2.8 Hz), 6.29 (m, 1H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][S:6][C@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:14][C:15]([O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[O:16])[C:3]1=[O:24].C(=O)(O)[O-].[Na+].[CH2:30]([O:32][C:33](=[O:44])[C:34](=O)[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:31].C([BH3-])#N.[Na+]>C(O)(C)C>[CH2:30]([O:32][C:33]([CH:34]([NH:1][CH:2]1[CH2:7][S:6][C@H:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:4]([CH2:14][C:15]([O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:23])[CH3:22])=[O:16])[C:3]1=[O:24])[CH2:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:44])[CH3:31]
Reactant: C[Si](C)(C)CCOC(=O)CN1C(=O)C(N)CS[C@@H]1c1ccccc1
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)C(CCc1ccccc1)NC1CS[C@H](c2ccccc2)N(CC(=O)OCC[Si](C)(C)C)C1=O
Reaction time: 1 h

Procedure:
A solution of (R)-dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester (9 mmole) in dry isopropanol (12 ml.) under nitrogen is treated with sodium bicarbonate (2.25 mmole) followed by ethyl-2-oxo-4-phenylbutyrate (9.3 g., 45 mmole) dissolved in isopropanol (8 ml.). To the resulting suspension is added powdered 3 A° molecular sieves (8 g.). The reaction mixture is stirred for one hour while the pH is maintained at around 7.0. Next a solution of sodium cyanoborohydride (1.13 g., 18 mmole) in isopropanol (14 ml.) is added incrementally over a 5 hour period while continuing to maintain neutral pH. The reaction mixture is then stirred overnight at room temperature, then filtered (celite), concentrated in vacuo, and partitioned between ether and water. Normal work up of the organic extract followed by column chromatography on silica gel yields (R)-dihydro-5-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester as a mixture of diastereomers.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[O:19]=[C:20]1[NH:25][CH:24]([C:26](O)=[O:27])[CH2:23][CH2:22][CH2:21]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O.C(N(CC)CC)C>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:26]([CH:24]2[NH:25][C:20](=[O:19])[CH2:21][CH2:22][CH2:23]2)=[O:27])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: O=C1CCCC(C(=O)O)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C2CCCC(=O)N2)CC1
Temperature: 25 °C
Yield: 47 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (500 mg), 6-oxopiperidine-2-carboxylic acid (261 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (403 mg), 1-hydroxy-1H-benzotriazole monohydrate (322 mg), triethylamine (0.627 mL), and N,N-dimethylformamide (5 mL) was stirred at room temperature for over-night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with 1 M sodium hydroxide solution, saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (280 mg, 47%) as a colorless solid.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16](=[O:19])([O-])[O-].[K+].[K+].[CH2:22](O)[CH3:23]>CN(C)C=O>[CH:8]1([C:23]2[CH:22]=[CH:5][C:4]([C:16]([N:10]3[C:9]4[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=4[NH:7][C:6]4[N:1]=[CH:2][CH:3]=[CH:4][C:5]=4[CH2:11]3)=[O:19])=[CH:3][CH:2]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:9]1
Reactant: CCO
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(C2CCCCC2)cc1)N1Cc2cccnc2Nc2ccccc21
Reaction time: 1 h

Procedure:
A suspension of 4-cyclohexylbenzoic acid (1.30 g, 6.4 mmol) in thionyl chloride (6 mL) was heated at reflux for 30 minutes. After cooling, the thionyl chloride was removed in vacuo. The residue was dissolved in toluene and concentrated in vacuo to give the acid chloride as a golden oil. The acid chloride was then dissolved in N,N-dimethylformamide (5 mL) and slowly added to a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (1.0 g, 5.1 mmol) and potassium carbonate (0.77 g, 5.6 mmol) in N,N-dimethylformamide (15 mL). After stirring for one hour, the reaction was quenched with water and extracted with ethyl acetate. The organic extracts were washed with 1 N sodium hydroxide, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a light pink solid. The solid was dissolved in a large volume of boiling ethanol and filtered hot. The title compound (1.19 g) crystallized as an off-white solid, m.p. 230–233° C.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]C[CH:2]1C=O.[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:20][CH2:21][CH2:22]CCC>CO>[NH:19]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][C:14]=2/[CH:2]=[N:1]/[CH:10]2[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]2[CH3:4])[CH2:22][CH2:21][CH2:20]1
Reactant: NC1CCCCC1
Reactant: O=CC1CCc2ccccc2N1
Reactant: CCCCCC
Solvent: CO
Product: CC1CCCCC1/N=C/c1cccc2c1NCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
1.06 g of tetrahydroquinolino aldehyde was dissolved in 17 ml of methanol and then 1.3 ml of cyclohexyl amine was slowly added thereto. After the mixture was stirred at room temperature overnight, the solvent was eliminated under a reduced pressure and the resulting product was dissolved again in hexane to provide a thick solution, which was then kept in a freezer. In this solution, two types of stereomeric products were mixed at a ratio of 1.5:1. After the solution was left alone for about two days, a white crystalline solid product was found to be formed. The same procedures were repeated with the remaining mother liquor and all of the solid products thus obtained were collected and washed with cold methanol and hexane, and then dried to provide a pure stereomeric product. (Yield: 50%)
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[N-:23]=[N+:24]=[N-:25].[Na+]>CC(C)=O.O>[N:5]1[CH:6]=[CH:7][C:2]([C:1]([N:23]=[N+:24]=[N-:25])=[O:9])=[CH:3][CH:4]=1
Reactant: O=C(O)c1ccncc1
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: [N-]=[N+]=NC(=O)c1ccncc1
Temperature: -10 °C

Procedure:
6.15 g of isonicotinic acid and 5.55 g of triethylamine were dissolved in 50 ml of acetone. 6 g of ethyl chloroformate were added dropwise to this solution which had been cooled to -10° C. After 2 hours a solution of 5 g of NaN3 dissolved in 20 ml of H2O was added dropwise at 0° C. After 1 hour at room temperature the solid was filtered off and discarded. The solution was distilled at room temperature and the residue was extracted with dichloromethane. After drying over MgSO4 the solvent was distilled off and the liquid remaining behind was filtered over silica gel with dichloromethane as the eluent. There was obtained 4-pyridylcarboxylic acid azide as a colorless liquid which crystallized in a deep freezer (-18° C.). IR: 2141, 2190 cm-1 (N3).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][C:9]([CH3:11])=[CH:8][C:6]=2[N:7]=1.[CH2:13]([NH2:17])[CH2:14][CH2:15][NH2:16].[NH:18]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH2:22][NH:21][CH2:20][CH2:19]1>>[CH3:11][C:9]1[S:10][C:5]2[C:4]([NH:16][CH2:15][CH2:14][CH2:13][NH2:17])=[N:3][C:2]([N:21]3[CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[NH:18][CH2:19][CH2:20]3)=[N:7][C:6]=2[CH:8]=1
Reactant: NCCCN
Reactant: Cc1cc2nc(Cl)nc(Cl)c2s1
Reactant: c1ccc2c(c1)CNCCN2
Product: Cc1cc2nc(N3CCNc4ccccc4C3)nc(NCCCN)c2s1

Procedure:
The title compound was prepared in analogy to Example 1-1 in Scheme 1 by using 2,4-dichloro-6-methylthieno[3,2-d]pyrimidine and propane-1,3-diamine, followed by reaction with 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine. MS obsd. (ESI+) [(M+H)+] 369, 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.35 (d, J=7.1 Hz, 1H), 7.00-7.07 (m, 1H), 6.76-6.87 (m, 3H), 4.82 (s, 2H), 4.01-4.06 (m, 2H), 3.70 (t, J=6.6 Hz, 2H), 3.18-3.23 (m, 2H), 2.87 (t, J=6.4 Hz, 2H), 2.54 (s, 3H), 1.91-1.99 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=3I)[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:35][C:36]1[C:41]([CH:42]([CH3:44])[CH3:43])=[CH:40][C:39](B(O)O)=[C:38]([O:48][CH3:49])[CH:37]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>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.CCO>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=3[C:39]3[CH:40]=[C:41]([CH:42]([CH3:44])[CH3:43])[C:36]([F:35])=[CH:37][C:38]=3[O:48][CH3:49])[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(OC(F)(F)F)ccc1I
Reactant: COc1cc(F)c(C(C)C)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C

Procedure:
In a microwave tube were placed (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethoxy)benzyl]-4-methyl-1,3-oxazolidin-2-one (41.6 mg, 0.0679 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (18 mg, 0.085 mmol), DME (305 μL), EtOH (100 μL), and 1M aqueous Na2CO3 (140 μL, 0.140 mmol). The mixture was degassed with N2. Next, Pd(PPh3)4 (4 mg, 3.4×10−3 mmol) was added and the mixture was degassed again with N2. The tube was sealed and irradiated in a microwave for 10 minutes at 150° C. and 200 W. The reaction was then cooled to room temperature, diluted with EtOAc (40 mL), and washed with water and brine (15 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (2 to 15% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethoxy)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf=0.24 (15% EtOAc/hexanes). LCMS=654.3 (M+1)+. 1H NMR (CDCl3, 500 MHz, rotamers present) δ 7.85 (s, 1H), 7.69 (s, 2H), 7.21-7.30 (m, 4H), 6.95-7.00 (m, 1H), 6.65-6.68 (m, 1H), 5.59 (d, J=8.0 Hz), 5.41 (d, J=8.0 Hz), 4.74-4.81 (m, 1H), 3.75-4.09 (m, 5H), 3.19 (m, 1H), 1.16-1.27 (m, 6H), 0.51 (d, J=6.7 Hz), 0.36 (d, J=6.6 Hz).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2[Cl:22])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.Cl>>[ClH:22].[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C1CNCCN1
Reactant: CCCCc1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Agent: Cl
Product: CCCCc1ccc(-n2c(N3CCNCC3)c(C=O)c3ccccc32)cc1
Yield: 46 %

Procedure:
1-(4-Butylphenyl)-2-chloro-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 and subsequently treated with hydrochloric acid as described in Example 44 to afford 1-(4-butylphenyl)-2-(piperazin-1-yl)-1H-indole-3-carboxaldehyde hydrochloride (46% yield) as a cream solid. ESI/MS 362 (M+H); RT=3.02 min; NMR 10.13 (1H, s); 8.12 (1H, d, J=9 Hz); 7.48 (4H, s); 7.21 (2H, m); 6.94 (1H, d, J=9 Hz); 3.41 (4H, br m); 2.97 (4H, br m); 2.74 (2H, t); 1.64 (2H, p); 1.37 (2H, m); 0.97 (3H, t).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:34])[C:14]2[O:20][C:19]3[C:21]([Cl:30])=[CH:22][C:23]([NH:25][C:26](=[O:29])[CH2:27]Cl)=[CH:24][C:18]=3[CH2:17][S:16](=[O:32])(=[O:31])[C:15]=2[CH:33]=1)=[O:10]>CN(C=O)C>[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:34])[C:14]2[O:20][C:19]3[C:21]([Cl:30])=[CH:22][C:23]([NH:25][C:26](=[O:29])[CH2:27][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:24][C:18]=3[CH2:17][S:16](=[O:32])(=[O:31])[C:15]=2[CH:33]=1)=[O:10]
Reactant: C1CCNCC1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CCl)cc(Cl)c1O2
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CN3CCCCC3)cc(Cl)c1O2
Temperature: 110 °C
Reaction time: 5 h

Procedure:
Piperidine (0.2 mL, 1.80 mmol) was added to a solution of Example 133 (0.4 g, 0.90 mmol) in dry DMF (10 mL). The reaction mixture was stirred at 110° C. for 5 h, concentrated, treated with water and the solid that precipitated was filtered, washed with water and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.250 g, (56.30%); 1H NMR (CDCl3): δ 1.65-1.70 (m, 6H, piperidinyl), 2.45-2.50 (m, 4H, piperidinyl), 2.70 (s, 3H, CH3), 3.10 (s, 2H, CH2), 3.95 (s, 3H, OCH3), 4.70 (s, 2H, CH2), 7.55 (s, 1H, Ar), 7.80 (s, 1H, Ar), 8.10 (s, 1H, Ar), 8.50 (s, 1H, Ar), 9.50 (s, 1H, NH); MS: m/e (ES+) 493 (M+1).
Reaction SMILES: [F:1][C:2]1([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]#[C:3]1.FC(F)(F)C([O-])=O.[O:27]=[C:28]1[CH:32]=[CH:31][C:30](=[O:33])[N:29]1[CH2:34][CH2:35][CH2:36][NH3+:37].ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[O:27]=[C:28]1[CH:32]=[CH:31][C:30](=[O:33])[N:29]1[CH2:34][CH2:35][CH2:36][NH:37][C:15](=[O:17])[C:14]1[CH:13]=[CH:12][C:11]([CH2:10][C:2]2([F:1])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]#[C:3]2)=[CH:19][CH:18]=1
Reactant: [NH3+]CCCN1C(=O)C=CC1=O
Reactant: O=C(O)c1ccc(CC2(F)C#CCCCCC2)cc1
Agent: O=C([O-])C(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NCCCN1C(=O)C=CC1=O)c1ccc(CC2(F)C#CCCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
TEA (0.508 mL, 3.65 mmol) was added to a solution of cyclooctyne 3b (0.200 g, 0.768 mmol), amine 13 (0.235 g, 0.875 mmol), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N-tetramethyluronium hexafluorophosphate (HATU, 0.305 g, 0.802 mmol), and 1-hydroxybenzotriazole (HOBT, 0.123 g, 0.802 mmol) in CH2Cl2 (3 mL) at rt. The reaction was stirred for 15 min at rt, quenched with H2O (10 mL), and diluted with CH2Cl2 (50 mL). The organic layer was washed with 1 N HC, (3×50 mL), saturated NaHCO3 (3×50 mL), and brine (2×25 mL) and dried over MgSO4. Chromatography of the crude product (2:1 to 1:1 hexanes/EtOAc) yielded the desired product as a white solid (0.198 g, 65%, Rf=0.30 in 1:1 hexanes/EtOAc), mp 122.0-124.0° C. (dec). IR: 3413, 2931, 2854, 2222, 1705, 1640 cm−1. 1H NMR (CDCl3, 400 MHz): δ 1.39 (m, 1H), 1.74 (m, 2H), 1.81-2.06 (m, 6H), 2.14-2.32 (m, 3H), 3.05 (d, 1H, J=2.8 Hz), 3.09 (s, 1H), 3.40 (q, 2H, J=6.4 Hz), 3.67 (t, 2H, J=6.0 Hz), 6.75 (s, 2H), 6.93 (m, 1H), 7.41 (d, 2H, J=8.0 Hz), 7.81 (d, 2H, J=8.0 Hz). 13C NMR (CDCl3, 100 MHz): δ 20.5, 26.0, 28.1, 29.4, 34.0, 34.8, 36.2, 44.6 (d, J=25.0 Hz), 47.8 (d, J=24.0 Hz), 90.7 (d, J=32.0 Hz), 95.3 (d, J=174.0 Hz), 104.5 (d, J=10.0 Hz), 126.7, 130.5, 132.9, 134.2, 139.6, 167.1, 171.1. 19F NMR (CDCl3, 376 MHz): δ −139.0 (m). FAB—HRMS: Calcd. for C23H26N2O3F+ [M+H]+: 397.1927, found: 397.1920.
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5]([C:7]1[N:8]=[C:9]([CH:12]2[CH2:17][CH2:16][NH2+:15][CH2:14][CH2:13]2)[S:10][CH:11]=1)=[O:6])[CH3:3].[Cl:18][C:19]1[C:20]([C:29]([F:32])([F:31])[F:30])=[N:21][N:22]([CH2:25][C:26](O)=[O:27])[C:23]=1[CH3:24]>>[Cl:18][C:19]1[C:20]([C:29]([F:31])([F:30])[F:32])=[N:21][N:22]([CH2:25][C:26]([N:15]2[CH2:16][CH2:17][CH:12]([C:9]3[S:10][CH:11]=[C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[N:8]=3)[CH2:13][CH2:14]2)=[O:27])[C:23]=1[CH3:24]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: CCOC(=O)c1csc(C2CC[NH2+]CC2)n1
Agent: [Cl-]
Product: CCOC(=O)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)n1

Procedure:
4-[4-(Ethoxycarbonyl)-1,3-thiazol-2-yl]piperidinium chloride (VI-1, 5.50 g) is reacted analogously to Example IV-1 with [4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (4.82 g). This gives, after chromatographic purification, ethyl 2-(1-{[4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (6.00 g, 65%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][C:19]([NH:22]C(OC(C)(C)C)=O)([CH3:21])[CH3:20])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9](=[O:30])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][C:19]([NH2:22])([CH3:20])[CH3:21])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(Cc1cccc(C=CC(=O)OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(N)Cc1cccc(C=CC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-[3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-phenyl]-acrylic acid benzyl ester (preparation 141), (2.23 g, 5.45 mmol), and trifluoroacetic acid (5 mL) in dichloromethane (10 mL) was stirred for 1 hour at room temperature. The mixture was then concentrated in vacuo and the residue was diluted with sodium hydrogen carbonate solution (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic solution was dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a yellow oil in quantitative yield.