Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:6]([N:10]2[CH:14]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:12]=[N:11]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:25]1[C:26]2[CH:33]=[CH:32][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:27]=2[N:28]=[CH:29][N:30]=1.O1CCOCC1.C(=O)(O)[O-].[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.C(OCC)(=O)C.O>[CH:1]1([CH:6]([N:10]2[CH:14]=[C:13]([C:25]3[C:26]4[CH:33]=[CH:32][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:27]=4[N:28]=[CH:29][N:30]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[N:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Reactant: CC1(C)OB(c2cnn(C(CC#N)C3CCCC3)c2)OC1(C)C
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: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C4CCCC4)c3)ncnc21
Temperature: 90 °C
Yield: 83.6 %

Procedure:
Into a 25 ml round bottom flask equipped with a stir bar, condenser, thermocouple and 3-way valve was charged 3-cyclopentyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile (23, 0.697 g, 2.21 mmol, 1.3 equiv), 4-chloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (3a, 0.506 g, 1.69 mmol), 1,4-dioxane (4.44 mL), water (4.44 mL), and sodium bicarbonate (NaHCO3, 0.666 g, 7.93 mmol, 4.7 equiv) at room temperature. The resulting mixture was degassed four times backfilling with nitrogen each time before tetrakis(triphenylphosphine)palladium(0) (91.6 mg, 0.079 mmol, 0.047 equiv) was added. The resulting reaction mixture was degassed four times backfilling with nitrogen each time. The reaction was then warmed to 90° C. for 2-6 h. When TLC and HPLC showed that the coupling reaction was deemed complete, the reaction mixture was allowed to cool to room temperature followed by dilution with water (5 mL) and ethyl acetate (10 mL). The two layers were separated, and the aqueous layer was back extracted with ethyl acetate (10 mL). The combined organic fractions were washed with water (10 mL) and saturated aqueous NaCl solution (10 mL), dried over magnesium sulfate (MgSO4), and concentrated under reduced pressure to give the crude product (9) as an amber oil. The crude product was purified by flash column chromatography (SiO2, 0% to 40% ethyl acetate/hexane gradient elution) to afford racemic 3-cyclopentyl-3-{4-[7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrazol-1-yl}propionitrile (9, racemic SEM-protected compound, 617 mg, 737.9 mg theoretical, 83.6% yield) as a yellow oil. For 9: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.83 (s, 1H), 8.75 (s, 1H), 8.39 (s, 1H), 7.77 (d, 1H, J=3.7 Hz), 7.09 (d, 1H, J=3.7 Hz), 5.63 (s, 2H), 4.53 (td, 1H, J=19.4, 4.0 Hz), 3.51 (t, 2H, J=8.1 Hz), 3.23 (dq, 2H, J=9.3, 4.3 Hz), 2.41 (m, 1H), 1.79 (m, 1H), 1.66-1.13 (m, 7H), 0.81 (t, 2H, J=8.2 Hz), 0.124 (s, 9H); C23H32N6OSi (MW, 436.63), LCMS (EI) m/e 437 (M++H) and m/e 459 (M++Na).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[C:15](=[CH:20]\[O:21][CH3:22])/[C:16]([O:18][CH3:19])=[O:17])[CH:3]=1.[C:23](=[O:26])([O-])[O-].[K+].[K+].C1N2[CH2:35][CH2:36][N:31](CC2)C1>CN(C=O)C>[C:36]([C:35]1[CH:11]=[CH:10][CH:9]=[CH:14][C:23]=1[O:26][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[C:15](=[CH:20]\[O:21][CH3:22])/[C:16]([O:18][CH3:19])=[O:17])[CH:3]=1)#[N:31]
Reactant: C1CN2CCN1CC2
Reactant: O=C([O-])[O-]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Cl)ncn1
Agent: [K+]
Solvent: CN(C)C=O
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Oc2ccccc2C#N)ncn1
Temperature: 80 °C
Reaction time: 1.25 h
Yield: 83.2 %

Procedure:
To a solution of methyl (E)-2-{2-[6-chloropyrimidin-4-yloxy]phenyl}-3-methoxyacrylate (96.2 g; prepared as described in WO 92/08703) in DMF (approximately 100 g) was added a DMF solution of 2-cyanophenyl (78.5 g at 50% w/w 2-cyanophenyl) followed by potassium carbonate (63.5 g) and DABCO (0.34 g). The mixture was heated to 80° C. and held for 75 minutes. The DMF was removed by vacuum distillation to a final temperature of 100° C. Toluene (165.8 g) was charged to the distillation residues and the temperature brought to 75° C. before adding hot water (318.6 g) and stirring for 30 minutes at 80° C. The aqueous phase was removed and then the toluene layer was sampled and analysed. The solution yield of methyl (E)-2-{2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate (azoxystrobin) was 90.0%. The toluene was distilled off under vacuum. Methanol (88 g) was added to the distillation residues at 70° C. and the mixture cooled to <5° C., filtered and the cake washed with methanol (2×30 ml) to give, after drying, methyl (E)-2-{2-[6-(2-cyano-phenoxy)pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate (83.2% yield).
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:19][CH2:20][N:21]1[CH2:29][CH:28]2[CH2:30][CH:24]3[CH2:25][CH:26]([CH2:31][CH:22]1[CH2:23]3)[CH2:27]2.Cl>O.C1(C)C=CC=CC=1>[CH:24]12[CH2:30][CH:28]3[CH2:27][CH:26]([CH2:31][CH:22]([N:21]([CH2:20][CH2:19][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:8]#[N:9])[CH2:29]3)[CH2:23]1)[CH2:25]2
Reactant: N#CC(c1ccccc1)c1ccccc1
Reactant: ClCCN1CC2CC3CC(C2)CC1C3
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC(CCN1CC2CC3CC(C2)CC1C3)(c1ccccc1)c1ccccc1

Procedure:
To a solution of 18 parts of α-phenylbenzeneacetonitrile in 140 parts of dry toluene is added, with stirring under nitrogen, approximately 4 parts of a 57% dispersion of sodium hydride in oil. The resultant mixture is heated to 90° and stirred thereat under nitrogen for 3/4 hr. The yellow-green flocculent suspension which eventuates is cooled to around 65°, whereupon 20 parts of 4-(2-chloroethyl)-4-azatricyclo[4.3.1.13,8 ]undecane [preparable by mixing the hydrochloride thereof (U.S. Pat. No. 3,845,038) with excess aqueous sodium carbonate, extracting the mixture with toluene, and consecutively washing the extract with water, drying it over anhydrous sodium sulfate, filtering out the drying agent, and removing the solvent by vacuum distillation] in 85 parts of dry toluene is introduced, with stirring, during 15 minutes. The mixture thus obtained is stirred for 2 hours at 90°-100°. The yellow-orange solution which results is cooled to room temperature, at which point 20 parts of water is stirred in. Aqueous and organic phases are separated, the aqueous phase is extracted with toluene and then discarded, and the extract and organic phases are combined and thereupon consecutively washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate is stripped of solvent by vacuum distillation, affording 4-[4-azatricyclo(4.3,1.13,8)undecan-4-yl]-2,2-diphenylbutanenitrile as the residue. The product has the formula ##STR9##
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][Si:14](Cl)([CH3:16])[CH3:15].[CH3:18][C:19](=[O:32])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:13][Si:14]([CH3:16])([CH3:15])[O:32][C:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH2:18]
Reactant: C[Si](C)(C)Cl
Reactant: CCCCCCCCCCCCC(C)=O
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCN(CC)CC
Product: C=C(CCCCCCCCCCCC)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.1 h

Procedure:
To a stirred, room temperature solution of diisopropylamine (49 mL, 0.35 mol) in dry THF (500 mL) was added a 2.06M solution (170 mL, 0.35 mol) of n-butyl lithium in hexanes in one portion. The solution was cooled to -78° C. To the stirred solution was added neat trimethylsilylchloride (213 mL, 1.68 mol) over 6 minutes. Stirred for 6 minutes. To this solution was added a solution of 2-tetradecanone (71.40 g, 0.3362 mol) in dry THF (710 mL) over 33 minutes. Stirred 5 minutes. To the mixture was added triethylamine (375 mL, 2.7 mol) over 6 minutes followed by a saturated sodium bicarbonate solution (780 mL). The mixture was allowed to warm. When the temperature reached 0° C., petroleum ether (1.7 L) was added, and the organic layer was washed with chilled H2O (2×1.4 L), chilled 0.1M citric acid (3× 2 L) and saturated NaCl. The organic layer was dried (Na2SO4) and rotoevaporated and dried in vacuo to give a yellow oil; yield 97.6 g (102%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:23][CH2:24][CH3:25])[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+].[C:31]([C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32].ClCCl>O1CCCC1.CO.ClCCl>[C:31]([C:35]1[CH:36]=[CH:37][C:38]([C:39]([NH:2][C:3]2[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:23][CH2:24][CH3:25])[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=3)=[CH:7][CH:8]=2)=[O:40])=[CH:42][CH:43]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: CCO[C@@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(NC(=O)c3ccc(C(C)(C)C)cc3)cc2)cc1)C(=O)O
Yield: 88.9 %

Procedure:
3-{4-[2-(4-Aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid hydro chloride (described in Example 56a) (0.2 g; 0.547 mmole) was dissolved in tetrahydrofurane (5 ml). Sodium hydrogencarbonate (0.053 g; 0.631 mmole) was added and the mixture was stirred for a little while. 4-tert-Butylbenzoyl chloride (0.118 g; 0.6 mmole) was added. The reaction mixture was stirred overnight and then evaporated to dryness. Dichloromethane and water were added to the residue and the phases were separated. The organic phase was dried with magnesium sulfate and the solvent was evaporated. Chromatography of the residue on silica gel(Isolute, SI) using dichloromethane:heptane (1:1), then dichloromethane and finally methanol: dichloromethane (1:99) as eluants gave 0.238 g (89% yield) of 3-{4-[2-{4-(4-[tert-butyl]benzoyl)aminophenyl}ethoxy]phenyl}-2-(S)-ethoxypropanoic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[CH3:15].C(N(CC)CC)C.[OH-].[Na+].CC(OC)(C)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]([CH2:9][C@@H:10]([OH:14])[C:11]([OH:13])=[O:12])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(CC(=O)C(=O)O)cc(C)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc(C[C@@H](O)C(=O)O)cc(C)c1Cl
Reaction time: 2 h

Procedure:
12.3 g (54.4 mmol) 3-(4-chloro-3,5-dimethyl-phenyl)-2-oxo-propionic acid in 130 mL THF and 7.6 mL (54.4 mmol) triethylamine were combined at -35° C. with a solution of 21.0 g (65.3 mmol) (1R)-B-chlorodiisopinocampheylborane in 65 mL THF within 30 min and stirred for 2 h at this temperature. After the reaction had ended the reaction mixture was made alkaline at 0° C. with 50 mL 1 M NaOH (exothermic), stirred for 3 h, combined with 30 mL TBME and the phases were separated. The organic phase was washed with 50 mL water and 30 mL 1 M NaOH. The combined aqueous phases were acidified with 2 M HCl and extracted with TBME. The organic phases were dried over Na2SO4 and evaporated down i. vac. The product was reacted further without purification.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:13][O:14][Si](C(C)(C)C)(C)C)=[O:6])[CH:2]=[CH2:3].N[OH:23].O[C@H:25]1[CH2:29]N[C@H:27](C(O)=O)[CH2:26]1>CO>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[C:13]([OH:14])=[O:23])=[O:6])[C:2]1[CH:3]=[CH:27][CH:26]=[CH:25][CH:29]=1
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1CO[Si](C)(C)C(C)(C)C
Reactant: NO
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Solvent: CO
Product: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1

Procedure:
A solution of benzyl chloroformate (12.5 mL, 87.7 mL) in toluene (40 mL) was added to a solution of trans-4-hydroxy-L-proline 11 (10 g, 76.3 mmol) and NaHCO3 (16 g, 190 mmol) in H2O (165 mL) over a period of 15 minutes. After stirring at room temperature for 12 hours the two phases were allowed to separate. The aqueous phase was washed with diethyl ether (4×50 mL), cooled in an ice bath, and then acidified to pH 2 with conc. HCl. The resultant product was extracted with ethyl acetate (5×50 mL) and the combined organic extracts were dried (MgSO4) and the excess solvent evaporated in vacuo to afford a colourless viscous oil (20.30 g, 100%). [α]27D=−565° (c 0.1, MeOH). 1H NMR (CDCl3): δ2.07-2.31 (m, 3H, H1), 3.52-3.59 (m, 2H, H3), 4.43-4.53 (m, 2H, H2, H11a), 5.8 and 5.11 (s, 2H, minor and major rotamers of H6, 1:2), 6.0 (bs, 2H, OH), 7.26-7.29 and 7.32-7.34 (m, 5H, minor and major rotamers of H arom, 1:2). IR (thin film): ν=3414 (OH), 2940 (OH), 1682 (C═O), 1495, 1429, 1359 (CO2−), 1314, 1269, 1205, 1180, 1174, 1127, 1082, 1051, 993, 914, 866, 826, 769, 741, 697 cm−1. MS (EI): m/e (relative intensity): 266 (M+., 1), 265 (6), 220 (5), 176 (15), 130 (34), 108 (2). 91 (100), 86 (4), 68 (11). HRMS calcd. for C13H15NO5=265.0950 found 265.0976.
Reaction SMILES: [OH-:1].[K+].C(C1[N:10]2[N:11]=[C:12]([CH3:23])[C:13]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])=[C:9]2[N:8]=[C:7]([CH3:24])[C:6]=1[C:25]([O:27]CC)=[O:26])#N.[CH2:30]([OH:32])[CH3:31]>>[C:15]1([CH3:22])[CH:16]=[C:17]([CH3:21])[CH:18]=[C:19]([CH3:20])[C:14]=1[C:13]1[C:12]([CH3:23])=[N:11][N:10]2[C:31]([C:30]([OH:1])=[O:32])=[C:6]([C:25]([OH:27])=[O:26])[C:7]([CH3:24])=[N:8][C:9]=12
Reactant: [OH-]
Reactant: CCOC(=O)c1c(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn2c1C#N
Reactant: CCO
Agent: [K+]
Product: Cc1cc(C)c(-c2c(C)nn3c(C(=O)O)c(C(=O)O)c(C)nc23)c(C)c1

Procedure:
Potassium hydroxide (441 mg, 11.04 mmol) was added to a solution of ethyl 7-cyano-3-mesityl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-6-carboxylate (800 mg, 2.21 mmol) in ethanol (15 mL), followed by heating under reflux for two hours. The reaction mixture was evaporated, water was added. Under ice-cooling, 2N hydrochloric acid was added to adjust the pH of the mixture to pH 1. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated, to give the title compound (780 mg).
Reaction SMILES: C([CH:3]1[CH2:8][CH2:7][CH2:6][C:5]([SH:10])(O)[CH2:4]1)C.N[C:12](N)=[S:13].Cl.[OH-].[Na+].[C:18](=O)=O>O>[CH2:12]([S:13][CH:4]1[CH2:3][CH2:8][CH2:7][CH2:6][CH:5]1[SH:10])[CH3:18]
Reactant: CCC1CCCC(O)(S)C1
Reactant: NC(N)=S
Reactant: O=C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCSC1CCCCC1S

Procedure:
154 g (0.96 mole) of 3-ethyl mercapto cyclohexanol, 76 g of thiourea (1 mole) and 150 ml of concentrated hydrochloric acid were kept under reflux for 3 hours. The isothiuronium salt solution was separated off from oily secondary products in a separation funnel and then heated with 70 g of NaOH (1.75 mole) in 100 ml of water for 1 hour in a steam bath. Carbon dioxide was added for neutralisation, the mercaptan phase was separated off in the separation funnel and fractionated in vacuo.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:28]#[C:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:8][C:9]=1[N:10]([CH2:20][CH2:21][P:22]([O:25][CH2:26][CH3:27])([CH3:24])=[O:23])[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[Li+].[OH-].O.Cl>C1COCC1.CO>[CH3:32][C:30]([CH3:31])([CH3:33])[C:29]#[C:28][C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([CH2:20][CH2:21][P:22]([O:25][CH2:26][CH3:27])([CH3:24])=[O:23])[C:11]([CH:13]2[CH2:14][CH2:15][CH:16]([CH3:19])[CH2:17][CH2:18]2)=[O:12])[CH:8]=1
Reactant: CCOP(C)(=O)CCN(C(=O)C1CCC(C)CC1)c1cc(C#CC(C)(C)C)sc1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCOP(C)(=O)CCN(C(=O)C1CCC(C)CC1)c1cc(C#CC(C)(C)C)sc1C(=O)O
Yield: 68.4 %

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[[2-(ethoxy-methyl-phosphinoyl)-ethyl]-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (251 mg, 0.51 mmol) was dissolved in THF (7.3 mL) and MeOH (7.3 mL). A 1N solution of LiOH in H2O (1.52 mL, 1.52 mmol) was added to the reaction drop-wise at room temperature. The reaction was run at room temperature until complete, as determined by LC/MS. The reaction was cooled in an ice bath and then acidified to pH 3 with 1N HCl. The entire mixture was then evaporated in vacuo and stored under high vacuum overnight. 5-(3,3-Dimethyl-but-1-ynyl)-3-[[2-(ethoxy-methyl-phosphinoyl)-ethyl]-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (168 mg, 69%) was isolated from the residue by reverse phase HPLC. MS (m/z): 481.93 [M+H]+; 31P NMR (161.9 MHz, CDCl3): d 56.771, 55.816.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@H:7]2[NH:12][C:10](=[O:11])[O:9][C@H:8]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[C:30](Cl)(=[O:32])[CH3:31]>C1COCC1.O>[C:30]([N:12]1[C@H:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[C@H:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:10]1=[O:11])(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: O=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)O1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 1.13 h
Yield: 100.4 %

Procedure:
To a stirred suspension of 5.100 g (4R,5S)-(+)-cis-4,5-diphenyl-2-oxazolidinone (20.89 mmol) in 102 mL THF, were added 13.65 mL n-butyllithium in hexane (1.5 M, 20.47 mmol, 0.98 eq) at −78° C. during 6 min. The resulting dark red solution was stirred for additional 68 min at −78° C. During this period, the solution became colorless. Stirring was continued for 15 min at −25° C., before it was cooled again to −78° C. A solution of 1.536 mL acetyl chloride (21.31 mmol, 1.02 eq) in 15.3 mL THF was then added within 5 min. After 52 min, the mixture was poured on 510 mL water and the product was extracted three times with 305 mL, in total 915 mL dichloromethane. The combined organic phases were washed with 715 mL aqueous NaHCO3 and with 715 mL brine. The solution was dried over 25 g sodium sulfate (30 min) and filtered. The filter cake was washed with 50 mL dichloromethane. After removal of solvent in a rotary evaporator (40° C., 30 mbar), the crude product (5.899 g, 100% by weight) was obtained as a white solid. Purification was accomplished by recrystallization from 13 mL toluene. The heterogeneous mixture was heated to reflux until a clear solution was obtained, which was then allowed to slowly cool down to room temperature. After two days, the title compound was collected by filtration as white crystals (5.157 g, 18.332 mmol, 88% by weight).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]([O:28]CC)=[O:27])=[CH:9]2.[OH-].[Na+].Cl>O1CCCC1.CO.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:17])=[O:18])[CH:14]=1)[NH:11][C:10]([C:26]([OH:28])=[O:27])=[CH:9]2
Reactant: CCOC(=O)c1cc2cc(OCCOC)cc(N(C)S(=O)(=O)c3ccccn3)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)O)cc2c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
To a solution of ethyl 5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylate (5.67 g) in tetrahydrofuran (50 mL) and methanol (25 mL) was added 2M aqueous sodium hydroxide solution, and the mixture was stirred at 50° C. for 4 hr. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and neutralized with 1M hydrochloric acid. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was recrystallized from a mixed solvent of ethyl acetate-hexane to give the title compound (5.30 g, yield 100%) as a white solid. MS: 406 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:29]=[CH:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=1)[CH2:22][C:23]1[CH:27]=[N:26][N:25]([CH2:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])[CH:24]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCCCl
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(CCCN(C)C)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 179.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.52 g) and 3-chloro-N,N-dimethylpropylamine hydrochloride (0.49 g) as starting materials, 5-benzyloxy-N-(4-isopropylphenyl)-N-({1-[3-(dimethylamino)propyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.1 g) was obtained. By the reaction and treatment in the same manner as in Example 105 using this compound, N-({1-[3-(dimethylamino)propyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.73 g) was obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[N:14]([C:15](=[O:36])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Br:33])=[O:25])=[C:19]([O:34][CH3:35])[CH:18]=2)[C@H:13]([CH2:37][O:38][C:39]2[CH:48]=[CH:47][C:42]([C:43]([O:45]C)=[O:44])=[CH:41][CH:40]=2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.C1COCC1>[CH2:1]([O:8][CH2:9][C@@H:10]1[N:14]([C:15](=[O:36])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Br:33])=[O:25])=[C:19]([O:34][CH3:35])[CH:18]=2)[C@H:13]([CH2:37][O:38][C:39]2[CH:40]=[CH:41][C:42]([C:43]([OH:45])=[O:44])=[CH:47][CH:48]=2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(OC[C@@H]2CC[C@H](COCc3ccccc3)N2C(=O)Cc2ccc(NC(=O)Nc3ccccc3Br)c(OC)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(CC(=O)N2[C@@H](COCc3ccccc3)CC[C@H]2COc2ccc(C(=O)O)cc2)ccc1NC(=O)Nc1ccccc1Br
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of methyl 4-[5-(R)-benzyloxymethyl-1-[4-[N′-(2-bromophenyl)ureido]-3-methoxyphenylacetyl]-2-(S)-pyrrolidinylmethoxy]benzoate (178 mg, 0.25 mmol) in MeOH-THF (2:5, 7 ml) was added 1.0M-NaOH (750 ml, 0.75 mmol) at rt, and the resulting mixture was heated at 80° C. with stirring for 1.5 h. The reaction mixture was poured into 1N-HCl, then extracted with CHCl3. The organic layer was washed with brine, drying over anhydrous Na2SO4, then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl3-MeOH (15:1) as eluent to give 128 (159 mg, 91%) as a colorless amorphous solid MW 702.59 1H-NMR (CD3OD), mixture of rotamars δ1.88-2.35 (series of m, 4 H), 3.51-4.49 (series of m, 8 H), 3.64 and 3.72 (s, total 3 H), 4.87 (s, 2 H), 6.65-8.05 (series of m, 16 H); MS (ESI) m/z, 702 (M+), 704 (M++2); Anal. Calcd. for C36H36BrN3O7.H2O: C, 60.00; H, 5.32; N, 5.83. Found: C, 59.66; H, 5.04; N, 5.65.