Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:35][O:36][CH2:37][CH:38]([NH2:40])[CH3:39]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:40][CH:38]([CH3:39])[CH2:37][O:36][CH3:35])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: COCC(C)N
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Product: COCC(C)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 1-(methyloxy)-2-propanamine using methods similar to Example 563 to provide a white solid: 1H NMR (CDCl3) δ 10.17 (1H, d, J=8 Hz), 8.54 (1H, s), 8.27 (1H, s), 7.23 (2H, dd, J=5, 8 Hz), 6.98 (2H, t, J=8 Hz), 4.31-4.43 (3H, m), 4.15 (2H, s), 3.53 (2H, b), 3.47 (2H, d, J=5 Hz), 3.40 (3H, s), 3.36 (2H, b), 2.35 (2H, b), 1.75 (4H, b), 1.30 (3H, d, J=7 Hz); ES+ MS: 511 (M+H+).
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([NH:28]CC(O)=O)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>>[NH2:28][CH2:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: ClCC=Cc1ccccc1
Product: NCC=Cc1ccccc1

Procedure:
Aminomethyl styrene resin was prepared from chloromethyl styrene resin (Polumer Laboratories, PL-CMS Resin, 1.0 meq/g) using the procedure of Weinshenker. Weinshenker, N. M.; Shen, C. M.; Wong, J. Y., Organic Synthesis, vol. 56, pp. 95-99. The aminomethyl resin was coupled with N-(Fmoc)glycine using a procedure similar to that described in Example 7. The Fmoc group was removed using a procedure similar to that described in Example 8. This sequence was repeated three times to give the title compound, which has three glycine residues attached to the polystyrene resin.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:18][C@@H:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:16]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:15]1[C:35](=[O:37])[CH3:36])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[CH2:7]([N:14]1[CH2:18][C@@H:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:16]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:15]1[CH:35]([OH:37])[CH3:36])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)C1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)CN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)C1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)CN1Cc1ccccc1

Procedure:
1 M lithium aluminiumhydride in tetrahydrofuran (1.5 ml, 1.5 mmol) was added slowly to a solution of (3R,4R)-1-benzyl-3,4-dibenzyloxy-2-acetylpyrrolidine (390 mg, 0.94 mmol) in dry tetrahydrofuran (5 ml) at 0-5° C. Stirring was continued for 11/2 hour at room temperature. Water (1 ml) was slowly added. The mixture was filtered and the filtrate was evaporated to dryness in vacuo to give the title compound as an oil. Purification of the crude product on a silica gel column (Eluent: methylene chloride: ethyl acetate (9:1)) afforded (3R,4R)-1-benzyl-3,4-dibenzyloxy-2-(1-hydroxyethyl)pyrrolidine (90 mg, yield 23%) as an oil.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][C:20](=[S:22])[NH2:21])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:24][C:25](=O)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]4[S:22][CH:24]=[C:25]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:21]=4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1csc(-c2cc3cc(CC(N)=S)ccc3o2)n1
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1csc(Cc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)n1
Yield: 62.7 %

Procedure:
A mixture of crude 4-tert-butyl-2-[5-(thiocarbamoylmethyl)benzofuran-2-yl]thiazole (0.73 g) and ethyl 4-chloroacetoacetate (0.92 g) in ethyl acetate (30 ml) was stirred under reflux for 18 hours. After being cooled, the resulting mixture was poured into aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with ethyl acetate. The fractions containing object compound were combined and concentrated under reduced pressure to give 4-tert-butyl-2-{5-{[4-(ethoxycarbonylmethyl)thiazol-2-yl]methyl}benzofuran-2-yl}thiazole (0.61 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][N:28]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[C:17]([CH:18]3[CH2:23][O:22][CH2:21][CH2:20][O:19]3)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=2[N:13]=1)=[O:7].[CH3:29][CH2:30][O-:31].[Na+]>C(O)C>[O:19]1[CH2:20][CH2:21][O:22][CH2:23][CH:18]1[C:17]1[C:11]2[S:10][C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:26]=[CH:27][N:28]=[C:3]([CH2:2][O:31][CH2:30][CH3:29])[CH:4]=3)=[N:13][C:12]=2[C:14]([O:24][CH3:25])=[CH:15][CH:16]=1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(CCl)c3)nc12
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOCc1cc(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)ccn1
Yield: 67.9 %

Procedure:
To a solution of 50 mg (0.12 mmol) (+)-2-chloromethyl-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide in 2 ml ethanol was added 1.32 ml (3.57 mmol) sodium ethylate solution (2.71 M solution in ethanol) and the mixture ultrasonicated at room temperature for 2 h. The reaction mixture was then poured onto water and extracted three times with dichloromethane. The organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/1 acetone/heptane) followed by trituration in ether afforded 35 mg (68%) (+)-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-2-ethoxymethyl-isonicotinamide as an off-white solid. [α]D20=+60.7° (c=0.94, CHCl3), ES-MS m/e (%): 430 (M+H+, 100).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[I:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(I)c(O)c1
Reactant: BrCc1ccccc1
Product: O=[N+]([O-])c1ccc(I)c(OCc2ccccc2)c1
Yield: 90.4 %

Procedure:
According to the method described in example 4.1., starting from 20.8 g (78.5 mmol) of 2-iodo-5-nitrophenol and 9.3 mL (78.5 mmol) of benzyl bromide, we obtain 25.2 g of 2-(benzyloxy)-1-iodo-4-nitrobenzene in the form of oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[CH3:12][CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([C:33]3[CH:34]=[N:35][C:30]([CH3:29])=[CH:31][CH:32]=3)[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=3[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]=2[CH:6]=[N:7]1)[CH3:13]
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C
Reactant: Cc1ccc(B(O)O)cn1
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(C)nc2)cc2c1cnn2C(C)C

Procedure:
The title compound was prepared in a similar manner as described for example 8 from 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (100 mg, 0.225 mmol) and (6-methyl-3-pyridinyl)boronic acid (46 mg, 0.337 mmol). The product was collected as a white solid (99 mg, 94%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.47 (br. s., 1H) 8.96 (d, J=2.02 Hz, 1H) 8.67 (br. s., 1H) 8.40 (s, 1H) 8.20 (s, 1H) 8.17 (dd, J=8.08, 2.53 Hz, 1H) 7.89 (s, 1H) 7.39 (d, J=8.08 Hz, 1H) 5.91 (s, 1H) 5.18 (quin, J=6.57 Hz, 1H) 4.43 (br. s., 1H) 4.42 (br. s., 1H) 2.52-2.58 (m, 5H) 2.13 (s, 3H) 1.52-1.58 (m, 2H) 1.52 (s, 3H) 1.50 (s, 3H) 0.88 (t, J=7.33 Hz, 3H). LC-MS (ES) m/z=458.3 [M+H]+
Reaction SMILES: [CH:1]([O:4][P:5]([CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:12](O)=[O:13])([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])([CH3:3])[CH3:2].[NH3:25].C(Cl)(Cl)Cl>C(Cl)(=O)C(Cl)=O>[CH:1]([O:4][P:5]([CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:12]([NH2:25])=[O:13])([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCCC(C(=O)O)P(=O)(OC(C)C)OC(C)C
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCC(C(N)=O)P(=O)(OC(C)C)OC(C)C
Temperature: 35 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
553 g (1.57 moles) of alpha-(diisopropyl phosphono)lauric acid was placed in a 3 liter flask. 791 g (6.28 moles) of distilled oxalyl chloride was carefully added while maintaining the temperature at or slightly below 35° C. (Temperatures much above 35° C. result in oxalyl chloride attack on the phosphonate esters, and too rapid addition results in foaming.) The temperature was maintained at 35° C. for 4 hours, after which I.R. analysis revealed all the acid had converted to the acid chloride. Excess oxalyl chloride was distilled off while maintaining the temperature at 35° C. or below. The product was then diluted with an equal volume of freshly distilled THF and added to a 3 liter flask containing about 1 liter of condensed ammonia. Following a vigorous reaction, the mixture was allowed to stand and warm overnight. Excess ammonia was driven off using a steam bath, and 1 liter of chloroform was added and heated to reflux. The hot chloroform solution was filtered to remove insoluble ammonium chloride and then flash evaporated. The solid residue was dissolved as a 30% solution in pentane, chilled to -78° C. and then placed in a refrigerator. After standing overnight, a crystalline product was collected, dried and ground to a powder. The product weighed 417 g (70% yield) and was pure as verified by TLC and 1H NMR.
Reaction SMILES: [O:1]=[CH:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]=[CH:22]/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([N:21]2[CH:22]=[CH:23][C@H:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:3]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:2]2=[O:1])(=[O:19])=[O:20])=[CH:16][CH:17]=1
Reactant: COc1ccc(S(=O)(=O)N=C/C=C/c2ccccc2)cc1
Reactant: CCOC(=O)/C=C/C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C[C@@H]1C(=O)N(S(=O)(=O)c2ccc(OC)cc2)C=C[C@@H]1c1ccccc1
Yield: 90 %

Procedure:
The title compound was prepared according to the general procedure from ethyl trans-4-oxo-2-butenoate and trans-N-(4-methoxybenzenesulfonyl)-3-phenyprop-2-ene-1-imine using 10 mol % 9 as the catalyst in 90% yield as a white solid. [α]D20 (c 1.19, CHCl3)=+105.2; mp=111-113° C.; 1H NMR (400 MHz, CDCl3) δ 8.04 (dd, 2H, J=7.0, 2.1 Hz), 7.16-7.12 (m, 2H), 7.06-6.99 (m, 4H), 6.58 (dd, 2H, J=8.0, 1.1 Hz), 5.60 (dd, 1H, J=8.0, 6.5 Hz), 4.18-4.08 (m, 2H), 3.92 (s, 3H), 3.65 (t, 1H, J=6.9 Hz), 3.55-3.53 (m, 1H), 2.57 (dd, 1H, J=17.3, 6.1 Hz), 1.94 (dd, 1H, J=17.3, 7.5 Hz), 1.21 (t, 3H, J=7.0 Hz); 13C NMR (100 MHz, CDCl3) δ 171.7, 169.0, 164.3, 136.8, 131.4, 129.2, 128.9, 127.9, 127.9, 124.6, 114.3, 113.6, 61.0, 56.0, 44.1, 42.0, 31.6, 14.3; IR (thin film) ν 3086, 2982, 1720, 1594, 1496, 1454, 1406, 1367, 1264, 1132, 1091, 1026 cm−1; HRMS (ESI) calcd for C22H23NO6S [M+Na]+ 452.1138, found 452.1160; >99% ee (3R,4R)-isomer as determined by HPLC (AS-H, 9:1 hexanes/i-PrOH), tr (3S,4S)=53.9 min, tr (3R,4R)=39.2 min. For the (3R,4R) enantiomer (Table 2, entry 2), [α]D20 (c 0.98, CHCl3)=−112.7.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[C:19]2[O:20][CH:21]([CH2:24][OH:25])[CH2:22][O:23][C:18]=2[CH:17]=[CH:16][CH:15]=1.Cl>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:25][CH2:24][CH:21]2[O:20][C:19]3[C:14]([O:13][CH3:12])=[CH:15][CH:16]=[CH:17][C:18]=3[O:23][CH2:22]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cccc2c1OC(CO)CO2
Agent: Cl
Solvent: c1ccncc1
Product: COc1cccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Temperature: 25 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
A solution of toluene-4-sulphonyl chloride (5.84 g) in pyridine (10 ml) was added dropwise at 10°-15° C. to a solution of 1-(8-methoxy-1,4-benzodioxan-2-yl)methanol (5.0 g) in pyridine (30 ml) and the mixture was stirred at ambient temperature for 20 hours. The mixture was poured onto an excess of ice and dilute hydrochloric acid. The resulting solid was collected by filtration, washed with water and dried in vacuo to yield 8-methoxy-1,4-benzodioxan-2-ylmethyl toluene-4-sulphonate as a white solid (6.61 g), m.p. 66°-68° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH:8]=[C:7]2[C:15]([F:18])([F:17])[F:16])([O-:3])=[O:2].[OH-].[K+].[CH3:21]I>>[CH3:21][N:10]1[C:11]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=2)[C:7]([C:15]([F:18])([F:16])[F:17])=[CH:8][C:9]1=[O:14]
Reactant: CI
Reactant: O=c1cc(C(F)(F)F)c2cc([N+](=O)[O-])ccc2[nH]1
Agent: [K+]
Agent: [OH-]
Product: Cn1c(=O)cc(C(F)(F)F)c2cc([N+](=O)[O-])ccc21
Yield: 57.6 %

Procedure:
6-Nitro-4-trifluoromethyl-1H-quinolin-2-one (2.50 g, 9.7 mmol) was methylated with KOH (5.46 g, 97.3 mmol) & MeI (6.1 mL, 97.3 mmol), as to give 1-methyl-6-nitro-4-trifluoromethyl-1H-quinolin-2-one (1.52 g, 57%): δH (CDCl3)=3.80 (s, 3H), 7.20 (s, 1H), 7.55 (d, 1H), 8.50 (dd, 1H), 8.75 (d, 1H). An EtOAc (50 mL) solution of this compound (1.26 g, 4.6 mmol) was treated with a slurry of Pd (10% on C, 95 mg, 0.09 mmol) in i-PrOH (2 mL). The mixture was stirred under a H2 atmosphere for 80 min, then more Pd (10% on C, 24 mg, 0.02 mmol) was added. After 20 min under H2, the mixture was filtered through Celite & the solvent removed to yield the title compound (1.06 g, 95%): δH (CDCl3)=3.70 (s, 3H), 3.75–3.85 (br s, 2H), 7.00–7.10 (m, 3H), 7.20 (d, 1H).
Reaction SMILES: [Br:1][Si](C)(C)C.[CH2:6]([O:8][C:9](=[O:18])[CH2:10][C:11]1[CH:12]=[N:13][C:14](Cl)=[N:15][CH:16]=1)[CH3:7].C(OCC)C.[OH-].[Na+]>C(#N)CC>[CH2:6]([O:8][C:9](=[O:18])[CH2:10][C:11]1[CH:12]=[N:13][C:14]([Br:1])=[N:15][CH:16]=1)[CH3:7]
Reactant: CCOC(=O)Cc1cnc(Cl)nc1
Reactant: C[Si](C)(C)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCC#N
Product: CCOC(=O)Cc1cnc(Br)nc1
Temperature: 101.5 °C
Yield: 90.6 %

Procedure:
Bromotrimethylsilane (1.7 mL, 12 mmol) was added to a solution of (2-chloro-pyrimidin-5-yl)acetic acid ethyl ester (Example 43-(2); 810 mg, 4.04 mmol) in propionitrile (4 mL), and the mixture was heated under reflux at an external temperature of 98 to 105° C. for nine hours. After cooling the reaction mixture to room temperature, diethyl ether was added to the reaction mixture, which was neutralized with a 2 N sodium hydroxide aqueous solution (6.3 mL). The reaction mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=2/1) to give the title compound (897 mg, 91%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>C(#N)C>[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][O:1][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([NH2:7])=[O:6])=[CH:20][CH:19]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: NC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cccc(OCc2ccc(Br)cc2)c1

Procedure:
To 3-hydroxybenzamide (2.0 mM) under nitrogen was added anhydrous acetonitrile (20 ml), potassium carbonate (2.0 mM), and p-bromobenzyl bromide (2.0 mM). The mixture was refluxed for 3 hours, and the progress of the reaction monitored by TLC. The excess solvent was removed under vacuum, until dry, and the title compound was recrystallised from hot dichloromethane (minimum amount). A white crystalline solid was isolated and dried. Melting point: 160-161° C.; Infrared data: cm-1 : KBr disc: 3323; 3146; 1670; 1622. 1H NMR: d6DMSO: δ=5.26 (s; 2H; CH2); 7.3 (dd; 1H: H4); 7.49-7.75 (m, 9H; PhBr; NH2 ; PhO); 13C NMR: d6DMSO: δ=114.031; 118.123; 120.402; 121.295; 129.704; 130.107; 131.690; 136.094; 136.723; 158.371; 167.843. Mass spectra: m/z: EI: 307 (M+1); 262; 212; 169 (100%) 101;90. Elemental analysis: Expect C: 55.26%; H: 3.29%; N: 4.61%; Found C: 54.61%; H: 3.66%; N: 4.47%.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:27][O:28][CH2:29][CH2:30][OH:31]>O>[CH3:27][O:28][CH2:29][CH2:30][O:31][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1
Reactant: COCCO
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COCCOc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 80 °C

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.27 g of potassium carbonate and 3 ml of 2-methoxyethanol was stirred while heating at 80° C. for 2.5 hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.23 g of 2-[3-(2-methoxyethoxy)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 120”).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:18][C:19]([C:21]3[C:22]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=3)=[O:20])[CH:15]=2)[CH2:10]1.[CH2:38](N(CC)CC)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH3:38])[CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:18][C:19]([C:21]3[C:22]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:33]=4)=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=3)=[O:20])[CH:15]=2)[CH2:10]1
Reactant: CCN(CC)CC
Reactant: Cc1cccc(C(=O)Nc2ccc3c(c2)CC(NCc2ccccn2)C3)c1-c1ccc(C(F)(F)F)cc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccc(C(=O)Nc2ccc3c(c2)CC(N(C)Cc2ccccn2)C3)c1-c1ccc(C(F)(F)F)cc1
Reaction time: 2 h

Procedure:
To a solution of 6-methyl-4′-trifluoromethylbiphenyl-2-carboxylic acid [2-(2-pyridylmethylamino)-indan-5-yl] amide (the compound of Example 20f, 0.4 g, 0.8 mmol) in methylene chloride (5 mL) is added triethylamine (0.12 g, 1.15 mmol) and paraformaldehyde (0.024 g, 0.8 mmol). The mixture is stirred for two hours and then sodium triacetoxyborohydride (0.24 g, 1.12 mmol) is added. The mixture is stirred overnight and then washed with dilute sodium bicarbonate, dried over sodium sulfate, and evaporated. The residue is purified by flash chromatography (SiO2; ethyl acetate) to afford 6-methyl-4′-trifluoromethylbiphenyl-2-carboxylic acid [2[(2-pyridylmethyl)(methyl)amino]-indan-5-yl] amide as a white solid, mp 105-115°.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=S)[CH2:24][C:25](=O)[CH3:26])=[O:4].O.[NH2:30][NH2:31]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[CH:24]=[C:25]([CH3:26])[NH:31][N:30]=1)=[O:4]
Reactant: NN
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(C)=O
Solvent: O
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)[nH]n1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-1-(3-oxo-thiobutyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192 g) was reacted with hydrazine monohydrate (CAS Reg. No. 7803-57-8) to give the title compound as yellow solid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:20])=[CH2:19])=[CH:14][CH:13]=1)([CH3:11])=[CH2:10].Cl>C(O)(=O)C>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[C:9]([C:12]1[CH:13]=[CH:14][C:15]([C:18]([C:6]2[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=2[OH:5])([CH3:20])[CH3:19])=[CH:16][CH:17]=1)([CH3:11])[CH3:10]
Reactant: Oc1cccc(O)c1
Reactant: C=C(C)c1ccc(C(=C)C)cc1
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)(c1ccc(C(C)(C)c2ccc(O)cc2O)cc1)c1ccc(O)cc1O
Temperature: 70 °C
Reaction time: 17 h
Yield: 77 %

Procedure:
110.0 g Resorcinol, 15.8 g p-diisopropenylbenzene and 200 ml glacial acetic acid were added to a flask and heated to about 70° C. to dissolve the reactants. Anhydrous hydrogen chloride was condensed into the reaction mixture until saturated. The reaction was allowed to cool and stand at ambient temperature for 17 hours. The product was precipitated in water, washed with water and vacuum dried at 60° C. About 29.1g of product with a melting point of about 110° to 115° C. was obtained.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([S:20]([NH2:23])(=[O:22])=[O:21])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.[O-]S(C(F)(F)F)(=O)=O.[C:32]([O:37][CH3:38])(=[O:36])[C@H:33]([CH3:35])O>O1CCCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([S:20]([NH:23][C@H:33]([CH3:35])[C:32]([O:37][CH3:38])=[O:36])(=[O:22])=[O:21])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1
Reactant: NS(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Reactant: COC(=O)[C@H](C)O
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)[C@@H](C)NS(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: -30 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
A solution of potassium tert-butoxide (0.87 ml, 1M in tetrahydrofuran) was added to a solution of [4-(4-chlorophenyl)piperazine-1-sulfonyl]amine (200 mg, 0.73 mmol), [prepared as described in Step 1 above], in tetrahydrofuran (10 ml) at -60° C. After 10 min., a solution of the triflate derivative of methyl (S)-lactate (604 mg, 2.56 mmol) in tetrahydrofuran (3 ml) was added and the reaction mixture was allowed to warm to -30° C. over 30 min. The reaction mixture was quenched with saturated ammonium chloride and the product was extracted into ethyl acetate. The solvent was removed in vacuo and the residue was chromatographed (SiO2, 30% ethyl acetate/hexane) to give methyl 2-(R)-{[-4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}propionate as a colorless oil (66%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11](Cl)=[O:12].[CH:15]([OH:18])([CH3:17])[CH3:16]>C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[C@@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([O:18][CH:15]([CH3:17])[CH3:16])=[O:12]
Reactant: CC(C)O
Reactant: COC(=O)/C=C/[C@H]1[C@@H](C(=O)Cl)C1(C)C
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: COC(=O)/C=C/[C@H]1[C@@H](C(=O)OC(C)C)C1(C)C

Procedure:
Using the procedure of Example 3, 1.51 g of (1R,cis) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane -1-carboxylic acid chloride in benzene and 0.61 ml of isopropanol were reacted to obtain 0.820 g of isopropyl (1R,cis) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =-28°±1.5°(c=1% in chloroform).