Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+:2].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([P:18]([OH:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:9]>O.CO>[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([P:18]([O-:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:9].[Na+:2]
Reactant: CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O
Temperature: 25 °C
Yield: 97.3 %

Procedure:
A solution of sodium hydroxide (0.63 g) in water:methanol (20:80 v/v, 10 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water:methanol (20:80 v/v, 53 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for an additional 1.5 hours to obtain a pH of 4.15. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was filtered, washed with methanol (2×25 ml), and dried in a vacuum oven at 50° C. for 21 hours to give 5.2 g of ibandronate sodium crystal form R.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8](Cl)=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[CH2:12]([SH:15])[CH:13]=[CH2:14]>C(O)C>[N+:1]([C:4]1[CH:10]=[CH:9][C:8]([S:15][CH2:12][CH:13]=[CH2:14])=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C=CCS
Solvent: CCO
Product: C=CCSc1ccc([N+](=O)[O-])c(N)c1
Yield: 53.9 %

Procedure:
To a solution of 7 g of 2-nitro-5-chloroaniline in 200 ml of absolute ethanol there is added 4.2 g of allyl mercaptan and 2.5 g of Na-methoxide. Then the mixture is refluxed for three hours, the solvent is evaporated and the residue is chromatographed on neutral alumina (Activity IV). Elution with ether-petroleum ether yields 4.6 g of 2-nitro-5(2-propenylthio)aniline.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH:15][C:16]2[CH:17]=[C:18]([CH:20]=[C:21]([CH2:23][OH:24])[CH:22]=2)[NH2:19])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH:25](=O)[CH3:26]>ClCCl.N1C=CC=CC=1>[CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH:15][C:16]2[CH:22]=[C:21]([CH2:23][OH:24])[CH:20]=[C:18]([N:19]=[CH:25][CH3:26])[CH:17]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: CC=O
Reactant: Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC=Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Reaction time: 5 h
Yield: 80.1 %

Procedure:
3-(9-acridinylamino)-5-(hydroxymethyl)aniline was dissolved in dichloromethane/pyridine(1/1, v/v, 40 ml), and thereto acetaldehyde (2.09 g, 47.56 mmol) was added. The resulting mixture was stirred for 5 hours, and the solvent used was removed under the reduced pressure. Then, the resulting product was purified by column chromatography to give the titled compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[NH:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.[OH-].[K+]>CS(C)=O>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([N:12]2[CH:16]=[CH:15][CH:14]=[CH:13]2)=[CH:8][C:6]=1[NH2:7])([O-:11])=[O:10]
Reactant: c1cc[nH]c1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1cc(-n2cccc2)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 5-chloro-2nitroaniline (1.73 g, 10 mmol), pyrrole (2.8 mL, 40 mmol) and KOH (85%, 990 mg, 15 mmol) in DMSO (8.6 mL) at 80° C. for 24 h according to the general procedure E (method a). Obtained as a brown solid (1.52 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:22])=[N:19][C:20]=1[CH3:21].C(#N)C>ClCCl>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:22][C:18]2[CH:17]=[CH:16][C:15]([CH3:14])=[C:20]([CH3:21])[N:19]=2)[CH:7]=1
Reactant: Cc1ccc(N)nc1C
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1ccc(C)c(C)n1
Temperature: 140 °C
Reaction time: 20 h
Yield: 46.7 %

Procedure:
A heavy walled sealable tube was charged with ethyl 4,6-dichloropyridazine-3-carboxylate (300 mg, 1.36 mmol) and 5,6-dimethylpyridin-2-amine (249 mg, 2.04 mmol). To the mixture was added acetonitrile (8.00 mL) and the reaction mixture was heated with stirring in an oil bath at 140° C. for 20 h. After cooling to room temperature the residue was suspended in dichloromethane and purified by flash chromatography (silica 20-45 μM, 40 g, Thomson) eluting with 0 to 10% over 20 min, acetone/dichloromethane to give ethyl 6-chloro-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxylate (195 mg, 46.8%) as an off-white solid. 1H NMR (CHLOROFORM-d) δ: 10.54 (s, 1H), 9.14 (s, 1H), 7.41 (d, J=8.3 Hz, 1H), 6.70 (d, J=8.3 Hz, 1H), 4.55 (q, J=7.2 Hz, 2H), 2.50 (s, 3H), 2.26 (s, 3H), 1.50 (t, J=7.2 Hz, 3H); LC-MS 307.0 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([OH:12])[CH:6]=1)C.[NH2:14][NH2:15]>>[OH:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[CH3:11])[C:4]([NH:14][NH2:15])=[O:3]
Reactant: CCOC(=O)c1ccc(C)c(O)c1
Reactant: NN
Product: Cc1ccc(C(=O)NN)cc1O
Temperature: 150 °C

Procedure:
A suspension of ethyl 3-hydroxy-4-methylbenzoate (14.42 g, 80 mmol) (from Example 32 supra) in anhydrous hydrazine (30 mL, 956 mmol) (Aldrich) was heated at reflux (150° C. bath temperature) for 2.0 hours. After cooling to room temperature, mixture was concentrated under reduced pressure (high vacuum) to give crude 3-hydroxy-4-methyl-benzoic acid hydrazide as an off-white solid. (Yield 13.26 g, 100%).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:24][C:25]1[N:26]=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([CH:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=2)[O:28][C:29]=1[CH3:30]>>[CH:37]([C:34]1[CH:33]=[CH:32][C:31]([C:27]2[O:28][C:29]([CH3:30])=[C:25]([CH2:24][N:11]3[C:12]4[C:8](=[CH:7][C:6]([CH2:5][CH:4]([O:15][C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[C:3]([OH:2])=[O:22])=[CH:14][CH:13]=4)[CH:9]=[CH:10]3)[N:26]=2)=[CH:36][CH:35]=1)([CH3:39])[CH3:38]
Reactant: Cc1oc(-c2ccc(C(C)C)cc2)nc1CCl
Reactant: COC(=O)C(Cc1ccc2[nH]ccc2c1)Oc1ccccc1
Product: Cc1oc(-c2ccc(C(C)C)cc2)nc1Cn1ccc2cc(CC(Oc3ccccc3)C(=O)O)ccc21

Procedure:
In analogy to the procedure described in example 44, rac-3-(1H-indol-5-yl)-2-phenoxy-propionic acid methyl ester (preparation 7) was reacted with 4-chloromethyl-2-(4-isopropyl-phenyl)-5-methyl-oxazole to give rac-3-{1-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-5-yl}-2-phenoxy-propionic acid as off-white solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[CH:3]=[N:2]1.CN(C=O)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Br:36][C:37]1[CH:42]=[CH:41][C:40]([C@@H:43]([NH2:45])[CH3:44])=[CH:39][CH:38]=1>>[Br:36][C:37]1[CH:42]=[CH:41][C:40]([C@@H:43]([NH:45][C:6]([C:4]2[CH:3]=[N:2][NH:1][CH:5]=2)=[O:8])[CH3:44])=[CH:39][CH:38]=1
Reactant: O=C(O)c1cn[nH]c1
Reactant: C[C@H](N)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1cn[nH]c1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 5.0 g (44.6 mmol) 4-pyrazolecarboxylic acid in 100 mL DMF 15.2 mL (89.2 mmol) DIPEA and 15.7 g (49.1 mmol) TBTU are added and the mixture is stirred for 10 min at rt. Subsequently 8.9 g (44.6 mmol) (S)-1-(4-bromophenyl)ethylamine are added and stirring is continued over night. The mixture is poured on water and is extracted with ethyl acetate. The combined organic layers are dried over sodium sulphate and the solvent is removed in vacuo. The residue is triturated with DCM to yield the desired product.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]=[C:10](Cl)[CH2:11][CH2:12][C:13](=[O:16])[O:14][CH3:15].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC(Cl)C.ClCCl>[CH3:8][S:7][C:1]1[CH:6]=[CH:5][C:4]([C:10](=[O:9])[CH2:11][CH2:12][C:13]([O:14][CH3:15])=[O:16])=[CH:3][CH:2]=1
Reactant: COC(=O)CCC(=O)Cl
Reactant: CSc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: COC(=O)CCC(=O)c1ccc(SC)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Thioanisole (12.4 g) and 1,4-dioxo-4-methoxybutyl chloride (16.5 g) in dichloroethane (100 ml) were cooled to 0° C. and aluminum chloride (16 g) was added, followed by another equivalent (16 g) and the reaction mixture was stirred at 0° C. for 2 hours. Ice was added, followed by 1N HCl. Dichloromethane (100 ml) was then added and the organic layer was separated, washed with water and then brine and dried with Na2SO4. Removal of the solvents yielded the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18].[NH4+].[OH-]>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([N+:17]([O-:19])=[O:18])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Clc1ccnc2ccccc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: O=[N+]([O-])c1cccc2c(Cl)ccnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
4-Chloroquinoline (10.0 g, 61.3 mmol) was added in small portions to sulfuric acid (45 mL) taking care to maintain the temperature at or below 15° C. Then the solution was cooled and maintained at −5° C. during the addition of fuming nitric acid (9 mL). The mixture was allowed to warm to room temperature and stirred for an additional 3 h. The reaction mix was poured on ice and basified (pH 9) with NH4OH. The resulting precipitate was filtered, washed well with water, dried, and recrystallized from methanol to provide 7.5 g (59%) of 6a as golden-brown needles; mp 128-129° C. (lit.32mp 129-130° C.); 1H NMR (CDCl3) δ 7.67 (d, 1H, J=4.5), 7.75 (dd, 1H, J=8.6, J=7.6), 8.10 (dd, 1H, J=7.6, J=1.3), 8.48 (dd, 1H, J=8.6, J=1.3), 8.94 (d, 1H, J=4.5); 13C NMR (CDCl3) δ 123.0, 124.4, 126.5, 127.5, 128.3, 140.6, 143.2, 148.7, 152.1. The mother liquor was evaporated and chromatographed in 19:1 hexanes-ethyl acetate, to provide 2.05 g (16%) of the 5-nitro isomer 6d as a very light yellow solid; mp 144-146° C. (lit.31 mp 150° C.); 1H NMR (CDCl3) δ 7.65 (d, 1H, J=4.7), 7.82 (m, 2H), 8.35 (dd, 1H, J=2.5, J=7.3), 8.90 (d, 1H, J=4.7); 13C NMR (CDCl3) δ 118.2, 123.4, 125.1, 128.8,134.2,135.6, 139.1,149.7,151.2.
Reaction SMILES: [C:1]1([C:7]([NH:9][CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:27](OC3C=CC([N+]([O-])=O)=CC=3)=[O:28])[CH2:11]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:39]1[CH2:44][CH2:43][CH:42]([OH:45])[CH2:41][CH2:40]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:45][CH:42]1[CH2:43][CH2:44][N:39]([C:27]([N:12]2[CH2:13][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:20][CH:21]=3)[CH2:15][CH:10]([NH:9][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:8])[CH2:11]2)=[O:28])[CH2:40][CH2:41]1
Reactant: OC1CCNCC1
Reactant: O=C(NC1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NC1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1)c1ccccc1

Procedure:
550 mg (1.04 mmol) of 4-nitrophenyl 3-[(phenylcarbonyl)amino]-5-[4-(trifluoromethoxy)phenyl]piperidine-1-carboxylate were initially charged in 14 ml of DMF, and 315 mg (3.12 mmol) of piperidin-4-ol and 144 mg (1.04 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150° C. for 15 min. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 430 mg (84% of theory)
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:4].C([O-])=[O:16].[Na+]>CO>[OH:16][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Reactant: O=C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(CO)c1ccc(C(F)(F)F)cc1
Yield: 80.1 %

Procedure:
A mixture of 2-bromo-4′-trifluoromethyl acetophenone (40.0 g), sodium formate (40.0 g) and methanol (200 ml) was stirred with heating under reflux for 6 hours. The reaction mixture was concentrated and poured into water (500 ml). The precipitated crystals were filtered, washed with water, and air-dried to give crystals of 2-hydroxy-4′-trifluoromethyl acetophenone (24.5 g, 80%). Melting point 112-114° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH:11]1[CH2:16][N:15]([N:17]=O)[CH2:14][CH2:13][N:12]1[C:19](=[O:21])[CH3:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O.C(O)(=O)C.[Zn]>[CH2:1]([NH:8][C:9]([CH:11]1[CH2:16][N:15]([NH2:17])[CH2:14][CH2:13][N:12]1[C:19](=[O:21])[CH3:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)N1CCN(N=O)CC1C(=O)NCc1ccccc1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)N1CCN(N)CC1C(=O)NCc1ccccc1
Temperature: 55 °C
Reaction time: 2 h
Yield: 43.9 %

Procedure:
To a mixture of rac-N-benzyl-1-acetyl-4-nitrosopiperazine-2-carboxamide (655 mg) in water (2 ml) and acetic acid (0.65 ml) was added zinc powder (443 mg) as portions during the period of 2 hours at 8-13° C. (exothermic reaction) with ice-water cooling bath. After removal of the bath, the temperature was raised till 55° C. and the reaction mixture was additionally stirred at 30-40° C. for 2 hours. The zinc residue was filtered off and washed with methanol (50 ml) on the Celite. The combined filtrate was added into dichloromethane (40 ml) and sodium hydroxide (460 mg) in water (6 ml) below 35° C. The resulting precipitate was filtered off with Celite and the residue was washed with chloroform (50 ml). The combined filtrate was washed with water, dried over magnesium sulfate and concentrated to give rac-N-benzyl-1-acetyl-4-aminopiperazine-2-carboxamide (274 mg). This product was used for next step without purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6]([C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C:23]3=[O:31])[CH2:18][CH2:17]2)=[O:15])=[CH:5]1.[C:32](Cl)(=[O:34])[CH3:33].C(N(CC)CC)C>C(Cl)Cl>[Cl:13][C:10]1[CH:11]=[C:12]2[C:7]([C:6]([C:14]([N:16]3[CH2:17][CH2:18][CH:19]([N:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24][C:23]4=[O:31])[CH2:20][CH2:21]3)=[O:15])=[CH:5][N:4]2[CH2:3][CH2:2][NH:1][C:32](=[O:34])[CH3:33])=[CH:8][CH:9]=1
Reactant: CC(=O)Cl
Reactant: NCCn1cc(C(=O)N2CCC(N3C(=O)Cc4ccccc43)CC2)c2ccc(Cl)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCn1cc(C(=O)N2CCC(N3C(=O)Cc4ccccc43)CC2)c2ccc(Cl)cc21

Procedure:
A solution of 1-{1-[1-(2-amino-ethyl)-6-chloro-1H-indole-3-carbonyl]-piperidin-4-yl}-1,3-dihydro-indol-2-one (1 eq) in dry CH2Cl2 was treated with acetyl chloride (1.1 eq) and triethylamine at RT for 15 h. Quenching with H2O and extraction into CH2Cl2 followed by concentration and purification by prep HPLC gave the title compound.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19])(=[O:3])[CH3:2].OC1C([O:29][S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])=C(I)C=CC=1>>[S:30]([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)([O:32][CH:4]([C:1](=[O:3])[CH3:2])[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:16])([F:15])[F:17])=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19])(=[O:31])=[O:29]
Reactant: CC(=O)Cc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)Oc2c(O)cccc2I)cc1
Product: CC(=O)C(OS(=O)(=O)c1ccc(C)cc1)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 25.3 %

Procedure:
α-(Acetyl)4-(trifluoromethyl)-2,6-dinitrotoluene (5.00 g, 17.10 mmol) was heated to 80° C. for 10 minutes under nitrogen. Hydroxy(tosyloxy) iodobenzene (13.40 g, 34.18 mmol) was then added slowly keeping the temperature constant at 80° C. The reaction mixture was allowed to stir for 1 hour, carefully avoiding overheating. After cooling, the reaction mixture was purified by column chromatography over silica gel (60-200 mesh) using CH2Cl2 /hexane (1:1) as the eluant. Recrystallization with chloroform/petroleum ether gave 2 g (25%) of pure product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@:8]2([CH3:25])[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:12](=[O:23])[C@H:11]([CH3:24])[O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:26]([N-]C(C)C)(C)C.[Li+].IC>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C@@:8]2([CH3:25])[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:12](=[O:23])[C:11]([CH3:26])([CH3:24])[O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[N-]C(C)C
Reactant: COc1ccc(CN2C(=O)[C@H](C)OC[C@@]2(C)c2cccc(Br)c2)cc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)C(C)(C)OC[C@@]2(C)c2cccc(Br)c2)cc1
Temperature: -75 °C
Reaction time: 0.25 h

Procedure:
A dried flask was charged under an argon atmosphere with a solution of the crude (2S,5R)-5-(3-bromo-phenyl)-4-(4-methoxy-benzyl)-2,5-dimethyl-morpholin-3-one (622 mg) in tetrahydrofuran (16 ml) which was cooled to −75° C. Lithium diisopropylamide (1.54 ml, 3 mmol) was rapidly added, followed by iodomethane (502 mg, 3.5 mmol). After 15 minutes at −75° C. the reaction was complete. For the workup, the cold reaction mixture was quenched with a saturated ammonium chloride solution (15 ml) and extracted with a mixture of dichloromethane (40 ml) and water (15 ml). The organic layer was dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel using a gradient of heptane and ethyl acetate=100/0 to 66/34 as the eluent. The (R)-5-(3-bromo-phenyl)-4-(4-methoxy-benzyl)-2,2,5-trimethyl-morpholin-3-one was obtained as a white solid (495 mg, 77% of theory). Mass (calculated) C21H24BrNO3 [418.334]; (found) [M+H]+=418, [M+2-H]+=420.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[NH:10][CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=1.[NH:16]([CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.S(Cl)(Cl)=O>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[NH:10][CH2:11][C:12]([N:16]([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Reactant: CCOC(=O)CC(Nc1ccccc1)c1ccccc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CC(c1ccccc1)N(C(=O)CNC(=O)Nc1cccc(C)c1)c1ccccc1
Yield: 17.6 %

Procedure:
The procedure is as in Example 1, but using 11.6 g of 2-[3-(3-methylphenyl)ureido]acetic acid, 15 g of ethyl (RS)-3-anilino-3-phenylpropionate and 4 cm3 of thionyl chloride as starting materials. The product obtained is purified by chromatography on 250 g of silica (0.04-0.063 mm) contained in a column 5 cm in diameter [eluent: methanol/dichloromethane (2/98 by volume)], using an excess pressure of 40 kPa of nitrogen and collecting 75-cm3 fractions. Fractions 19 to 21 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. and the residue obtained is recrystallized from ethyl acetate. 4.5 g of ethyl (RS)-3-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}-3-phenylpropionate melting at 146° C. are then obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[N:12]=[CH:13][N:14]([CH3:16])[CH3:15])#[N:2].C1CCCCC=1>CO.[Pd]>[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([N:12]=[CH:13][N:14]([CH3:15])[CH3:16])=[C:3]([C:1]#[N:2])[CH:8]=1
Reactant: CN(C)C=Nc1ccc([N+](=O)[O-])cc1C#N
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CO
Product: CN(C)C=Nc1ccc(N)cc1C#N

Procedure:
A solution of 6.0 g (27.5 mmol) of N'-(2-cyano-4-nitrophenyl)-N,N-dimethylformamidine, 33.9 g (41.8 ml, 412.4 mmol) of cyclohexene, and 0.6 g of 10% Pd/C in 360 ml of methanol was refluxed for 4 hrs. The hot mixture was filtered through Celite. Solvent was removed and the residue was recrystallized from chloroform-carbon tetrachloride giving 4.9 g (95%) of the title compound as a light gray crystalline solid. mass spectrum (m/e):188.9 (M+H, electrospray).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[OH-].[Na+].[CH2:11](Br)[C:12]#[CH:13]>O>[CH3:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:13][C:12]#[CH:11])=[CH:1][CH:2]=1
Reactant: C#CCBr
Reactant: Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C#CCOc1ccc(C)cc1

Procedure:
To a solution of 10.8 g (0.1 mol) of p-cresol in 70 ml of absolute ethanol,there were added 4 g of sodium hydroxide. The reaction mixture was refluxeduntil complete dissolution and then treated with 16.36 g (0.1 mol) of propargyl bromide (80% in toluene). Reflux was resumed for 14 additional hours. The reaction mixture was then cooled, poured into water and extracted with hexane (3×100 ml). The combined organic extracts werewashed with 20% aqueous sodium hydroxide solution and water, dried over sodium sulfate and the solvent removed by evaporation. The residue was distilled at 102° C./15 mm to yield 3-(p-methylphenoxy)-1-propyne, identical to an authentic sample.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]([CH3:19])[C:9]=1[C:20]([O:22][CH3:23])=[O:21].Cl[CH2:25][C:26]#[N:27].O>CS(C)=O>[C:26]([CH2:25][O:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]([CH3:19])[C:9]=1[C:20]([O:22][CH3:23])=[O:21])#[N:27]
Reactant: COC(=O)c1c(O)c2cc(OC)ccc2n1C
Reactant: N#CCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1c(OCC#N)c2cc(OC)ccc2n1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 59.2 %

Procedure:
A suspension of potassium tert-butoxide (3.2 g, 29 mmol) in 60 mL of dimethyl sulfoxide is treated in portions with methyl 3-hydroxy-5-methoxy-1-methyl-1H-indole-2-carboxylate (5.6 g, 24 mmol; Unangst P. C., et al., J. Heterocyclic Chem., 24:811 (1987)). The mixture is stirred for 15 minutes, and chloroacetonitrile (4.8 mL, 5.7 g, 76 mmol) is added dropwise. The mixture is heated at 80° for 90 minutes, cooled, and added to 800 g of ice and water. The precipitated solid is filtered, washed with 10% methanol-water, and recrystallized from aqueous acetonitrile to give 3.9 g (60%) of product, mp 136°-137° C.
Reaction SMILES: [NH:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]([C:9]([OH:11])=[O:10])=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:45][C@H:46]([CH2:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:57][CH:56]=1)[CH2:47][C:48]1([C:51]([OH:53])=[O:52])[CH2:50][CH2:49]1>C(Cl)Cl>[C:58]1([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[CH:57]=[CH:56][C:55]([CH2:54][C@@H:46]([NH:45][C:6]([C:5]2[CH:4]=[C:3]([C:9]([OH:11])=[O:10])[NH:2][N:1]=2)=[O:8])[CH2:47][C:48]2([C:51]([OH:53])=[O:52])[CH2:50][CH2:49]2)=[CH:60][CH:59]=1
Reactant: O=C(O)c1cc(C(=O)O)[nH]n1
Reactant: N[C@H](Cc1ccc(-c2ccccc2)cc1)CC1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H](Cc1ccc(-c2ccccc2)cc1)CC1(C(=O)O)CC1)c1cc(C(=O)O)[nH]n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 21.8 %

Procedure:
3,5-Pyrazoledicarboxylic acid (35.2 mg, 226 μmol, 1.0 eq.), DIPEA (126 μL) and HATU (85.9 mg, 226 μmol, 1.0 eq.) and DCM (5 mL) were combined and stirred for 5 minutes at room temperature. 1-((R)-2-Amino-3-biphenyl-4-yl-propyl)-cyclopropanecarboxylic acid (86.7 mg, 294 μmol, 2.3 eq,) and DIPEA (0.5 mL) in DCM (5 mL) was added, and the resulting mixture was stirred for 1 hour. The reaction was quenched with saturated aqueous NH4Cl and the product was extracted with DCM, dried and evaporated. The resulting product was combined with AcOH (1.5 mL) and purified with preparative HPLC to yield the title compound (21.4 mg; 93% purity). MS m/z [M+H]+ calc'd for C24H23N3O5, 434.16; found 433.5.