Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10].[ClH:16].S(=O)(O)O>O>[ClH:16].[NH:5]([C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])[NH2:1]
Reactant: O=N[O-]
Reactant: COC(=O)c1cccc(N)c1
Agent: Cl
Agent: O=S(O)O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cccc(NN)c1
Reaction time: 0.08 h

Procedure:
A solution of 5.75 g of sodium nitrite in 30 ml of water was dropwise added to a solution of 11.7 g of methyl 3-aminobenzoate and 20 ml of concentrated hydrochloric acid in 200 ml of water, at about 0° C. with cooling with ice-methanol. The mixture was stirred at the same temperature for 5 minutes. The mixture was then added to 650 ml of a 6% aqueous sulfurous acid solution being ice-cooled. The resulting mixture was stirred at 50-60° C. for 2 days. The reaction mixture was allowed to cool and then extracted with ethyl acetate. The aqueous layer was made basic with an aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with water and an aqueous sodium chloride solution in this order, then dried with anhydrous sodium sulfate, and concentrated under reduced pressure. To the residue was added ethanol. The mixture was made acidic with concentrated hydrochloric acid and then concentrated under reduced pressure. To the residue was added a slight amount of ethanol. The resulting insolubles were collected by filtration, washed with ethanol, and dried to obtain 3.1 g of methyl 3-hydrazinobenzoate hydrochloride as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([N:13]=[C:14]=[O:15])=[N:10][C:9]=2[CH3:16])=[CH:4][C:3]=1[S:17]([CH3:20])(=[O:19])=[O:18].ClC1C=CC(C2SC(N)=NC=2C)=CC=1S(C)(=O)=O.[C:39]([Si:43]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[O:44][CH:45]1[CH2:48][NH:47][CH2:46]1)([CH3:42])([CH3:41])[CH3:40]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([NH:13][C:14]([N:47]3[CH2:46][CH:45]([O:44][Si:43]([C:39]([CH3:42])([CH3:41])[CH3:40])([C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=4)[C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[CH2:48]3)=[O:15])=[N:10][C:9]=2[CH3:16])=[CH:4][C:3]=1[S:17]([CH3:20])(=[O:18])=[O:19]
Reactant: Cc1nc(N=C=O)sc1-c1ccc(Cl)c(S(C)(=O)=O)c1
Reactant: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Agent: Cc1nc(N)sc1-c1ccc(Cl)c(S(C)(=O)=O)c1
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)sc1-c1ccc(Cl)c(S(C)(=O)=O)c1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 5-(4-chloro-3-methanesulfonyl-phenyl)-2-isocyanato-4-methyl-thiazole [prepared by the same procedure as example 88a replacing 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) in this example with 5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 83)] (0.2 g, 0.61 mmol) in DMF is treated with 3-(tert-butyl-diphenyl-silanyloxy)-azetidine (162b) (0.25 g, 0.8 mmol) and the reaction mixture is heated to 120° C. After 30 minutes, the reaction is complete. The product is purified by chromatography on silica eluting with ethyl acetate-hexane (1:2) to give the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11](=O)[CH3:12].Cl.[NH2:15][OH:16].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11](=[N:15][OH:16])[CH3:12]
Reactant: COc1ccccc1C=CC(C)=O
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1C=CC(C)=NO
Yield: 54 %

Procedure:
In a 250 ml single neck flask was charged 5.28 g (.30.0 mmoles, 1.0 eq.) of 4-(2-methoxyphenyl)-3-buten-2-one and 5.2 g (75.4 mmoles, 2.5 eq) of hydroxylamine hydrochloride and 6 g of 50% sodium hydroxide (75 mmoles, 2.5 eq) and 100 ml of methanol. The reaction mixture was stirred at reflux for 2 hours. The reaction mixture was concentrated, diluted with water (50 ml), and then extracted with ethyl acetate (2×50 ml). The organic phase was dried and concentrated, to obtain 3.1 g of 4-(2-methoxyphenyl)-3-buten-2-one 2-oxime (E/Z mixture of isomers) as an oil in 54.1% yield.
Reaction SMILES: [CH2:1]([N:4]1[C:18](=[O:19])[C:17]2[C:11]3([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[C:7]=2[NH:6][C:5]1=[S:24])[CH:2]=[CH2:3].Br.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29]Br.[OH-].[K+].O>C(O)C>[CH2:1]([N:4]1[C:18](=[O:19])[C:17]2[C:11]3([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)[CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[C:7]=2[N:6]=[C:5]1[S:24][CH2:29][CH2:28][N:27]([CH3:31])[CH3:26])[CH:2]=[CH2:3]
Reactant: CN(C)CCBr
Reactant: C=CCn1c(=S)[nH]c2c(c1=O)C1(CCCCC1)Cc1ccccc1-2
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCn1c(SCCN(C)C)nc2c(c1=O)C1(CCCCC1)Cc1ccccc1-2

Procedure:
A mixture of 3-allyl-2-thioxo-2,3-dihydro-1H-spiro[benzo[h]quinazoline-5,1′-cyclohexan]-4(6H)-one (5, 0.100 g, 0.295 mmol), beta-dimethylaminoethyl bromide hydrobromide (0.076 g, 0.325 mmol), potassium hydroxide (0.041 g, 0.739 mmol) in Ethanol (1.738 ml) was refluxed ON. To the cooled solution, water (1 ml) was added and the mixture was extracted with EtOAc 2×. The organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.12, 7.37-7.22, 5.95, 4.71, 3.48, 3.05, 2.76, 2.64-2.58, 2.36, 1.74-1.72, 1.59-1.53, 1.42-1.39; MS (EI) m/z 410 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:17](O)=[O:18])[C:10](=[O:25])[CH:9]=2)[CH:7]=1.[NH2:28][C:29]1[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:31][CH:30]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]([CH3:23])([CH3:24])[CH3:22])[C:17]([NH:28][C:29]3[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])=[CH:31][CH:30]=3)=[O:18])[C:10](=[O:25])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC(C)(C)C)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cn(C(CC(C)(C)C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Reaction time: 0.58 h

Procedure:
110 mg (283 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4-dimethylpentanoic acid (racemate), 65.6 mg (339 μmol) of tert-butyl 4-aminobenzoate, 129 mg (339 μmol) of HATU and 148 μl (849 μmol) of N,N-diisopropylethylamine in 9 ml of dimethylformamide were reacted according to General Method 5A. The solvent was removed and the residue was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125×30 mm, mobile phase: acetonitrile/0.05% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 100 mg (62% of theory)
Reaction SMILES: Br.[OH:2][C:3]1[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][C:7]=2[CH:13]=1.[C:18]([Br:21])(=[O:20])[CH3:19]>FC(F)(F)C(O)=O>[BrH:21].[C:18]([O:2][C:3]1[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][C:7]=2[CH:13]=1)(=[O:20])[CH3:19]
Reactant: CS(=O)(=O)c1cc2c(cc1O)CCNCC2
Reactant: CC(=O)Br
Agent: Br
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Oc1cc2c(cc1S(C)(=O)=O)CCNCC2

Procedure:
A mixture of 8-hydroxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (3.2 g, 0.01 m) in trifluoroacetic acid (25 ml) is stirred at 25° and treated with acetyl bromide (1.4 g, 0.011 m). The mixture is stirred at 25° and concentrated in vacuo to give 8-acetoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[C:20]([CH2:21][CH2:22][CH3:23])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[OH:4].[CH2:30]1[C@H:33]([C:34]([OH:36])=[O:35])[NH:32][CH2:31]1.C1CCN2C(=NCCC2)CC1>CS(C)=O>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[C:20]([CH2:21][CH2:22][CH3:23])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][N:32]1[CH2:31][CH2:30][C@@H:33]1[C:34]([OH:36])=[O:35]
Reactant: CCCc1c(-c2nc(-c3ccc(C(O)CBr)cc3)no2)noc1-c1ccccc1
Reactant: O=C(O)[C@H]1CCN1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: CCCc1c(-c2nc(-c3ccc(C(O)CN4CC[C@@H]4C(=O)O)cc3)no2)noc1-c1ccccc1
Temperature: 80 °C

Procedure:
To a mixture of 2-bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol, Preparation 1C (30 mg, 0.066 mmol) and D-Azetidine-2-carboxylic acid (20.03 mg, 0.198 mmol) in DMSO (2 mL) was added DBU (0.030 mL, 0.198 mmol). The reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 16 mg of (2R)-1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl) azetidine-2-carboxylic acid as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (2H, dd, J=8.57, 2.86 Hz), 7.82 (2H, dd, J=8.02, 1.65 Hz), 7.58-7.70 (5H, m), 5.16-5.29 (1H, m), 4.89-5.10 (1H, m), 3.84-4.05 (2H, m), 3.18-3.41 (2H, m), 2.96-3.03 (2H, m), 2.51-2.61 (1H, m), 1.63-1.76 (2H, m), 0.97 (3H, t, K=7.25 Hz). MS (m+1)=475. HPLC Peak RT=3.5 minutes (Analytical Method A). Purity=90%.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>CN(C=O)C.O>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[N:4]([S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)c1ccc2[nH]cc(I)c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)O)ccc32)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.6 %

Procedure:
A solution of 3-iodo-1H-indole-5-carboxylic acid (3.70 g, 12.89 mmol) in DMF (9.5 mL) at 0° C. was treated with NaH (60% in mineral oil) (1.289 g, 32.2 mmol). After 15 min at 0° C., p-toluenesulfonyl chloride (2.95 g, 15.47 mmol) was added in 1 g portions at 0° C. every 15 min and the reaction was warmed slowly in the ice bath to 10° C. After 2 h, the mixture was dumped into H2O and the mixture was acidified with 5 M HCl. The precipitate was collected by filtration, washed with water and dried to afford crude 3-iodo-1-tosyl-1H-indole-5-carboxylic acid (5.72 g) as a tan solid. MS (ESI, pos. ion) m/z: 442 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.20 (1H, s), 8.03-8.09 (1H, m), 7.93-8.02 (3H, m), 7.91 (1H, s), 7.42 (2H, d, J=8.0 Hz), 2.33 (3H, s)
Reaction SMILES: Cl[C:2]([F:6])=[C:3]([F:5])[F:4].C([Li])CCC.Cl[Si:13]([CH3:16])([CH3:15])[CH3:14]>>[F:4][C:3]([F:5])=[C:2]([F:6])[Si:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: FC(F)=C(F)Cl
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Product: C[Si](C)(C)C(F)=C(F)F

Procedure:
Chlorotrifluoroethylene of the formula (10) is treated with n-butyl lithium and then reacted with chlorotrimethylsilane of the formula (11) to obtain 1,1,2-trifluoro-2-trimethylsilylethylene of the formula (12). Then, without isolation, this compound (12) is reacted further with a lithium compound of the formula (13) to obtain a difluoroethylene compound of the formula (14).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH3:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[C:14]([CH3:28])[O:13][N:12]=1>N1C=CC=CC=1>[CH3:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([S:24]([NH:9][C:6]3[N:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:26])=[O:25])=[CH:22][CH:23]=2)=[C:14]([CH3:28])[O:13][N:12]=1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(N)nn1
Solvent: c1ccncc1
Product: COc1ccc(NS(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)nn1
Temperature: 20 °C
Reaction time: 18 h
Yield: 4.1 %

Procedure:
To a solution of 6-methoxypyridazin-3-amine (125 mg, 1.0 mmol) in pyridine (8 mL) at room temperature, was added 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonyl chloride (0.302 g, 1.0 mmol). The reaction mixture was stirred at 20° C. for 18 hours. The solvent was evaporated in vacuo and passed through an aminopropyl (NH2) solid phase extraction (SPE) cartridge eluting with methanol, followed by a sulphonic acid (SCX) SPE cartridge eluting with methanol. The crude was then purified by flash silica (Si) chromatography (0-100% ethyl acetate-cyclohexane+0-25% methanol gradient), to provide the title compound (16 mg). LCMS (2 min, formic) Rt 0.83 min, m/z (ES+) 391 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([Cl:11])[N:3]=1.[CH3:12][S-:13].[Na+].O>CN(C=O)C>[Cl:11][C:4]1[N:3]=[C:2]([S:13][CH3:12])[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[CH:5]=1
Reactant: Clc1cc2nc[nH]c2c(Cl)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc(Cl)cc2nc[nH]c12
Temperature: 120 °C

Procedure:
To a solution of 4,6-dichloro-3H-imidazo[4,5-c]pyridine (2.01 g, 10.7 mmol) in DMF (21 mL) at room temperature was added sodium methanethiolate (1.88 g, 26.8 mmol). Mixture was heated at 120° C. for eight hours. An additional 801 mg of sodium methanethiolate was added and mixture stirred at 120° C. for fifteen hours. After adding an additional 340 mg of sodium methanethiolate and heating at 120° C. for five hours, reaction mixture was cooled to room temperature and poured into 100 mL of water. This was then extracted with ethyl acetate (5×150 mL) and combined organic layers were washed with 50% Brine (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to yield 6-chloro-4-(methylthio)-3H-imidazo[4,5-c]pyridine 2.01, which was used in the next step without further purification.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:26])OC2C=CC([N+]([O-])=O)=CC=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34].C(N(CC)CC)C>C(Cl)Cl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15](=[O:26])[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Oc1ccc(Oc2ccccc2)cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCCCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCCCCO)Oc1ccc(Oc2ccccc2)cc1
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A solution of the carbonate prepared in Example 1 (10.0 g, 28.4 mmol) in 75 mL of methylene chloride was added under nitrogen dropwise to a solution of 6-amino-1-hexanol (3.34 g, 28.4 mmol) and triethylamine (19.8 mL, 142 mmol) in 100 mL of methylene chloride at ice-bath temperature. The reaction was stirred at ice bath temperature for approximately eight hours and at room temperature overnight. The reaction was extracted one time with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 8.1 g of a solid. Recrystallization of the solid from diisopropyl ether gave 6.55 g (70%) of the title compound as a white crystalline solid, mp 72°-75° C.
Reaction SMILES: C([CH2:4][N:5]1[CH2:10][C:9](=[O:11])[N:8]([CH2:12]C(O)=O)[CH2:7][C:6]1=[O:16])(O)=O.FC(F)(F)S(O)(=O)=O.O1P2[O:31][P:32]3[O:34]P(O2)OP1[O:33]3.[C]=O>O>[P:32]([CH2:4][N:5]1[CH2:10][C:9](=[O:11])[N:8]([CH2:12][P:32]([OH:31])([OH:33])=[O:34])[CH2:7][C:6]1=[O:16])([OH:34])([OH:33])=[O:31]
Reactant: O=C(O)CN1CC(=O)N(CC(=O)O)CC1=O
Reactant: O1P2OP3OP1OP(O2)O3
Agent: O=S(=O)(O)C(F)(F)F
Agent: [C]=O
Solvent: O
Product: O=C1CN(CP(=O)(O)O)C(=O)CN1CP(=O)(O)O
Temperature: 75 °C
Reaction time: 16 h

Procedure:
In a round-bottom flask equipped with a mechanical stirrer, a thermometer, a condenser 4.00 g (17.2 mmole) N,N′-bis(carboxymethyl)-2,5-diketopiperazine was mixed with 25 ml trifluoromethanesulfonic acid. Subsequently, the reaction mixture was heated to 75° C. and 1.89 g (8.6 mmole) tetraphosphorus hexaoxide was added slowly. Afterwards the reaction mixture was stirred for 16 hour at 75° C. During the addition and during the reaction time the evolution of carbon monoxide was observed. At ambient temperature 30 ml of water was added to the reaction mixture which subsequently was heated to 95° C. for 6 hour. A white solid precipitated that was removed by filtration at ambient temperature (yield: 4.35 g). The solid consisted of N,N′-bis(phosphonomethyl)-2,5-diketopiperazine at 98.9% by weight.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[C:9]([CH2:25][N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)=[C:8]2[C:33]([NH:35][C@H:36]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:37]([F:40])([F:39])[F:38])=[O:34])(=[O:4])=[O:3].C(O)(=O)C.[CH3:51][C@H:52]1[CH2:56][CH2:55][CH2:54][NH:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:51][C@@H:52]1[CH2:56][CH2:55][CH2:54][N:53]1[CH:29]1[CH2:28][CH2:27][N:26]([CH2:25][C:9]2[C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=3)=[N:11][C:12]3[C:7]([C:8]=2[C:33]([NH:35][C@H:36]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:37]([F:40])([F:39])[F:38])=[O:34])=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:14][CH:13]=3)[CH2:31][CH2:30]1
Reactant: C[C@H]1CCCN1
Reactant: CS(=O)(=O)c1ccc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(=O)CC3)c(C(=O)N[C@H](c3ccccc3)C(F)(F)F)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@@H]1CCCN1C1CCN(Cc2c(-c3cccc(C(F)(F)F)c3)nc3ccc(S(C)(=O)=O)cc3c2C(=O)N[C@H](c2ccccc2)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.1 %

Procedure:
6-(Methylsulfonyl)-3-[(4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.093 g, 0.140 mmol) was dissolved in dichloromethane (1.4 mL) and acetic acid (0.012 mL, 0.210 mmol). (S)-2-Methylpyrrolidine (0.036 g, 0.420 mmol) was added followed by sodium triacetoxyborohydride (59.4 mg, 0.280 mmol). The mixture was stirred at room temperature for 2 d. The solvent was removed under reduced pressure, and the residue was purified via HPLC (Waters, Sunfire 30×100 mm, 26-60% CH3CN/H2O with 0.1% TFA) to afford 3-({4-[(2R)-2-methyl-1-pyrrolidinyl]-1-piperidinyl}methyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.035 g, 32% yield). MS (m/z) 733.3 (M+H+).
Reaction SMILES: Cl.[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.O>[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH:11][CH2:18][C:17]2[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:22])[F:23])=[CH:21][CH:20]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)c1ccc(CN[C@@H]2C[C@H]2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.9 %

Procedure:
A mixture of (trans)-2-phenylcyclopropanamine hydrochloride (0.23 g, 1.36 mmol) and 4-(trifluoromethyl)benzaldehyde (0.20 mL, 1.49 mmol) in CH2Cl2 (8 mL) and water (0.5 mL) was vigorously stirred at room temperature for 10 min. Then, NaBH(OAc)3 (0.37 g, 1.76 mmol) was slowly added and stirring continued for 30 min. The reaction mixture was washed with an aqueous saturated solution of NaHCO3 (8 mL), the organic layer was dried over anhydrous Na2SO4, filtered and, after removal of the solvent, the residual oil was purified by column chromatography on silica gel (1% MeOH/CH2Cl2) affording 0.15 g of N-[(trans)-2-phenylcyclopropyl]-N-[4-(trifluoromethyl)benzyl]amine [Rf=0.6 (5% MeOH/CH2Cl2), colorless oil, 38% yield].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][CH:12]=[CH2:13])=[CH:7][C:8]=1[O:9][CH3:10].CO[CH:16]([O:21][CH3:22])[C:17](=[CH2:20])[C:18]#[N:19].C(Cl)Cl>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:17]([C:18]#[N:19])=[CH:16][O:21][CH3:22])[C:6]([CH2:11][CH:12]=[CH2:13])=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C=C(C#N)C(OC)OC
Reactant: C=CCc1ccc(OC)c(OC)c1
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCc1cc(OC)c(OC)cc1CC(C#N)=COC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 10 g. of methyl eugenol and 8.1 g. of 2-dimethoxymethylacrylonitrile in 200 ml. of dry methylene chloride was added 1.97 ml. of stannic chloride. After stirring for 5 hours at room temperature, 300 ml. of ether was added and the mixture washed with a 5% sodium bicarbonate solution (until basic). The organic layer was dried (MgSO4) and the solvent removed under reduced pressure. The residue was triturated with ether to give 1,2-dimethoxy-4-(2-propenyl)-5-(2-cyano-3-methoxy-2-propenyl)benzene, m.p. 77°-79°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][N:10]([CH3:15])[S:11](Cl)(=[O:13])=[O:12].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][S:11](=[O:13])(=[O:12])[N:10]([CH3:15])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(Cl)c1
Reactant: CN(C)S(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN(C)S(=O)(=O)Oc1cccc(Cl)c1
Yield: 22.3 %

Procedure:
A solution of 25.7 g (0.2 mole) of 3-chlorophenol and 34.9 g (0.24 mole) of dimethylsulfamoyl chloride (Aldrich) in 150 ml of toluene was stirred and heated at reflux for 16 h, cooled and treated with 300 ml of 15% sodium hydroxide solution. The layers were separated and the organic layer was washed with two 200 ml portions of 15% sodium hydroxide solution, 300 ml of water and dried (magnesium sulfate). The solvent was evaporated under reduced pressure and the brown viscous oil was purified by chromatography (4.5×90 in glass column, 530 g of silica gel, ethyl acetate-hexanes, 1:6). Fractions containing the desired product were combined and the solvents were evaporated under reduced pressure to yield 10.5 g (47%) of the title compound as a light yellow liquid.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29])([CH3:22])[CH3:21].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=1)([CH3:22])[CH3:21]
Reactant: CC(C)c1ccccc1O
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccccc2C(C)C)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 2-isopropyl-phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid. MS (ES) for C21H26O5 [M+Na]+: 381.4.