Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1([CH3:28])[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([C:25](=[O:27])[CH3:26])[C:15]([O:20][CH2:21][CH2:22][CH2:23]Br)=[C:16]([CH2:17][CH2:18][CH3:19])[C:9]=2[O:8]1)[CH3:2].[OH:30][C:31]1[C:36]([CH2:37][CH2:38][CH3:39])=[C:35]([OH:40])[CH:34]=[CH:33][C:32]=1[C:41](=[O:43])[CH3:42].C(=O)([O-])[O-].[K+].[K+].Cl>CCOCC.O.CN(C)C=O.CC(C)=O>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1([CH3:28])[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([C:25](=[O:27])[CH3:26])[C:15]([O:20][CH2:21][CH2:22][CH2:23][O:40][C:35]3[CH:34]=[CH:33][C:32]([C:41](=[O:43])[CH3:42])=[C:31]([OH:30])[C:36]=3[CH2:37][CH2:38][CH3:39])=[C:16]([CH2:17][CH2:18][CH3:19])[C:9]=2[O:8]1)[CH3:2]
Reactant: CCCc1c2c(cc(C(C)=O)c1OCCCBr)CCC(C)(CCC(=O)OCC)O2
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2c(C(C)=O)cc3c(c2CCC)OC(C)(CCC(=O)OCC)CC3)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.7 %

Procedure:
A mixture of 335 mg of racemic-6-acetyl-7-(3-bromopropoxy)-3,4-dihydro-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester, 143 mg of 2',4'-dihydroxy-3'-n-propylacetophenone, 217 mg of anhydrous potassium carbonate, 6 ml of anhydrous acetone, and 3 ml of anhydrous N,N-dimethylformamide was stirred and refluxed for 17 hours. An additional 100 mg of potassium carbonate was added and stirring, and refluxing were continued for 4 hours. After being cooled to room temperature, the mixture was cautiously acidified to pH 1 by the addition of 1N hydrochloric acid. Water was added and the mixture was worked-up with ether in the usual manner. The residue was chromatographed on 50 g of silica gel. Elution with 9:1 toluene-ethyl acetate afforded 219 mg (52.6%) of racemic-6-acetyl-7-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:45][S:46]([N:49]([CH3:51])[CH3:50])(=[O:48])=[O:47])[CH:5]=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[N:10](COCC[Si](C)(C)C)[CH:9]=2)[CH:7]=1.FC(F)(F)C(O)=O.N>>[OH:1][C:2]1[CH:3]=[C:4]([NH:45][S:46]([N:49]([CH3:51])[CH3:50])(=[O:48])=[O:47])[CH:5]=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[NH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(O)cc(NS(=O)(=O)N(C)C)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cc(O)cc(NS(=O)(=O)N(C)C)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 100.1 %

Procedure:
N′-[3-Hydroxy-5-(4-{[(1S)-1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl]amino}-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl]-N,N-dimethylsulfamide (8 mg, 0.01 mmol) was treated with trifluoroacetic acid (160 μl, 2.08 mmol) and a solution of ammonia (7N in methanol, 160 μl, 1.12 mmol) according to the method described in Example 27. The residue was purified using SP1® Purification System (0% to 15% dichloromethane-2-propanol) to obtain 6 mg (91% yield) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]([F:52])([F:51])[F:50])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH2:53][OH:54])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O>ClCCl>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][CH2:48][C:49]([F:52])([F:51])[F:50])=[CH:45][CH:46]=4)[CH:34]=3)[O:32][C@@:10]1([CH:53]=[O:54])[CH2:11][O:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(F)(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: ClCCl
Product: O=C[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(F)(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a solution of [(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-(2,2,2-trifluoroethoxyl) phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 171 (2.3 g, 3.02 mmol) in dichloromethane (100 mL) was added 2-iodoxybenzoic acid (1.70 g, 6.04 mmol) at room temperature. The mixture was refluxed for 20 hours, then cooled to room temperature and filtered. The filtrate was washed with saturated aqueous sodium chloride (50 mL) and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=10/1 to give the title compound 17m as pale yellow viscous oil (1.85 g, 80.4%, HPLC: 76.76%). This material was not further purified.
Reaction SMILES: S(=O)(=O)(O)O.CC(C)=[O:8].OS(O)(=O)=O.O=[Cr](=O)=O.[Cl:19][C:20]1[CH:21]=[C:22]([C@@H:26]2[C@@H:31]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[N:30]([CH2:39][CH:40]3[CH2:42][CH2:41]3)[C:29](=[O:43])[C:28]([CH2:52][CH2:53][OH:54])([CH2:44][CH2:45][N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)[CH2:27]2)[CH:23]=[CH:24][CH:25]=1>O.CC(C)=O.[O-2].[Cr+6].[O-2].[O-2]>[Cl:19][C:20]1[CH:21]=[C:22]([C@@H:26]2[C@@H:31]([C:32]3[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=3)[N:30]([CH2:39][CH:40]3[CH2:42][CH2:41]3)[C:29](=[O:43])[C@:28]([CH2:52][C:53]([OH:8])=[O:54])([CH2:44][CH2:45][N:46]3[CH2:47][CH2:48][O:49][CH2:50][CH2:51]3)[CH2:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)=O
Reactant: O=C1N(CC2CC2)[C@H](c2ccc(Cl)cc2)[C@@H](c2cccc(Cl)c2)CC1(CCO)CCN1CCOCC1
Agent: O=[Cr](=O)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)C[C@@]1(CCN2CCOCC2)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
An ice-cooled solution of 403 mg (4.03 mmol) of chromium(VI) oxide in water (1 mL) was treated with 343 μL (6.44 mmol) of sulfuric acid via syringe. The solution was diluted with additional water (1 mL) and stored at 0° C. at prior to use. In a separate flask, (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-(2-hydroxyethyl)-3-(2-morpholinoethyl)piperidin-2-one (Example 70, Step A, mixture of diastereomers) was dissolved in acetone (5 mL) and then treated with Jones reagent (see above) slowly via pipette at room temperature. After 30 min, the resulting dark red solution was heated at 55° C. for an additional 17 h. The reaction was concentrated under reduced pressure, then was diluted with water and extracted with ethyl acetate (3×). The organic layers were over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by reversed phase prep. HPLC (SunFire™ Prep C18 OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 40% MeCN in water to 60% MeCN in water over a 35 min period, where both solvents contain 0.1% TFA) provided the title compound (single enantiomer) as a white solid. [Note that the desired (3S)C-3 epimer is the less polar epimer and elutes off second].
Reaction SMILES: Cl.[NH2:2][CH2:3][P:4]([CH2:7][NH2:8])(=[O:6])[OH:5].[C:9]([O:13][C:14]([NH:16][C@H:17]([C:25]([OH:27])=O)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>>[C:9]([O:13][C:14]([NH:16][C@H:17]([C:25]([CH:3]([P:4]([CH:7]([NH2:8])[C:25](=[O:27])[C@H:17]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[NH:16][C:14]([O:13][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:15])(=[O:5])[OH:6])[NH2:2])=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])([CH3:11])([CH3:12])[CH3:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: NCP(=O)(O)CN
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)C(N)P(=O)(O)C(N)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Synthesis in analogy to Example 1 from bis(aminomethyl)phosphinic acid hydrochloride and tert.-butoxycarbonyI-L-phenylalanine
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].C([Li])CCC.[CH:17]([CH:19]=[CH2:20])=[O:18].OS(O)(=O)=O>C1COCC1.CCCCCC>[CH:19]([CH:17]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:8]([F:9])([F:10])[F:11])[C:2]=1[F:1])[OH:18])=[CH2:20]
Reactant: Fc1ccccc1C(F)(F)F
Reactant: C=CC=O
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CC(O)c1cccc(C(F)(F)F)c1F
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
A solution of 360 g (2.194 mol) of 1-fluoro-2-trifluoromethylbenzene in 3.4 l of anhydrous THF is cooled to -70° C. under a nitrogen atmosphere. 1.508 l (2.412 mol) of a 1.6M solution of n-butyllithium in hexane are added dropwise over 70 minutes while maintaining the temperature below -67° C. and then the mixture is stirred for 30 minutes at -70° C. 154 ml (2.305 mol) of acrolein are then added dropwise over 30 min while maintaining the temperature below -60° C. The mixture is then stirred for 30 min at -70° C. The mixture is allowed to return to room temperature and is poured onto a mixture of 3.8 kg of ice and 300 ml of concentrated H2SO4.
Reaction SMILES: C([O:5][C:6](=[O:45])[C@H:7]([CH2:43][SH:44])[NH:8][C:9]([OH:42])([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:11])(C)(C)C.FC(F)(F)C(O)=O>>[CH2:12]([C:10](=[O:11])[C:9]([NH:8][C@H:7]([C:6]([OH:45])=[O:5])[CH2:43][SH:44])([OH:42])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCCCC(O)(N[C@@H](CS)C(=O)OC(C)(C)C)C(=O)CCCCCCCCCCCCCC
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCCC(O)(N[C@@H](CS)C(=O)O)C(=O)CCCCCCCCCCCCCC

Procedure:
N-(α-Tetradecyl-β-hydroxyoctadecanoyl)cysteine tert.-butyl ester (1 g, 1.5 mmol) is treated with anhydrous trifluoroacetic acid for 1/2 h, and the latter is then removed in a rotary evaporator under high vacuum. The residue is dissolved in tert.-butanol and is freeze-dried.
Reaction SMILES: [C:1](OCC)(=[O:18])[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13](OCC)=[O:14].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:14][CH2:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][CH2:1][OH:18]
Reactant: CCOC(=O)CCOCCOCCOCCC(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCOCCOCCOCCCO

Procedure:
Prepared exactly as described, using tetrahydrofuran as solvent. (1.7 g, 5.5 mmol 14, 50 mL distilled [CaHz] THF, 0.66 g, 16.5 mmol lithium aluminum hydride). Once addition was complete, excess LAH was quenched with ethanol, and the salts precipitated by dropwise addition of saturated sodium sulfate solution until a white precipitate formed. The solvent was removed, the precipitate washed 6×30 mL with THF and the combined organic extracts were evaporated to yield an oil. Final product is purified by silica chromatography (first with methylene chloride then with ethyl acetate and finally with acetone).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[N:19]1([CH2:25][CH2:26][CH2:27][NH2:28])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:28][CH2:27][CH2:26][CH2:25][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NCCCN1CCOCC1
Product: O=C(NCCCN1CCOCC1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-(3-morpholin-4-ylpropyl)isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 1.0 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 1.6 mmol of 3-morpholin-4-yl-propylamine. LC/MS [4.66 min; 485 (M+1)]
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([CH:18]([N:24]([CH3:26])[CH3:25])[CH2:19][CH2:20][CH2:21][CH2:22][OH:23])[CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1.C(N(CC)CC)C>CCOCC>[CH3:1][O:2][CH2:3][C:4]([O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]([C:14]1([C:11]2[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][CH:12]=2)[CH2:15][CH2:16][CH2:17]1)[N:24]([CH3:26])[CH3:25])=[O:5]
Reactant: CN(C)C(CCCCO)C1(c2ccc(Cl)cc2)CCC1
Reactant: COCC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COCC(=O)OCCCCC(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Reaction time: 24 h

Procedure:
Methoxyacetyl chloride was added dropwise to a solution of the product of Example 144 and triethylamine in ether and the mixture stirred for 24 hours and then poured into ice-cold aqueous sodium hydroxide solution. The mixture was extracted with ether and the extract washed, dried and evaporated to give an oil. which was purified by flash chromatography on a silica column using ether as eluant to give 5-[1-(4-chlorophenyl)cyclobutyl]-5-dimethylaminopentyl 2-methoxyacetate as an oil the boiling point of which was not determined.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=12.[CH3:11][C:12]1([CH3:28])[C:16]([CH3:18])([CH3:17])[O:15][B:14](C2C=NN3C=CC=CC=23)[O:13]1>>[CH3:11][C:12]1([CH3:28])[C:16]([CH3:18])([CH3:17])[O:15][B:14]([C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[CH:9][N:8]=[CH:7][C:6]=23)[O:13]1
Reactant: Brc1cnn2ccncc12
Reactant: CC1(C)OB(c2cnn3ccccc23)OC1(C)C
Product: CC1(C)OB(c2cnn3ccncc23)OC1(C)C

Procedure:
Obtained from 3-bromopyrazolo[1,5-a]pyrazine (Preparation 23c) following the experimental procedure as described in Preparation 27a, irradiating the reaction mixture at 100° C. for 1 h. The crude product was used without further purification in the next synthetic step.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:4]=1[C:5](OC)=[O:6].[CH3:16][NH2:17].C(Cl)Cl.CCOC(C)=O>C1COCC1.CCOC(C)=O>[CH3:16][N:17]1[CH2:2][C:3]2[C:4](=[C:9]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:11][CH:12]=2)[C:5]1=[O:6]
Reactant: CN
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN1Cc2cccc([N+](=O)[O-])c2C1=O

Procedure:
At room temperature, a solution of methyl 2-bromomethyl-6-nitrobenzoate (1.26 g, 4.63 mmol) in THF (13 mL) is treated with 2M soln. of methylamine in THF (14 mL), stirred for 5 h, diluted with EtOAc (100 mL), washed with sat. aqueous solution of NaHCO3 (15 mL) and brine (15 mL), dried (MgSO4), and evaporated. A flash chromatography (30 g of silica gel; CH2Cl2/EtOAc 1:1) gives N-Methyl-7-nitro-2,3-dihydroisoindole-1-one (0.561 g, 2.92 mmol) in 63%. Yellow solid. Rf (CH2Cl2/EtOAC 1:1) 0.46. 1H-NMR (400 MHz, CDCl3) 3.21 (s), 4.44 (s), 7.63-7.69 (m, 2H), 7.70-7.75 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7])#[N:2].CO.[NH2:14][NH2:15]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:14][NH2:15])=[O:7])#[N:2]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: NN
Solvent: ClCCl
Solvent: CO
Product: N#Cc1cccc(C(=O)NN)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 38.5 %

Procedure:
3-cyanobenzoyl chloride (4.8 g, 29.0 mmol) was dissolved in DCM (20 ml) and MeOH (40 ml) was added in portions at 0° C. The mixture was stirred at 0° C. for 1 h and at rt for 2 h. The solvents were evaporated and the crude methyl ester was dissolved in EtOH (50 ml) and hydrazine (24% aq., 9 ml, 45 mmol) was added. The reaction mixture was refluxed for 48 h and the solvents were evaporated (coevaporation with water). The residue was purified with prep. HPLC to give the title compound (1.8 g, 39%). 1H NMR (DMSO-d6): 9.98 (br s, 1 H), 8.21 (m, 1 H), 8.13 (m, 1 H), 7.99 (m, 1 H), 7.69 (t, 1 H), 4.61 (br s, 2 H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[N+:23]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])#[C-:24].CC(C)([O-])C.[K+].Cl>O.O1CCOCC1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N+:23]#[C-:24])[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: [C-]#[N+]CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: [C-]#[N+]C(C(=O)OCC)c1c(F)cc2c(=O)c(C(=O)OCC)cn(C3CC3)c2c1F
Reaction time: 2 h
Yield: 28.5 %

Procedure:
2.7 g of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylate and 1.92 g of ethyl isocyanoacetate are initially introduced into 30 ml of dioxane. 1.91 g of potassium tert-butoxide are added and the mixture is heated to reflux for 3 hours. 0.39 g of potassium tert-butoxide is then added once more and the mixture is once more boiled for 2 hours. It is then diluted using water, acidified using HCl and the solid is isolated. After separation on silica gel (eluant CH2Cl2 /MeOH 95/5), 1.0 g of the title compound is obtained.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH:4]=[CH:3][CH2:2]1.Cl([O-])=[O:18].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.CC(=CC)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:10]([OH:18])=[O:11])[CH2:2][CH:3]=[CH:4][CH2:5]1
Reactant: COc1ccc(C=O)cc1OC1CC=CC1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Product: COc1ccc(C(=O)O)cc1OC1CC=CC1
Reaction time: 5 h
Yield: 69.7 %

Procedure:
A stirred solution of 3-cyclopent-3-enyloxy-4-methoxybenzaldehyde (1.75 g) in t-butanol (36.5 mL) and 2-methyl-2-butene (9.0 mL) is treated dropwise with an aqueous solution (34 mL) containing sodium chlorite (80% technical grade; 1.0 g) and sodium dihydrogen phosphate (8.75 g). The resulting mixture is further stirred for 5 hours, the layers are separated and the aqueous layer is extracted with t-butyl methyl ether (3×30 mL). The combined organic layers are washed with water (2×15 mL), dried over sodium sulfate and the solvent removed under reduced pressure. The resulting residue is recrystallized from ethyl acetate to give 3-cyclopent-3-enyloxy-4-methoxybenzoic acid (1.31 g), in the form of a colorless solid, m.p. 171-173° C. [Elemental analysis: C,66.6; H,6.0%; calculated: C,66.7; H,6.0%].
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[Na+].[Na+].[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][C:20]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Brc1ccncc1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: FC(F)(F)c1ccc(-c2ccncc2)cc1
Reaction time: 0.17 h

Procedure:
In a 250-mL, round-bottomed flask were added 4-bromopyridine hydrochloride (Aldrich) (4.7 g, 24 mmol), tetrakis (triphenylphosphine) palladium (0) (Aldrich) (1.4 g, 1.2 mmol) and 1,2-dimethoxyethane (120 mL). After stirring under nitrogen for 10 min, a solution of Na2CO3 (5.2 g in 30 mL of water) and 4-trifluoromethylbenzeneboronic acid (5.1 g, 27 mmol) were added sequentially to the mixture. The reaction was stirred in a 90° C. oil bath overnight. The 1,2-dimethoxyethane was evaporated in vacuo, and EtOAc was added to the residue. The aqueous layer was separated and extracted with EtOAc (2×50 mL). The combined EtOAc extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by silica gel flash chromatography using 1:5 EtOAc/hexanes as eluent gave the title compound as a light-tan solid. MS (ESI, pos. ion) m/z: 224 (M+1).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH2:26][NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:8][CH:7]=1)([OH:5])[CH3:4].CCN(C(C)C)C(C)C.[C:45](Cl)(=[O:47])[CH3:46]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:28]1([N:27]([CH2:26][C@H:13]2[CH2:14][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:16][CH2:17][N:12]2[C:9]2[CH:8]=[CH:7][C:6]([C:3]([OH:5])([CH3:4])[C:2]([F:1])([F:34])[F:35])=[CH:11][CH:10]=2)[C:45](=[O:47])[CH3:46])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(=O)Cl
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CNc2ccccc2)cc1)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N(C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
To a solution of 1,1,1-trifluoro-2-(4-((2S)-2-((phenylamino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.130 g, 0.247 mmol, Example 203) in CH2Cl2 (3.0 mL) was added 4-dimethylaminopyridine (6.1 mg, 0.049 mmol), Hünig's base (0.129 mL, 0.742 mmol), and acetyl chloride (0.035 mL, 0.49 mmol, Aldrich, St. Louis, Mo.). The resulting mixture was stirred at room temperature for 30 min and then the solvent was removed in vacuo. The residue was purified by column chromatography (24 g of silica gel, 10% to 40% EtOAc in hexanes) to afford N-phenyl-N-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)acetamide (0.032 g) as a mixture of two isomers:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1.[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Fc1ccc(CCl)c(Cl)c1
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: O=C(O)Cc1ccc2ccn(Cc3ccc(F)cc3Cl)c2c1

Procedure:
The titled compound (38 mg) as a white solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 2-chloro-4-fluorobenzyl chloride according to the method of the process (7) of Example 4.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25]3([CH2:31]I)[CH2:29][O:28][C:27](=[O:30])[NH:26]3)=[C:18]([Cl:33])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:34](OCC)([O:38]CC)[O:35][CH2:36][CH3:37]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25]3([CH:31]=[P:34]([O:35][CH2:36][CH3:37])=[O:38])[CH2:29][O:28][C:27](=[O:30])[NH:26]3)=[C:18]([Cl:33])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(OCC)OCC
Reactant: O=C1NC(CI)(CCCc2ccc(Sc3cccc(OCc4ccccc4)c3)cc2Cl)CO1
Product: CCO[P+]([O-])=CC1(CCCc2ccc(Sc3cccc(OCc4ccccc4)c3)cc2Cl)COC(=O)N1

Procedure:
The compound of Example 188 (330 mg) was dissolved in triethyl phosphite (120 μL) and the solution was refluxed for 3 hours. Subsequently, the reaction mixture was purified on a silica gel column chromatography (hexane:ethyl acetate=1:1 to 1:5) to give the desired product as a pale yellow oil (320 mg).