Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]2[C:11]3[C:12](Cl)=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:9]=2[C:8]([O:19][CH3:20])=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[H][H]>[Pd].CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:10]2[C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:9]=2[C:8]([O:19][CH3:20])=[CH:7][CH:6]=1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(OC)c2oc3ccnc(Cl)c3c12
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OC)c2oc3ccncc3c12

Procedure:
A mixture of Methyl-1-chloro-6-Methoxybenzo[4,5]furo[3,2-c]pyridine-9-carboxylate (from step 11) (330 mg), 10% Pd on carbon (50 mg), triethyl amine (2.0 mL) and DMF (10.0 mL) was hydrogenated in a Parr apparatus at 50-55 psi of Hydrogen gas. Catalyst was removed by filtration and filtrate was concentrated under vacuo. The residue obtained was purified by silica gel column using chloroform:acetone (8:2) as an eluent to afford intermediate-13 (200 mg) as light yellow solid.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([OH:5])=O.[C:32]([NH:36]CC)([CH3:35])([CH3:34])[CH3:33]>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([NH:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:5]
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: CCNC(C)(C)C
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)NC(C)(C)C

Procedure:
Starting materials: 2,6,10,14,18-pentamethyl-22-oxo-2,6,10,14,18-tricosapentaenoic acid and tert-butylethylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:38])=[C:5]([C:29]([O:36][CH3:37])=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21]CC2C=CC=CC=2)=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13].[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[C:4]([CH3:38])=[C:5]([C:29]([O:36][CH3:37])=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:21])=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)=[O:13]
Reactant: [H][H]
Reactant: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Agent: [Pd]
Solvent: CCO
Product: COc1c(C)c(Cc2ccc(O)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Yield: 96.1 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoyl]morpholine (1.27 g, 2.59 mmol) was dissolved in ethanol (50 ml) and the resulting solution was added to an ethanol suspension (5 ml) of 5% Pd—C (0.200 g) and stirred at room temperature for 16 hours in a hydrogen stream. The reaction solution was filtered, the filtrate was concentrated and the obtained residue was recrystallized from ether to obtain the titled compound (1.00 g, 2.49 mmol, 96%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]([F:32])([F:31])[C:14]1([CH2:17][CH:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])[CH2:16][CH2:15]1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[N:25][CH:26]=1)[CH2:17][C:14]1([C:13]([F:12])([F:31])[F:32])[CH2:16][CH2:15]1)=[O:6]
Reactant: O=C(O)c1cccc(F)c1Cl
Reactant: NCC(CC1(C(F)(F)F)CC1)c1ccc(C(F)(F)F)nc1
Product: O=C(NCC(CC1(C(F)(F)F)CC1)c1ccc(C(F)(F)F)nc1)c1cccc(F)c1Cl

Procedure:
From 2-chloro-3-fluorobenzoic acid and 3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5-yl)propan-1-amine. LCMS (MH+): m/z=469.1, tR (minutes, Method G)=2.54
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH2:13][C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[N:19][NH:20]2)=[CH:16][CH:15]=1>CCO.C(O)(=O)C>[NH:20]1[C:21]2[C:17](=[CH:16][CH:15]=[C:14]([N:13]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[CH:22]=2)[CH:18]=[N:19]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc2c(c1)C(=Nc1ccc3cn[nH]c3c1)C(=O)N2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 25.3 %

Procedure:
To a mixture of 5-methylisatin (80.5 mg, 0.5 mmol) and 6-aminoindazole (66.5 mg, 0.5 mmol) in EtOH (2 mL) was added 1 drops of acetic acid. The resulting mixture was capped and microwaved 30 min at 120° C. After cooling to rt, it was stirred for 5 min at rt and the resulting precipitate was collected by suction filtration to give the title compound (35 mg, 28%) as an orange red solid. 1H NMR indicated a 80:20 mixture of E/Z isomers. 1H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H, NH), 10.89 (s, 1H, NH), 8.10 (s, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.15 (d, J=7.2 Hz, 1H), 7.07 (s, 1H), 6.81-6.74 (m, 2H), 6.17 (s, 1H), 2.49 (s, 3H, CH3); MS ESI 277.0 [M+H]+, calcd for [C16H12N4O+H]+ 277.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:29])[NH:18][CH2:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[O:21])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](=O)(O)[O-:31].[Na+].C=O>O.CS(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17](=[O:29])[NH:18][CH:19]([CH2:30][OH:31])[C:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[O:21])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CNC(=O)C1CCN(C(=O)OCc2ccccc2)CC1)c1ccc(Cl)cc1
Reactant: O=C([O-])O
Agent: C=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(NC(CO)C(=O)c1ccc(Cl)cc1)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 6 h

Procedure:
To a stirred solution of the 4-[2-(4-chlorophenyl)-2-oxo-ethylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (8.91 g, 21.5 mmol), prepared as in Part B, and sodium bicarbonate (0.19 g, 2.3 mmol) in a mixture of water (10 mL) and dimethyl sulfoxide (50 mL) in a 50° C. water bath is added aqueous formaldehyde (3.30 mL, 44.0 mmol). After 6 h, the mixture is diluted with water (1 L) and allowed to stand overnight at RT. Filtration gives gummy solids which are triturated with ethyl acetate to give the desired product as white solids.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:10]([N+:11]([O-])=O)=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[N+:14]([O-])=O.[OH-].[Na+]>>[Cl:2][C:3]1[C:10]([NH2:11])=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[NH2:14]
Reactant: N#Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1cc(N)c(Cl)c(N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 352.5 grams (1.56 mole) of stannous chloride dihydrate in 860 ml. of concentrated hydrochloric acid is added 50 gm. (0.2195 mole) of 4-chloro-3,5-dinitrobenzonitrile. The mixture is stirred at room temperature for two hours and cooled to 0° in an ice-salt bath. A cold solution of 50% sodium hydroxide is added to the mixture until strongly basic. During the addition the temperature is kept below 30° .
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH:15]([O:16]C(=O)C3C=CC=CC=3)[CH2:14][CH:13]([CH:25]=[CH:26][P:27]([O:32]CC)([O:29]CC)=[O:28])[O:12]2)=[C:4](Cl)[N:3]=1.C[Si](Br)(C)C.[N:41]1C(C)=CC=CC=1C>CC#N>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[O:12][CH:13]([CH:25]=[CH:26][P:27](=[O:28])([OH:29])[OH:32])[CH2:14][CH:15]2[OH:16])=[C:4]([NH2:41])[N:3]=1
Reactant: Cc1cccc(C)n1
Reactant: CCOP(=O)(C=CC1CC(OC(=O)c2ccccc2)C(n2cnc3c(Cl)nc(N)nc32)O1)OCC
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: Nc1nc(N)c2ncn(C3OC(C=CP(=O)(O)O)CC3O)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.3 %

Procedure:
Compound 13.1 (147.5 mg, 0.283 mmol) was dissolved in 3 mL CH3CN, treated with TMSBr (0.3 mL) and 2,6-lutidine (0.075 mL). The mixture was stirred at room temperature for 1.5 h, concentrated and coevaporated with CH3CN under reduced pressure. The residue was dissolved in 30% NH3 in water, and the mixture was stirred at 100° C. for 1.5 h. The mixture was then treated with NaHCO3 (500 mg) and concentrated under reduced pressure. The residue was subjected to reverse phase HPLC eluting with 0-25% CH3CN in water to yield compound 13.2 (81 mg, 74.3% yield). 1H NMR (D2O) δ 2.05-2.25 (m, 2H), 4.58 (m, 1H), 5.8 (d, 1H, J=1.5), 5.95 (m, 1H), 6.15 (m, 1H), 7.8 (s, 1H). 31P NMR (D2O) d 9.15. LRMS (ESI) MH+ C11H15N6O5P requires 343.3. Found 343.1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]3[CH2:19][CH2:18][CH2:17][C:16]([C:20]([O:22]C)=[O:21])=[CH:15][C:14]=3[CH:24]=2)=[CH:6][CH:5]=1)[CH3:2].[OH-].[Na+].Cl>CO.C1COCC1>[CH2:1]([O:3][C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]3[CH2:19][CH2:18][CH2:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][C:14]=3[CH:24]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(COc2ccc3c(c2)C=C(C(=O)OC)CCC3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(COc2ccc3c(c2)C=C(C(=O)O)CCC3)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To methyl 2-(4-ethoxybenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (296 mg, 0.84 mmol) dissolved in a mixed solvent of methanol (4 ml) and THF (4 ml) was added a 1N aqueous solution of sodium hydroxide (2.5 ml), and the resulting mixture was stirred at 50° C. for 4 hours. The reaction mixture was mixed with 1 N hydrochloric acid (2.5 ml) at 0° C., was concentrated under reduced pressure and was mixed with water, and an insoluble material was collected by filtration. The insoluble material was washed with water, and was dried under reduced pressure to obtain 2-(4-ethoxybenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (283 mg, 0.84 mmol).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6].[CH3:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][C:21]2([OH:27])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[OH:27][C:21]1([CH2:20][C:19]2[CH:18]=[CH:17][C:16]([CH3:15])=[CH:29][CH:28]=2)[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[O:6])[CH2:23][CH2:22]1
Reactant: COc1ccc(C(=O)CCCCl)cc1
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C(=O)CCCN2CCC(O)(Cc3ccc(C)cc3)CC2)cc1
Temperature: 107.5 °C
Yield: 77.6 %

Procedure:
A mixture of 1.62 g of 4-chloro-1-(4-methoxy-phenyl)-butan-1-one (1), 1.20 g of 4-(4-methyl-benzyl)-piperidin-4-ol (2), 1.62 g of K2CO3, and 0.49 g of KI in acetonitrile (30 mL) was stirred and refluxed at 105 to 110° C. for 9 hours under nitrogen atmosphere. After the solvent was removed, ice water was added and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and brine and dried over MgSO4. After the solvent was removed, the obtained oily residue was purified by silica gel chromatography (chloroform:methanol=20/1 to 10/1) and the purified product was recrystallized from AcOEt/Et2O to afford 1.73 g of compound (3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[N:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)C.[H][H]>[Ni].ClC1C=CC=CC=1Cl>[CH3:20][NH:19][C@@H:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Solvent: Clc1ccccc1Cl
Product: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 0.8 %

Procedure:
N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene]methanamine (Ketimine) (50 g), ethanol (300 ml), Raney Nickel (0.15 g wet basis) and o-dichlorobenzene (50 ml) are charged into a reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm2 over pressure of hydrogen for 6 to 7 hrs at about 28 to 30° C. The catalyst is removed by filtration and the cake is washed with 50 ml ethanol. The cis to trans ratio is 82 to 85/18 to 15. The amount of dehalogenated by product is <0.1%. Sertraline racemate free base thus formed is treated with hydrochloric acid (24 ml, 33%) and predominantly isomer of sertraline HCl racemate is filtered [Cis>98%, trans<2%, dehalogenation product<0.1%, yield 0.80 to 0.82%].
Reaction SMILES: [C:1]12([OH:13])[CH2:10][C:5]3([OH:11])[CH2:6][CH:7]([CH2:9][C:3]([OH:12])([CH2:4]3)[CH2:2]1)[CH2:8]2.C[N:15]([CH:17]=[O:18])[CH3:16]>>[CH3:16][NH:15][C:17]([O:13][C:1]12[CH2:10][C:5]3([O:11][C:17](=[O:18])[NH:15][CH3:16])[CH2:6][CH:7]([CH2:9][C:3]([O:12][C:17](=[O:18])[NH:15][CH3:16])([CH2:4]3)[CH2:2]1)[CH2:8]2)=[O:18]
Reactant: OC12CC3CC(O)(C1)CC(O)(C3)C2
Reactant: CN(C)C=O
Product: CNC(=O)OC12CC3CC(OC(=O)NC)(C1)CC(OC(=O)NC)(C3)C2
Temperature: 60 °C
Yield: 95 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1,3,5-adamantanetriol obtained by the method of Example 32 and one drop of pyridine were dissolved in 10 mL of DMF. To the mixture, 30 mmole of methylisocyanato was added dropwise with stirring. Cooling of the resultant mixture with ice was started at about the time exothermic reaction began. When the exothermic reaction is completed, the mixture was heated to 60° C. and then stirred for one hour. As a result, the conversion of 1,3,5-adamantanetriol was 99% and 1,3,5-tris(methylcarbamoyloxy)adamantane (yield 95%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)[S:8][C:4]=2[CH:3]=1.[CH3:17]OS(OC)(=O)=O.[I-:24].[K+]>O>[I-:24].[CH3:17][N+:12]1[CH:11]=[CH:10][C:9]([C:7]2[S:8][C:4]3[CH:3]=[C:2]([Cl:1])[CH:16]=[CH:15][C:5]=3[N:6]=2)=[CH:14][CH:13]=1
Reactant: Clc1ccc2nc(-c3ccncc3)sc2c1
Reactant: COS(=O)(=O)OC
Agent: [I-]
Agent: [K+]
Solvent: O
Product: C[n+]1ccc(-c2nc3ccc(Cl)cc3s2)cc1

Procedure:
10 parts of the compound obtained in example 6 and 7 parts of dimethylsulfate are stirred at 100° C. for 30 minutes. At room temperature, 100 parts of water and 12 parts of potassium iodide are added and the product filtered. The product is washed with water and dried to yield 11 parts of 1-methyl-4-(6-chlor-benzothiazol-2-yl)pyridinium iodide.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH3:13])[CH:10]1[O:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([Mg]Cl)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:1]([O:8][C@H:9]([CH:10]([OH:12])[CH2:11][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[Mg]CCc1ccccc1
Reactant: C[C@H](OCc1ccccc1)C1CO1
Product: C[C@H](OCc1ccccc1)C(O)CCCc1ccccc1

Procedure:
(2S)-2-benzyloxy-6-phenylhexan-3-ol was prepared from (3S)-3-benzyloxy-1,2-epoxybutane (obtained in Preparation 9) and phenethylmagnesium chloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][CH2:18][CH:19]([CH2:25][CH2:26][CH2:27][F:28])[C:20]([O:22]CC)=[O:21])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>O.C(O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][CH2:18][CH:19]([CH2:25][CH2:26][CH2:27][F:28])[C:20]([OH:22])=[O:21])[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(CCCF)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CCC(CCCF)C(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 1-tert-Butyl 6-ethyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-(3-fluoropropyl)-hexanedioate (1f) (90.0 mg, 0.22 mmol) and lithium hydroxide (53.0 mg, 2.22 mmol) in 1 mL water/ethanol (1:1) was stirred for 14 h at r.t. The mixture was acidified to pH 2 by addition of 2 N aqueous hydrochloric acid and extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:10])=[O:11])[C:5]([O:8][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cc(Br)cnc1O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2ncc(Br)cc2S(=O)(=O)NC(C)(C)C)cc1
Temperature: 100 °C
Yield: 54 %

Procedure:
To a solution of 5-bromo-N-(tert-butyl)-2-hydroxypyridine-3-sulfonamide (2.00 g, 6.47 mmol) in DMF (40 mL) was added 4-methoxybenzyl chloride (1.76 mL, 12.9 mmol) followed by K2CO3 (1.78 g, 12.9 mmol) at ambient temperature. The reaction mixture was heated to 100° C. for 14 h, diluted with cold water (100 mL). The aqueous mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give a residue which was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 40 g, 50% EtOAc/hexanes) to obtain 5-bromo-N-(tert-butyl)-2-((4-methoxybenzyl)oxy)pyridine-3-sulfonamide (1.50 g, 54.0%). LCMS Condition B-39: retention time 2.53 min, [M+1]=429.0. 1H NMR (400 MHz, CDCl3) 1.25 (s, 9H), 3.81 (s, 3H), 6.88-6.91 (m, 2H), 7.24-7.30 (m, 4H), 7.55 (d, J=2.8 Hz, 1H), 8.11 (d, J=2.8 Hz, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)([CH:10]([CH3:12])[CH3:11])[C:6]([O:8][CH3:9])=[O:7].[CH3:23][NH:24][CH2:25][CH2:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31]>>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([C:5]([C:6]([O:8][CH3:9])=[O:7])([CH:10]([CH3:12])[CH3:11])[CH2:4][CH2:3][CH2:2][N:24]([CH3:23])[CH2:25][CH2:26][C:27]2[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=2)[C:30]([O:32][CH3:33])=[O:31])[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: COC(=O)C(CCCCl)(c1ccc(OC)c(OC)c1)C(C)C
Reactant: CNCCc1cccc(C(=O)OC)c1
Product: COC(=O)c1cccc(CCN(C)CCCC(C(=O)OC)(c2ccc(OC)c(OC)c2)C(C)C)c1

Procedure:
Reaction of 1e with 2d produced 3aj. MS found M+H=486. The oxalate salt of 3aj was recrystallized from ethyl acetate; mp 87-90° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([C:9]([NH:11][O:12][CH2:13][CH2:14][OH:15])=[O:10])[C:3]=1[NH:16][C:17]1[CH:36]=[CH:35][C:20]([C:21](OC2C(F)=C(F)C(F)=C(F)C=2F)=[O:22])=[CH:19][CH:18]=1.[BH4-].[Na+].Cl>C1COCC1.O>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:36]=[CH:35][C:20]([CH2:21][OH:22])=[CH:19][CH:18]=2)=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[C:9]([NH:11][O:12][CH2:13][CH2:14][OH:15])=[O:10]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.7 %

Procedure:
The product of Example 17, Step C, 2,3,4,5,6-pentafluorophenyl 4-[[2,3-difluoro-6-[[(2-hydroxyethoxy)amino]carbonyl]phenyl]amino]benzoate (150 mg, 0.29 mmol) was dissolved in THF (2 mL), then added dropwise to a solution of NaBH4 (110 mg, 2.90 mmol) in water (2 mL). This mixture was stirred at room temperature for 2 hours, acidified with 1 M HCl, and diluted with water (50 mL). The resulting aqueous mixture was extracted with EtOAc (2×50 mL), then the combined EtOAc fractions washed with water (50 mL), saturated NaCl (50 mL), and dried (Na2SO4). The solvent was removed under reduced pressure and the resulting residue purified by column chromatography on flash silica (50% EtOAc/hexanes as eluant) to afford 3,4-difluoro-N-(2-hydroxyethoxy)-2-[[4-(hydroxymethyl)phenyl]amino]benzamide as a cream solid (36 mg, 37%); m.p. (EtOAc/hexanes) 73-77° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.73 (br s, 1 H), 8.68 (br s, 1 H), 7.41-7.35 (m, 1 H), 7.15 (d, J=8.5 Hz, 2 H), 7.14-7.06 (m, 1 H), 6.79 (dd, J=8.5, 2.3 Hz, 2 H), 4.99 (t, J=5.7 Hz, 1 H), 4.72 (br s, 1 H), 4.38 (d, J=5.6, 2 H), 3.80 (t, J=4.9 Hz, 2 H), 3.54 (t, J=4.9 Hz, 2 H). Anal. Calcd for C16H16F2N2O4: C, 56.8; H, 4.8; N, 8.3. Found: C, 56.3; H, 4.7; N, 8.1.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][N:10]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:43]([O-])=O)=[C:25]([NH:27][C:28]3[S:29][C:30]([C:40]([NH2:42])=[O:41])=[C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=4)[N:32]=3)[CH:26]=2)[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O1CCC[CH2:47]1.[Cl-].[NH4+].C(OCC)(OCC)OCC>[Zn].C(O)(=O)C>[N:1]1([CH2:7][CH2:8][CH2:9][N:10]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]3[N:43]=[CH:47][N:27]([C:28]4[S:29][C:30]([C:40]([NH2:42])=[O:41])=[C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=5)[N:32]=4)[C:25]=3[CH:26]=2)[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1sc(Nc2cc(CN(CCCN3CCOCC3)CCCN3CCOCC3)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: NC(=O)c1sc(-n2cnc3ccc(CN(CCCN4CCOCC4)CCCN4CCOCC4)cc32)nc1-c1cccc(Cl)c1

Procedure:
To a mixture of 0.150 g (0.23 mmole) of 2-(5-{[bis-(3-morpholin-4-yl-propyl)-amino]-methyl}-2-nitro-phenylamino)-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (VI.49a), 20 mL of tetrahydrofuran, and 20 mL of saturated ammonium chloride solution was added 0.089 g (1.38 mg-atom) of zinc powder. After 5 minutes the mixture was filtered and the filtrate partitioned between 50 mL of saturated ammonium chloride and 50 mL of tetrahydrofuran. The tetrahydrofuran layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was stirred for 3 hours with 30 mL of acetic acid and 0.178 g (1.2 mmole) of triethyl orthoformate. The mixture was concentrated under reduced pressure, diluted with 100 mL of dichloromethane and washed with saturated sodium bicarbonate solution, then brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol-ammonium hydroxide (92:8:1) to give 0.075 g of 2-(6-{[bis-(3-morpholin-4-yl-propyl)-amino]-methyl}-benzoimidazol-1-yl)-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (I.49) as a light pink solid. MH+/Z=638.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([CH2:8][CH:9]([C:13]#[N:14])[C:10]([NH2:12])=[O:11])=O)=[CH:4][CH:3]=1.CCOCC.C(Cl)(Cl)[Cl:23]>>[Cl:23][C:13]1[NH:14][C:6]([C:5]2[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11]
Reactant: ClC(Cl)Cl
Reactant: N#CC(CC(=O)c1ccc(Cl)cc1)C(N)=O
Solvent: CCOCC
Product: NC(=O)c1cc(-c2ccc(Cl)cc2)[nH]c1Cl
Yield: 46 %

Procedure:
Into a mixture of 3-(p-chlorobenzoyl)-2-cyanopropionamide (1.0 g, 0.0042 mol), ether and chloroform is bubbled dry hydrogen chloride for about 10 minutes. TLC shows no remaining 3-(p-chlorobenzoyl)-2-cyanopropionamide. Solvent is removed in vacuo and the residue is distributed between ethyl acetate and water. The organic phase is separated, washed with water and brine and dried over magnesium sulfate. Solvent is removed and the resulting solid is triturated with ether and collected to give the title compound as a light brown solid (0.50 g, 46%, mp >200° C.). Identified by IR and NMR spectral analyses.