Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1>C(O)C>[Cl:10][C:11]1[CH:18]=[CH:17][C:14](/[CH:15]=[N:1]\[CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[OH:9])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NCc1ccccc1O
Solvent: CCO
Product: Oc1ccccc1C/N=C\c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred suspension of 2-(aminomethyl)phenol, (4.0 g, 32.5 mmol) in ethanol (65 mL) was added 4-chlorobenzaldehyde (3.86 mL, 32.8 mmol). The resulting reaction mixture was stirred at rt for 3 h. The solvent was removed and 100 ml of toluene was added and concentrated in vacuum twice. The resulting imine was dried under vacuum overnight and used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[O:20][CH2:19][CH2:18][NH:17][CH2:16]2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.Cl[C:22]1[N:23]([CH3:35])[C:24](=[O:34])[CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[N:27]=1.C(N(CC)CC)C>O1CCCC1>[CH3:35][N:23]1[C:24](=[O:34])[CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[N:27]=[C:22]1[N:17]1[CH2:18][CH2:19][O:20][C@@H:15]([C:12]2[CH:11]=[CH:10][C:9]([N:2]([CH3:1])[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)=[CH:14][CH:13]=2)[CH2:16]1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: CN(c1ccc([C@H]2CNCCO2)cc1)c1ccccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(c1ccc([C@H]2CN(c3nc(-c4ccncc4)cc(=O)n3C)CCO2)cc1)c1ccccn1
Yield: 38.7 %

Procedure:
A solution of N-Methyl-N-(4-((2S)-morpholin-2-yl)phenyl)pyridin-2-amine (0.12 g, 0.46 mmol), 2-chloro-1-methyl-6-oxo-4-(pyridin-4-yl)-1,6-dihydropyrimidine (0.08 g, 0.37 mmol), and triethylamine (0.23 g, 2.3 mmol) in tetrahydrofuran (10 ml) was stirred at 95° C. for 3 hours. The solvent was removed under reduced pressure and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (chloroform-methanol, 10:1) to give 3-Methyl-2-((2S)-2-(4-(methyl(pyridin-2-yl)amino)phenyl)morpholin-4-yl)-6-(pyridin-4-yl)-pyrimidin-4(3H)-one (65 mg, 13%) as a yellow oil.
Reaction SMILES: [CH2:1](N(C(C)C)C(C)C)[CH3:2].[OH:10][C@@H:11]([C@H:13]1[C:19](=[O:20])[N:18]2[CH:14]1[S:15][C:16](=[S:34])[CH:17]2[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22])[CH3:12].ICC>O1CCCC1>[CH2:1]([S:34][C:16]1[S:15][CH:14]2[N:18]([C:19](=[O:20])[C@@H:13]2[C@H:11]([OH:10])[CH3:12])[C:17]=1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22])[CH3:2]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=S)SC12
Reactant: CCN(C(C)C)C(C)C
Solvent: CCI
Solvent: C1CCOC1
Product: CCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)C2S1
Reaction time: 16 h

Procedure:
To 0.200 ml of ethyl diisopropylamine was added to 0.426 g of 4-nitrobenzyl 6(S)-[1(R)-hydroxyethyl]-7-oxo-3-thioxo-4-thia-1-azabicyclo[3,2,0]heptane-2-carboxylate in dry tetrahydrofuran with stirring. 0.252 ml of iodoethane was then added and stirring was continued for 16 hours at room temperature. The reaction mixture was then evaporated to dryness and chromatographed on silica gel, eluting with ethyl acetate/hexane mixtures, to give the title product as a mixture of 5R and 5S isomers.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]([OH:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:30][C:31](Cl)=[O:32]>CCOCC>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:12][O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:26][CH2:30][C:31]1=[O:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(CCNCc1ccccc1)(COc1ccccc1)c1ccccc1
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C1COC(COc2ccccc2)(c2ccccc2)CCN1Cc1ccccc1
Reaction time: 2 h

Procedure:
60 g (0.17 mole) of the N-benzyl-3-hydroxy-3-phenyl-4-phenoxybutylamine obtained as described in (c) were dissolved in 600 ml of ether, 150 ml of 2N sodium hydroxide solution were added and 22.6 g (0.2 mole) of chloroacetyl chloride in 50 ml of ether were added dropwise at room temperature. The mixture was refluxed for 30 minutes, after which the ether phase was separated off and dried, and 150 ml of isopropanol were added. To this solution was added dropwise, in the course of 30 minutes, a solution of 3.4 g of sodium in 375 ml of isopropanol, which solution had been diluted beforehand with 1,200 ml of hexane. The mixture was stirred for 2 hours and then left to stand overnight, after which the solvent was distilled off, water was added and the product was extracted with chloroform. The extract was dried and evaporated down to give 4-benzyl-3-oxo-7-phenyl-7-phenoxymethyl-hexahydro-1,4-oxazepine, which was processed further in crude form.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[F-].[K+].Br[C:15]([CH3:25])([CH3:24])[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O.O>CN(C)C=O>[CH3:24][C:15]1([CH3:25])[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:1][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[O:11]1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: CC(C)(Br)C(=O)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)Oc2cc([N+](=O)[O-])ccc2N=C1c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.4 %

Procedure:
To a suspension of 2-amino-5-nitrophenol (3.00 g) in N,N-dimethyl-formamide (30 mL) was added potassium fluoride (3.40 g), and the mixture was stirred at room temperature for 15 minutes, and thereto was added 2-bromo-2-methylpropiophenone (4.42 g). The mixture was stirred at room temperature for 0.5 hour, at 60° C. for 20 hours and at 80° C. for 3 days. After cooling, to the reaction mixture was added cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (solvent; n-hexane/ethyl acetate=10/1) to give 2,2-dimethyl-7-nitro-3-phenyl-2H-1,4-benzoxazine (3.65 g) as a pale yellow powder.
Reaction SMILES: O.[NH2:2]N.C[N:5]([CH:7]=[C:8]1[C:13](=O)[CH2:12][CH2:11][CH:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)C>CO>[NH:2]1[C:13]2[CH2:12][CH2:11][CH:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9][C:8]=2[CH:7]=[N:5]1
Reactant: NN
Reactant: CN(C)C=C1CC(NC(=O)OC(C)(C)C)CCC1=O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCc2[nH]ncc2C1
Yield: 55.3 %

Procedure:
Hydrazine monohydrate (0.11 mL, 2.35 mmol) was added to a solution of tert-butyl {3-[(dimethylamino)methylene]-4-oxocyclohexyl}carbamate obtained in Example (242a) (526 mg, 1.96 mmol) in methanol (10 mL), and the mixture was heated under reflux for 18 hours. The reaction solution was concentrated. The resulting residue was azeotropically distilled with toluene and then purified by silica gel column chromatography (elution solvent: dichloromethane/methanol 20/1) to obtain 257 mg of the title compound as an amorphous compound (55%).
Reaction SMILES: Cl[C:2](=[N:9][OH:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:11]([O:15][C:16]([NH:18][CH2:19][C:20]#[CH:21])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C1COCC1>[C:11]([O:15][C:16]([NH:18][CH2:19][C:20]1[O:10][N:9]=[C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:21]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: ON=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1cc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.9 %

Procedure:
A solution of α-chlorobenzaldehyde oxime (Method 22; 1 g, 6.4 mmol) in THF (13 ml) was added dropwise to a solution of N-tert-butoxycarbonyl-propargylamine (0.5 g, 3.2 mmol) and triethylamine (0.9 ml, 6.4 mmol) in THF (25 ml) cooled with an ice bath. The mixture was allowed to warm to ambient temperature and stirred for 2 days. The volatiles were removed by evaporation and the residue dissolved in DCM. The solution was washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with isohexane/ether (9:1) and collected by filtration to give the title compound (473 mg, 54%). NMR (CDCl3) 1.45 (s, 9H), 4.45 (d, 2H), 5.10 (bs, 1H), 6.5 (s, 1H), 7.42 (m, 3H), 7.8 (m, 2H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([NH:15][CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=CC(=O)OCC
Reactant: NCc1ccccc1
Product: CCOC(=O)CCNCc1ccccc1

Procedure:
The title compound is prepared according to the method of Klioze and Ehrgott (U.S. Pat. No. 4,216,218) from ethyl acrylate and benzylamine.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=O.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([NH2:23])=[O:22])=[CH:16][CH:15]=1>>[C:9]1([C@H:20]2[C@H:20]([C:17]3[CH:16]=[CH:15][C:14]([Br:13])=[CH:19][CH:18]=3)[C:21](=[O:22])[NH:23][C:21]2=[O:22])[C:3]2=[C:4]3[C:5](=[CH:6][CH:7]=[CH:2]2)[CH2:19][CH2:14][CH2:15][N:12]3[CH:10]=1
Reactant: NC(=O)Cc1ccc(F)cc1Cl
Reactant: NC(=O)Cc1ccc(Br)cc1
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1ccc(Br)cc1

Procedure:
(±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(4-bromophenyl)pyrrolidine-2,5-dione was prepared according to Example 40 replacing 2-chloro-4-fluorophenylacetamide with 4-bromophenylacetamide. Yield 33.1 mg, 8.1%. 1H NMR (DMSO-d6) 400 MHz δ: 11.55 (s, 1H), 7.53 (dt, 2H, J=8.8 2.0 Hz), 7.34 (dt, 3H, J=8.0 2.0 Hz), 7.15 (dd, 1H, J=7.6 1.0 Hz), 6.86 (m, 2H), 4.53 (d, 1H, J=8.0 Hz), 4.37 (d, 1H, J=8.0 Hz), 4.10 (t, 2H, J=1.6 Hz), 2.90 (t, 2H, J=2.0 Hz), 2.12 (t, 2H, J=1.8 Hz).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[Br:10].[Li+].CC([N-]C(C)C)C.[Li]CCCC.[C:24](=[O:26])=[O:25]>>[Br:10][C:3]1[C:2]([F:1])=[C:7]([F:8])[C:6]([F:9])=[C:5]([CH:4]=1)[C:24]([OH:26])=[O:25]
Reactant: Fc1ccc(Br)c(F)c1F
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Product: O=C(O)c1cc(Br)c(F)c(F)c1F
Reaction time: 1.25 h

Procedure:
To a solution of 2,3,4-trifluorobromobenzene in appropriate solvent is added strong base (such as LDA, nBuLi, LiHDMS) under nitrogen atmosphere. The reaction is generally carried out at low temperature (−50-−80° C., prefer −78° C.). The reaction is kept stirring for some time (0.5-12 h, preferably select 0.5-2 h) and is added dry ice. The resulting mixture is kept stirring for some time (3-12 h, prefer 5-10 h) and 5-bromo-2,3,4-trifluorobenzoic acid is obtained after conventional workup.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([I:11])=[CH:9][N:8]([CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[N:7]=1)=O)C.[BH4-].[Li+]>C1COCC1>[I:11][C:10]1[C:6]([CH2:4][OH:3])=[N:7][N:8]([CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH:9]=1
Reactant: CCOC(=O)c1nn(CCOC2CCCCO2)cc1I
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1nn(CCOC2CCCCO2)cc1I
Temperature: 60 °C
Reaction time: 5 h
Yield: 62.5 %

Procedure:
A solution of Intermediate 74c (1.22 g, 3.09 mmol) in dry THF (12 mL) was treated with lithium borohydride (0.10 g, 4.64 mmol) and the mixture was stirred at 60° C. for 5 h then stood at RT overnight. The mixture was stirred at 60° C. for a further 5 h then cautiously quenched with water and diluted with EtOAc and water. The phases were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-100% EtOAc in cyclohexane, to give the title compound as a colorless oil (0.68 g, 62%). LCMS (Method 3): Rt 2.89 min, m/z 375 [M+Na+].
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH2:18][F:19])([CH2:16][F:17])[CH:3]=1.C([Li])CCC.[CH2:25]([N:27]=[C:28]=[S:29])[CH3:26]>C(OCC)C>[CH2:25]([NH:27][C:28]([C:2]1[C:7]2[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH2:18][F:19])([CH2:16][F:17])[CH:3]=1)=[S:29])[CH3:26]
Reactant: CCN=C=S
Reactant: FCC1(CF)C=C(Br)c2cc(C(F)(F)F)ccc2O1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCNC(=S)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Reaction time: 0.03 h
Yield: 56.9 %

Procedure:
An amount (103 mg) of 4-bromo-2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyran was dissolved in diethyl ether (0.3 ml); to the solution, 1.68 M n-butyllithium (0.18 ml) was added at 0° C. under a nitrogen atmosphere. After stirring the reaction mixture for 2 minutes, a diethyl ether solution (0.3 ml) of ethyl isothiocyanate (34 mg) was added and the mixture was stirred for 2.5 hours at 0° C. The reaction mixture was diluted with diethyl ether, washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluent; hexane/ethyl acetate=4/1) to give the titled compound (60 mg) as a pale yellow crystal.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].[I-].[K+].Br[CH2:16][CH2:17][CH2:18][OH:19]>C(O)C.O>[OH:19][CH2:18][CH2:17][CH2:16][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: OCCCBr
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(OCCCO)cc1
Reaction time: 24 h
Yield: 75.6 %

Procedure:
To a solution of 4-hydroxybenzoic acid (25.0 g, 0.18 mol), potassium hydroxide (27.6 g, 0.49 mol), and potassium iodide (3.0 g, 0.018 mol) in ethanol (75 mL) and water (5 mL) was added dropwise 3-bromopropanol (25.6 g, 0.19 mol). The reaction was allowed to continue for 24 h under reflux. The solid residue was filtered off, and the filtrate was evaporated to dryness. The resultant solid was dissolved in water (200 mL) and then acidified with a 10% HCl solution. The precipitate was filtered for recrystallization from ethanol: water (1:1) to yield 1(26.7 g, 75%). 1H NMR (200 MHz, DMSO-d6): δ 1.85 (quintet, 2H, —CH2—), δ 3.55 (t, 2H, —CH2OAr), δ 4.10 (t, 2H, HOCH2—), δ 6.95 (d, 2H, aromatic ring), δ 7.85 (d, 2H, aromatic ring).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C@@H:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[C:21]([F:30])[CH:20]=2)[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:9])[CH:5]=[CH:4][C:3]=1[OH:31].Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl.CCOC(C)=O>C1COCC1>[F:30][C:21]1[CH:20]=[C:19]([C@@H:11]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[NH:10][C:8]([C:6]2[N:7]=[C:2]3[NH:1][C:33](=[O:35])[O:31][C:3]3=[CH:4][CH:5]=2)=[O:9])[CH:24]=[CH:23][C:22]=1[O:25][C:26]([F:29])([F:27])[F:28]
Reactant: Nc1nc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)ccc1O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F)c1ccc2oc(=O)[nH]c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-6-amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-hydroxypicolinamide (300 mg, 0.681 mmol) in THF (10 mL) was added TEA (689.4 mg, 0.00068 mmol, S.d fine, India) and triphosgene (242 mg, 0.0008 mmol, Sigma Aldrich, India) at 0° C. The reaction mixture was stirred for 2 h at room temperature. After completion of the reaction, monitored by TLC (TLC eluent: 50% EtOAc in petroleum ether), the reaction mixture was quenched with sat'd NaHCO3 solution and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel (60-120 mesh) column chromatography eluting with 80-100% EtOAc in petroleum ether to afford the title compound as an off white solid. 1H-NMR (400 MHz, DMSO-d6): δ 12.8 (br. s., 1H), 9.46 (d, J=7.2 Hz, 1H), 8.55 (d, J=4.4 Hz, 1H), 7.83-7.77 (m, 3H), 7.57-7.49 (m, 3H), 7.33 (d, J=8.4 Hz, 1H), 6.55 (d, J=6.8 Hz, 1H). MS (ESI, positive ion) m/z: 467.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH2:28][C:29]([OH:32])([CH3:31])[CH3:30])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH2:28][C:29]([OH:32])([CH3:30])[CH3:31])(=[O:26])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CC(C)(O)CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Product: CC(C)(O)CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
8 g of methyl 4-amino-2-chlorobenzoate was dissolved in 16 mL of MeOH, 8 mL of H2O and 8 mL of concentrated hydrochloric acid and was then cooled to 0° C. A solution of 3.9 g of sodium nitrite in 15 mL of H2O was added dropwise over 30 min. The reaction was stirred at 0° C. for an additional 1 h. The cold diazonating mixture was added to a solution of 13.8 g of potassium ethyl xanthate in 10 mL of H2O at 50˜60° C. The reaction was heated to 65° C. for 2 h and monitored by TLC until complete. The mixture was cooled to 25° C. and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. Purified by silica gel chromatography (0-10% ethyl acetate/hexane) to afford methyl 2-chloro-4-(ethoxycarbonothioylthio)benzoate. A solution of 2.6 g of sodium hydroxide in 20 mL of H2O was added to 5.9 g of methyl 2-chloro-4-(ethoxycarbonothioylthio)benzoate in 40 mL of EtOH The reaction mixture was heated to 70° C. for 1 h. Upon completion, the mixture was cooled to 25° C., and then acidified to pH 3 by the addition of 10 N HCl. The solid was filtered and washed with H2O to give 2-chloro-4-mercaptobenzonic acid. 3.8 g of 2-chloro-4-mercaptobenzonic acid in 40 mL of 5% sulfuric acid-methanol was refluxed under nitrogen atmosphere for 3 h. After concentration of the reaction mixture, 10 mL of H2O was added and the resulting mixture was made alkaline with sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated to yield methyl 2-chloro-4-mercaptobenzoate. 80 mg of isobutylene oxide was reacted with methyl 2-chloro-4-mercaptobenzoate via Procedure S to afford methyl 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoate. 190 mg of methyl 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoate was hydrolyzed via Procedure M to give 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoic acid. 160 mg of 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoic acid was reacted via procedure R to give 2-chloro-4-(2-hydroxy-2-methylpropylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to 2-chloro-4-(2-hydroxy-2-methylpropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxy-2-methylpropylsulfonyl)benzamide. MS (Q1) 479.1 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([CH2:12][CH2:13][N:14]([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[C:10]#[N:11].[CH:21]([N:24]([CH:36]([CH3:38])[CH3:37])[CH2:25][CH2:26]C(C1C=CC=CC=1)C#N)([CH3:23])[CH3:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([CH2:26][CH2:25][N:24]([CH:36]([CH3:38])[CH3:37])[CH:21]([CH3:23])[CH3:22])([CH2:12][CH2:13][N:14]([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:16])[CH3:17])[C:10]#[N:11]
Reactant: CC(C)N(CCC(C#N)c1ccccc1)C(C)C
Reactant: CC(C)N(CCC(C#N)c1c(Cl)cccc1Cl)C(C)C
Product: CC(C)N(CCC(C#N)(CCN(C(C)C)C(C)C)c1c(Cl)cccc1Cl)C(C)C

Procedure:
Substitution of an equivalent quantity of the preceding acetonitrile for α-[2-(diisopropylamino)ethyl]-α-phenylacetonitrile called for in Example 2, Method B and substantial repetition of the procedure detailed in that example, affords α-(2,6-dichlorophenyl)-α,α-bis[2-(diisopropylamino)ethyl]acetonitrile, as an oil boiling at about 180°-185° C. at 0.3 mm. pressure.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3]C.N1CCOCC1.[CH3:12][O:13][C:14]([C:16]1[C:20](=O)O[C:18]2=[CH:22][CH:23]=[C:24]([CH:27]([CH3:29])[CH3:28])[CH:25]=[CH:26][C:17]=12)=[O:15]>C(O)C>[CH3:12][O:13][C:14]([C:16]1[C:17]2[C:18]([CH:22]=[CH:23][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:25][CH:26]=2)=[C:1]([CH2:2][CH3:3])[CH:20]=1)=[O:15]
Reactant: CCCC=O
Reactant: COC(=O)c1c2ccc(C(C)C)ccc-2oc1=O
Solvent: C1COCCN1
Solvent: CCO
Product: CCc1cc(C(=O)OC)c2ccc(C(C)C)ccc1-2

Procedure:
n-Butyraldehyde (61.5 g, 0.853 mole) and morpholine (61.9 g, 0.71 mole) are added to cooled ethanol (400 ml), and then the compound (5) (68 g, 0.276 mole) is added thereto. The obtained mixture is stirred and warmed to dissolve the solid substance homogeneously. It is heated under reflux for 8 hours, and then the solvent is distilled off under reduced pressure to precipitate an oily material. The obtained oily material is dissolved in benzene (450 ml), washed twice with the same volume of water, three times with 1N HC1 (400 ml), and further twice with water (400 ml). The obtained benzene solution is passed through alumina (500 g), and the eluted solution is concentrated to obtain the compound (1) at a yield of 57.4 g, 81.2%. It is recrystallized in n-hexane to give the purified product (55 g) in the purple crystalline form.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.C1C(=O)N([Br:20])C(=O)C1>C(#N)C>[NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([Br:20])=[C:6]([F:8])[CH:7]=1
Reactant: COC(=O)c1ncc(F)cc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COC(=O)c1nc(Br)c(F)cc1N
Yield: 41 %

Procedure:
To a solution of methyl 3-amino-5-fluoropicolinate (1.0 equiv.) in acetonitrile (0.3 M solution) was added NBS (1.1 equiv.) for 2 minutes at room temperature. After quenched with water, the reaction mixture was extracted with EtOAc. The crude product was purified by silica column chromatography (20% to 50% EtOAc in hexanes) to give methyl 3-amino-6-bromo-5-fluoropicolinate, (41%). LCMS (m/z): 249.1 (MH+); LC Rt=2.80 min.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12]OS(C3C=CC(C)=CC=3)(=O)=O)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH2:28]([NH:30][CH2:31][CH2:32][CH3:33])[CH3:29]>C(#N)C>[CH2:28]([N:30]([CH2:12][CH:8]1[O:7][C:6]2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:3]=[C:2]([F:1])[C:11]=2[O:10][CH2:9]1)[CH2:31][CH2:32][CH3:33])[CH3:29]
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: CCCNCC
Solvent: CC#N
Product: CCCN(CC)CC1COc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 42 using [5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), N-ethylpropan-1-amine (0.5 ml), ACN (2.5 ml). MS m/z (rel. intensity, 70 eV) 331 (M+, 0.5), 101 (7), 100 (bp), 98 (8), 58 (8).