Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[F-].[K+].[Si]([C:8]([F:11])([F:10])[F:9])(C)(C)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:24]2[C:32]3[C:27](=[C:28]([N:33]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[S:34]([CH3:37])(=[O:36])=[O:35])[CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25]2)([CH2:22][CH3:23])[C:20]#[CH:21])=[CH:15][CH:14]=1>CN(C=O)C.[Cu]I>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:24]2[C:32]3[C:27](=[C:28]([N:33]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[S:34]([CH3:37])(=[O:36])=[O:35])[CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25]2)([C:22]#[C:23][C:8]([F:11])([F:10])[F:9])[CH2:20][CH3:21])=[CH:15][CH:14]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C#CC(CC)(c1ccc(Cl)cc1)n1ccc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C#CC(F)(F)F)(c1ccc(Cl)cc1)n1ccc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A three-neck round-bottom flask was charged with CuI (38 mg, 0.2 mmol), Phen.H2O (40 mg, 0.2 mmol), KF (58 mg, 1.0 mmol) and stirring bar. The flask was dried at 130° C. in vacuo for 3 h. After cooling to RT, the flask was backfilled with air and TMSCF3 (142 mg, 1.0 mmol), DMF (2 mL) was added. Then the flask was heated to 130° C. for 30 min. A solution of N-(1-(3-(4-chlorophenyl)pent-1-yn-3-yl)-1H-indol-4-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)methanesulfonamide (102 mg, 0.2 mmol, enantiomer A) in DMF (1 mL) was slowly added to the mixture at 130° C. over 1 h. The resulting mixture was stirred for another 1 h at 130° C. The crude product was purified by Combiflash (mobile phase: CH3CN/water (0.08% of NH4HCO3)) to give the title compound. LC/MS m/z=606.7 [M+Na]
Reaction SMILES: [CH2:1]([C:3]1([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH:14]=[CH:13][C:12]=3[CH:16]=2)[O:7][CH2:6][CH2:5][O:4]1)[CH3:2].[Li]CCCC.CCCCCC.[Cl:28]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:28][C:14]1[O:15][C:11]2[CH:10]=[CH:9][C:8]([C:3]3([CH2:1][CH3:2])[O:4][CH2:5][CH2:6][O:7]3)=[CH:16][C:12]=2[CH:13]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CCC1(c2ccc3occc3c2)OCCO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC1(c2ccc3oc(Cl)cc3c2)OCCO1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 64.2 %

Procedure:
To a stirred solution of 5-(2-ethyl-1,3-dioxolan-2-yl)benzofuran (350 mg, 1.0 eq) in 20 mL anhydrous THF was added 2.5 M n-BuLi solution in hexane (1.6 mL, 2.4 eq) dropwise at 0° C., and the mixture was stirred at 0° C. for 50 min under nitrogen. A solution of hexachloroethane (915 mg, 2.4 eq) in 10 mL anhydrous THF was added dropwise. The reaction was stirred at rt for 1 h, quenched with sat NH4Cl (aq), and extracted with EtOAc. The extract was dried, concentrated, and purified by column chromatography to give the desired product (260 mg, 65%). 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=0.4 Hz, 1H), 7.37-7.38 (m, 2H), 6.57 (s, 1H), 4.01-4.05 (m, 2H), 3.77-3.80 (m, 2H), 1.94 (q, J=7.6 Hz, 2H), 0.88 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH3:23])[C:20]([S:24][CH:25]5[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]5)=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:34])=[N:5]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:36].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[C:20]([S:24]([CH:25]5[CH2:26][CH2:27][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:29][CH2:30]5)=[O:36])[C:21]([CH3:23])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][C:6]([CH3:34])=[N:5]1)([CH3:2])[CH3:3]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(SC4CCN(C(C)C)CC4)c(C)cc2OCC3)n(C(C)C)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2cc(S(=O)C4CCN(C(C)C)CC4)c(C)cc2OCC3)n(C(C)C)n1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To an ice-cooled solution of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-9-(1-isopropylpiperidin-4-ylsulfanyl)-8-methyl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene from Example 32 (112 mg, 0.233 mmol) in DCM (10 mL) was added TFA (90 μL, 1.165 mmol) followed by a solution of m-CPBA (44 mg, 0.256 mmol) in DCM (2 mL). The resulting mixture was stirred for 20 min at 0° C. then volatiles were removed under reduced pressure. The crude material was purified by column chromatography (C18, gradient 20-50% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3 in MeOH affording 225 as a white solid (100 mg, 87%). LCMS: RT 2.60 min [M+H]+ 497.1. 1H NMR (DMSO, 400 MHz): δ 8.72 (1H, s), 7.89 (1H, s), 7.00 (1H, s), 5.72-5.60 (1H, m), 4.62-4-47 (4H, m), 2.80 (2H, t, J=11.82 Hz), 2.72-2.57 (2H, m), 2.33 (3H, s), 2.25 (3H, s), 2.18-2.00 (2H, m), 1.81 (1H, bd, J=12.17 Hz), 1.63-1.38 (9H, m), 0.89 (6H, d, J=6.54 Hz)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:25])([F:26])[F:27])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C#N)c(C(F)(F)F)c2)CC1
Temperature: 100 °C
Yield: 68 %

Procedure:
A mixture of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (200 mg; 1.0 mmol), 4-fluoro-2-trifluoromethyl-benzonitrile (208 mg; 1.01 mmol) and potassium carbonate (276 mg; 2.0 mmol) in dimethylsulfoxide (3 mL) is heated to 100° C. over night. Water is then added and the precipitate formed is collected to afford the desired compound (250 mg; 0.68 mmol).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1Oc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
2-Fluoronitrobenzene (1.5 g) and 4-chlorophenol (1.3 g) were dissolved in dimethylformamide (20 ml) and potassium carbonate (1.4 g) was added thereto. The mixture was stirred overnight at 80° C. After the mixture was cooled, water (100 ml) was added thereto and the mixture was extracted with ethyl acetate (50 ml×2). The mixture was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was re-crystallized from methanol, to thereby yield the target compound (2.2 g) as pale-yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]([F:33])([C:29]([F:32])([F:31])[F:30])[CH2:20]OS(C(F)(F)F)(=O)=O>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:20][C:19]([F:33])([F:18])[C:29]([F:32])([F:31])[F:30])=[CH:7][N:6]=1)=[O:4]
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(OCC(F)(F)C(F)(F)F)cn1

Procedure:
In a manner analogous to that described in example 30a), the alkylation of the 5-hydroxy-pyridine-2-carboxylic acid methyl ester with potassium carbonate and trifluoro-methanesulphonic acid 2,2,3,3,3-pentafluoropropyl ester yielded the 5-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid methyl ester as a light yellow oil. MS (ISP): m/z=285 [M]+. b) In a manner analogous to that described in example 30b), the hydrolysis of the 5-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid methyl ester with lithium hydroxide yielded the 5-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid as a white solid. MS (ISP): m/z=271 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.CC(C)=[O:14].Cl>CO>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:14])[CH2:1]1
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Reactant: CC(C)=O
Agent: Cl
Solvent: CO
Product: CC1(C)CC(=O)CC(C)(C)N1
Temperature: 60 °C
Yield: 140 %

Procedure:
A solution of 19.2 g. of acetonine in 70 g. of acetone was added with 7 g. of methanol. Then, 0.9 g. of dry gaseous hydrogen chloride was introduced therein and absorbed. The solution was sealed and heated at 60°C. for 10 hours to effect the reaction. After completion of the reaction, the reaction mixture was purified in the same manner as in Example 1 to obtain triacetonamine in a yield of 140%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH2:23][CH3:24])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:12]2[N:11]=1)[CH3:2].[Cl:25][S:26](O)(=[O:28])=[O:27]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:26]([Cl:25])(=[O:28])=[O:27])=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH2:23][CH3:24])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:12]2[N:11]=1)[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CCCc1nc(CC)c2c(=O)[nH]c(-c3ccccc3OCC)nn12
Product: CCCc1nc(CC)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0° C., 1.70 g (5.21 mmol) of 2-(2-ethoxy-phenyl)-5-ethyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one are added slowly to 3.12 ml of chlorosulphonic acid. The reaction mixture is stirred at room temperature overnight and then poured into ice-water and extracted with dichloromethane. This gives 2.10 g (94%) of a colourless foam.
Reaction SMILES: [CH2:1]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[Na+:13].CC(O)C.[C:18](=[S:20])=[S:19]>>[CH2:7]([N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:18](=[S:19])[S-:20])[CH2:8][CH2:9][CH2:10][CH3:11].[Na+:13]
Reactant: CCCCCNCCCCC
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCCCCN(CCCCC)C(=S)[S-]

Procedure:
To a 250 mL 3-neck round bottom reaction flask equipped with an overhead stirrer, a thermocouple probe, a reflux condenser, a Claisen adapter, and a 25 mL addition funnel, 30.0 g (0.19 mol) of diamyl amine, 15.3 g of a 50 weight percent NaOH solution (0.19 mol NaOH) and 100 mL reagent 2-propanol was added. 12.5 mL (0.21 mol) carbon disulfide was charged to the addition funnel. Carbon disulfide was added over a half-hour period. The reaction temperature was maintained at 25°-30° C. The product was post-reacted at 25° C. for 1 hour.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18]C)=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1.N[C:21]1N=C(C2C=C(Br)C=CC=2O)C=C(Cl)N=1>CC(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH:17]([CH3:18])[CH3:21])=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1
Reactant: Nc1nc(Cl)cc(-c2cc(Br)ccc2O)n1
Reactant: CCCOc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Solvent: CC(C)O
Product: CC(C)Oc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Yield: 68 %

Procedure:
Following the method described in Example 135 for the synthesis of 4-(5-bromo-2-propoxy-phenyl)-6-chloro-pyrimidin-2-ylamine, 2-(2-amino-6-chloro-pyrimidin-4-yl)-4-bromo-phenol and 2-propanol provided 4-(5-bromo-2-isopropoxy-phenyl)-6-chloro-pyrimidin-2-ylamine (68% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1>>[C:34]([O:33][C:31]([N:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([F:16])[C:13]([CH3:17])=[CH:12][C:11]=3[O:18][CH3:19])=[CH:6][N:5]=2)[CH2:26][CH2:27]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCS(=O)c1ncc(C(=O)c2cc(F)c(C)cc2OC)c(N)n1
Product: COc1cc(C)c(F)cc1C(=O)c1cnc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc1N

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-4-methyl-phenyl)-methanone (Example 341) and 4-amino-1-Boc-piperidine (Astatech) to give 4-[4-amino-5-(5-fluoro-2-methoxy-4-methyl-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester as a white solid. MS (M+H)+, 460.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].[Br:15][CH2:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH2:18][CH2:17][CH2:16][Br:15])=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=1[OH:10])(=[O:12])[CH3:13]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCCBr)ccc(C(C)=O)c1O

Procedure:
A mixture of 2,4-dihydroxy-3-propylacetophenone (2.7 g), 1,3-dibromopropane (2.8 ml) and potassium carbonate (1.9 g) in acetone (50 ml) was refluxed for 3 hours. Insoluble materials were filtered off, and the filtrate was concentrated. The resulting syrup was purified by means of a silica gel flash chromatography (chloroform-hexane=1:1) to give 3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl bromide (2.9 g) as colorless and transparent syrup.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])=[CH:11][CH:10]=1)(O)[CH3:7])C.Cl.O=S(Cl)Cl>ClCCl>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([CH:6]([CH3:7])[CH2:5][C:4]([OH:23])=[O:3])=[CH:10][CH:11]=1
Reactant: CCOC(=O)CC(C)(O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
A solution of 3.2 g. of 3-(2',4'-difluoro-4-biphenylyl)-3-hydroxybutyric acid ethyl ester in 10 ml. of dichloromethane is saturated with dry HCl gas and 1 ml. of SOCl2 is added. The mixture is warmed to 50° for 2 hours and solvent is removed. The residue, 3'(2',4'-difluoro-4-biphenylyl)-3-chlorobutyric acid ethyl ester, is dissolved in 100 ml. of methanol and hydrogenated on 100 mg. of platinum oxide under normal pressure at 25°. The precipitate is filtered off. A solution of 0.4 g. of NaOH in 5 ml. of water is added to the filtrate. The mixture is heated under reflux for 2 hours and evaporated and the residue is dissolved in water and worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)butyric acid, m.p. 109°-110°.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].[C:11]([N:19]=[C:20]=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(C)=O>[C:11]([NH:19][C:20]([NH:7][C:6]1[CH:8]=[C:2]([Br:1])[C:3]([F:10])=[CH:4][C:5]=1[F:9])=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1cc(Br)c(F)cc1F
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1cc(Br)c(F)cc1F)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
To a solution of 5-bromo-2,4-difluoro aniline (1.0 g, 4.81 mmol) in acetone (25.0 mL) was added drop wise benzoyl isothiocyanate (0.71 mL, 5.29 mmol). The resulting reaction mixture was allowed to stir at room temperature for 30 min. After the completion of the reaction (TLC monitoring), the solvent was evaporated and the residue was washed with hexane and ether to get the title compound (1.70 g, quantitative yield) as a white solid. 1H-NMR (400 MHz, CDCl3): δ 7.02-7.06 (m, 1H), 7.56 (t, J=8.0 Hz, 2H), 7.68 (t, J=7.60 Hz, 1H), 7.91 (d, J=7.60 Hz, 2H), 8.67 (t, J=7.60 Hz, 1H), 9.15 (br s, 1H) and 12.65 (br s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:16]=[CH:15][CH:14]=[C:8]2[C:9]([NH:11][C:12](=[O:13])[C:7]=12)=[O:10].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C(OCC)C>[N:17]1([CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:16]=[CH:15][CH:14]=[C:8]3[C:9]([NH:11][C:12](=[O:13])[C:7]=23)=[O:10])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: O=C1NC(=O)c2c(CCCCBr)cccc21
Reactant: C1COCCN1
Solvent: CCOCC
Product: O=C1NC(=O)c2c(CCCCN3CCOCC3)cccc21

Procedure:
4-Bromobutylphthalimide (564 mg; 2.0 mmoles) and morpholine (0.35 ml; 4.0 mmoles) were dissolved in anhydrous ethyl ether (5 ml). Reaction times and process as per Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:12])[CH:4]=1.[C:13](=O)([O:16]C)[O:14]C.[Li+].CC([N-]C(C)C)C>C1COCC1>[C:13]([CH2:12][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])([OH:16])=[O:14]
Reactant: COc1ccc(C(=O)O)c(C)c1
Reactant: COC(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)c(CC(=O)O)c1
Reaction time: 4 h
Yield: 95.2 %

Procedure:
A mixture of 4-methoxy-2-methylbenzoic acid (10 g, 60 mmol) and dimethyl carbonate (10 ml, 120 mmol) in THF (80 ml) is added dropwise to LDA (120 ml of 2M in heptane/THF/ethylbenzene) at −78° C. The cold bath is removed, and after 4 h, water (100 ml) is added, and the resulting mixture is stirred overnight. After removal of organic solvents, the residue is acidified with c-HCl to pH 2. The resulting solid is filtered, dissolved in 1N—NaOH (80 ml), and then washed with ether (2×30 ml). The aqueous layer is acidified with c-HCl and the resulting white solid is filtered to give 12 g of 2-carboxymethyl-4-methoxy-benzoic acid. 1H NMR (DMSO) 12.3 (br s, 1H), 7.88 (d, 1H), 6.91 (d, 1H), 6.88 (s, 1H), 3.90 (s, 2H), 3.79 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[OH:12].Cl[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[N:15]=1.O>O1CCOCC1>[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[O:12][C:18]1[CH:19]=[CH:14][N:15]=[C:16]([NH:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[N:17]=1
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: N#Cc1ccc(Nc2nccc(Cl)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(Oc2ccnc(Nc3ccc(C#N)cc3)n2)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.3 %

Procedure:
To a suspension of NaH (0.006 mol) in 1,4-dioxane (30 ml), 2,4,6-trimethyl-phenol (0.006 mol) was added. The mixture was stirred for 15 minutes at room temperature, and a clear solution formed. 4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (0.004 mol) was added, and the reaction mixture was heated to reflux under Argon for 15 hours. The reaction mixture was allowed to cool to room temperature, 0.5 ml of water was added, followed by 4 g of silica gel, and the solvent was evaporated. The residue was purified by flash column chromatography over silica gel (eluent gradient: CH2Cl2:CH3OH 100:0:0 to 97:3). The pure fractions were collected and the solvent was evaporated, yielding 1.18 g (89.4%) of 4-[[4-(2,4,6-trimethylphenoxy)-2-pyrimidinyl]amino]benzonitrile (comp. 20).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17]C)[CH:15]=[CH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[N:19]1([CH2:25][CH2:26][O:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[Cl-].[Cl-].[Cl-].[Al+3].C(S)C>ClCCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:10]=3[C:9]=2[C:32]([C:31]2[CH:35]=[CH:36][C:28]([O:27][CH2:26][CH2:25][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:29][CH:30]=2)=[O:33])=[CH:4][CH:3]=1
Reactant: COc1ccc2cc(-c3ccc(F)cc3)sc2c1
Reactant: O=C(Cl)c1ccc(OCCN2CCCCC2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCS
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(F)cc2)sc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the product from Example 17, Step 1 (83 mg, 0.32 mmol) and 4-(2-Piperidin-1-yl-ethoxy)-benzoyl chloride (1.39 mL, 0.39 mmol) in 3.3 mL of 1,2-dichloroethane was added, in two portions, aluminum trichloride (322 mg, 2.4 mmol) and the reaction was heated at reflux for 1 hr. At this time the coupling was complete and demethylation was carried out cooling the reaction to room temperature, adding ethanethiol (0.10 mL, 1.41 mmol) dropwise and stirring at room temperature for a further 1.5 hrs. The reaction was quenched with saturated sodium bicarbonate solution and extracted twice with methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was chromatographed on silica gel using 1% MeOH:methylene chloride to 3% MeOH:methylene chloride as the gradient eluant to yield the title compound.
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:23][C:24]1[N:29]=[C:28]([NH2:30])[CH:27]=[CH:26][CH:25]=1>>[N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:30][C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:23])[N:29]=3)=[O:19])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cccc(N)n1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Product: Cc1cccc(NC(=O)c2ccc(S(=O)(=O)N3CCCc4ccccc43)cc2)n1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with 6-methylpyridin-2-amine (28 mg, 0.26 mmol) using method C. The residue was purified using flash chromatography eluting with 0-30% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(6-methylpyridin-2-yl)benzamide as a white solid. Yield: 14 mg (13%). 1H-NMR: 10.95 (s, 1H), 8.08 (d, J=8.5 Hz, 2H), 7.96 (d, J=8.5 Hz, 1H), 7.73 (t, J=8.0 Hz, 1H), 7.69 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.5 Hz, 1H), 7.24-7.18 (m, 1H), 7.12-7.07 (m, 2H), 7.04 (d, J=7.5 Hz, 1H), 3.82-3.78 (m, 2H), 2.47-2.42 (m, 5H), 1.65-1.57 (m, 2H).