Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([S:9][CH2:10][C:11]([N:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15][CH2:14]3)=[O:12])[S:8][C:4]=2[CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].CCN(CC)CC.[OH-].[Na+]>C(Cl)Cl.CO.C1COCC1>[N:13]1([C:11](=[O:12])[CH2:10][S:9][C:7]2[S:8][C:4]3[CH:3]=[C:2]([NH:1][S:26]([CH3:25])(=[O:28])=[O:27])[CH:24]=[CH:23][C:5]=3[N:6]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: Nc1ccc2nc(SCC(=O)N3CCCc4ccccc43)sc2c1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc2nc(SCC(=O)N3CCCc4ccccc43)sc2c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a 0° C. solution of compound 49 (170 mg, 0.48 mmol) in dry CH2Cl2 (5 mL) were added methanesulfonyl chloride (78 μL) followed by dropwise addition of Et3N (0.13 mL). The reaction was stirred for 2.5 h under N2 at room temperature. The reaction mixture was diluted with CH2Cl2 (40 mL), washed with 1N HCl (10 mL), water (2×10 mL), and saturated NaCl (2×10 mL). Dried over MgSO4 and filtered. The solvent was removed under reduced pressure, and the product was purified by column chromatography (EtOAc/hexanes 4:1) to afford a mixture of mono and bis-sulfonamides (215 mg). To a solution of the mixture of mono and bis-sulfonamides (200 mg) in 3 mL of MeOH and THF (2:1) was added NaOH (38 mg in 0.1 mL of H2O). The reaction was stirred for 45 min. at room temperature. Most of the solvent was evaporated under vacuum, the residue was dissolved in water (15 mL), and extracted with EtOAc. The combined organics were dried over MgSO4 and filtered. The solvent was removed under reduced pressure, and the product was purified by column chromatography (EtOAc/hexanes 2:1) to afford 53 as a white solid (120 mg); MS m/z: 434 (M+H)+. Anal. Calcd. For, C19H19N3O3S3.0.1H2O: C, 52.39; H, 4.86; N, 9.65; S, 22.08. Found: 52.06; H, 4.57; N, 9.45; S, 21.80.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:37])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:30]([C:35]#[N:36])=[N:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[OH:8][CH2:9][C:10]1([CH3:37])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:30]([C:35]#[N:36])=[N:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5cccnc5C#N)cc4)CC3)n2CCS1
Agent: Cl
Solvent: CO
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5cccnc5C#N)cc4)CC3)n2CCS1
Yield: 96.7 %

Procedure:
A solution of the compound (421 mg, 0.79 mmol) obtained in Example 44-1) and 4 M hydrochloric acid (1,4-dioxane solution, 1 mL) in methanol (4 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (319 mg, 97%) as a colorless solid.
Reaction SMILES: [S:1]1[C:5]2[C:6]([C:10](Cl)=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[CH:13]1[CH:14]=[CH:15][C:16](/[CH:19]=[CH:20]/[CH2:21][OH:22])=[CH:17][CH:18]=1.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[S:1]1[C:5]2[C:6]([C:10]([O:22][CH2:21][CH:20]=[CH:19][C:16]3[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=3)=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: O=C(Cl)c1cccc2nnsc12
Reactant: OC/C=C/c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCC=Cc1ccccc1)c1cccc2nnsc12
Temperature: 0 °C

Procedure:
3 g of benzo-1,2,3-thiadiazole-7-carboxylic acid chloride in 25 ml of dichloromethane are added dropwise at 15° C., with cooling and stirring, to a solution of 2.3 g of cinnamic alcohol, 3.5 g of triethylamine and a spatula tip of 4-dimethylaminopyridine in 13 ml of dichloromethane, the mixture is stirred for 16 hours at room temperature, ice-water is added, and the aqueous phase is extracted with dichloromethane. The extracts are washed with water, dried over Na2SO4 and concentrated by evaporation. The solid residue is triturated with a small amount of diethyl ether, yielding the title compound with a melting point of 70°-72° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:10]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])(=[O:14])[C:11]([CH3:13])=O>>[CH2:16]([O:15][C:10](=[O:14])[C@H:11]([CH3:13])[NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: CC(=O)C(=O)OCC(C)C
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: CC(C)COC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and iso-butyl pyruvate (prepared by following General Procedure AO above), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.55 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant);
Reaction SMILES: [Cl:1][C:2]([C:12]#[N:13])([CH2:8][CH2:9][CH:10]=[O:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:14](CC(OCC)=O)#N.ClC(Cl)(C#N)C(OCC)=O.C([O-])([O-])=O.[K+].[K+].C(=O)/C=C/C>CCOC(C)=O>[Cl:1][C:2]([C:12]#[N:13])([CH:8]([CH3:14])[CH2:9][CH:10]=[O:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(Cl)(C#N)CCC=O
Reactant: CCOC(=O)CC#N
Agent: C/C=C/C=O
Agent: CCOC(=O)C(Cl)(Cl)C#N
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cl)(C#N)C(C)CC=O
Yield: 34 %

Procedure:
Following the procedure for the preparation of ethyl 2-chloro-2-cyano-5-oxopentanoate (Example 1), 37.6 g of ethyl cyanoacetate, 60.5 g of ethyl dichlorocyanoacetate, 350 mL of EtOAc, 1.7 g of K2CO3, and 56 mL of crotonaldehyde were allowed to react for an extended period of time. The title compound was obtained in 34% yield after workup and distillation (b.p. 115° C./1.0 mm Hg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[S:30][C:11]3=[N:12][C:13]([N:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)=[CH:14][C:15](=[O:16])[N:10]3[N:9]=2)[CH:5]=[N:6][CH:7]=1.CC(OC([NH:38][CH2:39][C:40](O)=[O:41])=O)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[NH2:38][CH2:39][C:40]([NH:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[S:30][C:11]3=[N:12][C:13]([N:17]4[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]4)=[CH:14][C:15](=[O:16])[N:10]3[N:9]=2)[CH:3]=1)=[O:41]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)n3nc(-c4cncc(N)c4)sc3n2)CC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: NCC(=O)Nc1cncc(-c2nn3c(=O)cc(N4CCNCC4)nc3s2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 110.1 %

Procedure:
To a solution of tert-butyl 4-(2-(5-aminopyridin-3-yl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate (20 mg, 0.047 mmol) in DMF (1 ml) is added Boc-gly-OH (16 mg, 0.093 mmol), HATU (35 mg, 0.093 mmol) and Hunig's base (0.024 mmol, 0.14 mmol) and the mixture is stirred at room temperature for 3 h. EtOAc (10 ml) is added and the solution is washed with H2O and brine. The organic layer is dried over Na2SO4. After removing EtOAc in vacuo, the residue is purified by Biotage column chromatography (MeOH/DCM: 1/100 to 1/10 gradient) to give the desired product (20 mg, 73%).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18](B(O)O)[CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:18]3[CH:17]=[CH:16][N:15]=[C:14]([O:13][CH3:12])[CH:19]=3)=[CH:3][N:4]=2)[CH:7]=1
Reactant: Clc1ccc2ncc(Br)n2c1
Reactant: COc1cc(B(O)O)ccn1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2cnc3ccc(Cl)cn23)ccn1

Procedure:
To a solution of 3-bromo-6-chloro-imidazo[1,2-a]pyridine (1 eq, 0.72 mmol, 0.2 g), 2-methoxypyrid-4-yl boronic acid (1.0 eq, 0.72 mmol, 0.11 g), Na2CO3 (2 eq, 1.44 mmol, 0.152 g) in dioxane (0.6 ml) and water (0.2 ml), under an inert atmosphere of argon is added bis(triphenylphosphine)palladium II chloride (50 mg). The reaction mixture is heated using microwave radiation at 100° C. for 2 hours. The mixture is diluted with H2O (50 ml) and extracted with EtOAc. The combined organic portions are washed with brine, dried (MgSO4) and concentrated in vacuo. The residue is purified by flash chromatography on silica eluting with 0-25% EtOAc in iso-hexane to afford the title compound; [M+H]+=260 (262).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[C:4]([F:12])[CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[C:4]([F:12])[CH:3]=1
Reactant: COC(=O)c1ccc(N)cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1ccc(CO)c(F)c1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 74.3 %

Procedure:
To a 250 ml three necked round bottom flask, methyl 4-amino-2-fluorobenzoate (2.75 g, 0.0162 mole) was added in anhydrous THF (60 ml) under nitrogen atmosphere and cooled to 0-5° C. After 15 minutes, 2.0 M solutions of LAH in THF (24.3 ml, 0.0487 mole) was added dropwise and stirred for 10 min. The reaction mixture was allowed to warm up to room temperature and stirred at same temperature for 1 hr. After completion of the reaction, the reaction mixture was cooled to 5° C. and quenched with sat. NH4Cl (25 ml) and diluted with water (100 ml) followed by extraction with ethyl acetate. The combined organics were washed with water, dried over sodium sulphate and evaporated to afford brown solid (crude) product which was purified using column purification by eluting the compound with 20% ethyl acetate in hexanes to yield 1.7 g of (4-amino-2-fluorophenyl)methanol.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12]C)=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH-].[Na+]>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)c1ccc2[nH]ncc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2[nH]ncc2c1
Yield: 89 %

Procedure:
To a stirred solution of methyl 1H-indazole-5-carboxylate (500 mg, 2.84 mmol) in MeOH (15 mL) is added sodium hydroxide (20 mL of 2.5% aqueous solution). The mixture is heated at reflux for 1 h, followed by removal of the methanol in vacuo. The remaining aqueous solution is washed with EtOAc (5 mL), acidified with 1 N aqueous HCl to pH˜5-6. The resulting precipitate is collected by filtration, washed with water and dried in vacuo to afford 410 mg (89%) of 1H-indazole-5-carboxylic acid as a tan solid: IR (diffuse reflectance) 3290, 3115, 2964, 2954, 2813, 2606, 2557, 2505, 1687, 1627, 1321, 1274, 948, 937, 769 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 13.4 12.7, 8.5 8.2, 7.9, 7.6.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:13]=1[O:26]C)[CH:8]=[CH:7]2.B(Br)(Br)Br.C(Cl)Cl>O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[C:16]([C:18]([CH3:19])([CH3:20])[CH3:21])[CH:15]=[C:14]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:13]=1[OH:26])[CH:8]=[CH:7]2
Reactant: COc1c(-c2ccc3cccc(Br)c3n2)cc(C(C)(C)C)cc1C(C)(C)C
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1cc(-c2ccc3cccc(Br)c3n2)c(O)c(C(C)(C)C)c1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A mixture of 8-bromo-2-(3,5-di-tert-butyl-2-methoxyphenyl)quinoline (4.89 g, 11.5 mmol), BBr3 (1.63 mL, 18 mmol), and CH2Cl2 (50 mL) is stirred for 4 h at 20° C. The reaction mixture is then diluted with cold water (100 mL). The organic phase is separated, washed with water and brine, and then concentrated. The residue is recrystallized from hexane/benzene. Yield: 3.3 g (70%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:11][C:12]2[CH:16]=[C:15]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[O:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)=[O:5])C>CO.C1COCC1.O>[Cl:22][C:19]1[S:18][C:17]([C:15]2[O:14][N:13]=[C:12]([CH2:11][N:7]3[CH:8]=[CH:9][CH:10]=[C:6]3[C:4]([OH:5])=[O:3])[CH:16]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cccn1Cc1cc(-c2ccc(Cl)s2)on1
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccn1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Yield: 119.6 %

Procedure:
To a solution of 1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-pyrrole-2-carboxylic acid ethyl ester (135 mg) in MeOH/THF/H2O (3:1:1, 5 mL) was added LiOH monohydrate (100 mg). The mixture was refluxed for 2 h after which it was cooled to RT and concentrated. The mixture was acidified by the addition of 1 N aqueous KHSO4 solution and extracted with ethyl acetate. The combined organic phases were dried (MgSO4) and concentrated in vacuo to provide crude 1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-pyrrole-2-carboxylic acid (148 mg) which was directly used in the next step. MS (ESI−): m/e=307 [M−H]−, chloro pattern.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C([O-])(O)=O.[Na+].[O-]S([O-])=O.[Na+].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:6]
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(C(O)C(F)(F)F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(Br)cc(C(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-bromo-5-(2,2,2-trifluoro-1-hydroxyethyl)benzoate (8.8 g, 24.8 mmol) in dichloromethane (124 mL) was added Dess-MartinPeriodinane (15.8 g, 37.2 mmol). The mixture was stirred at ambient temperature. After 2 h, saturated NaHCO3 and saturated Na2SO3. The mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with water (6×), brine, dried over sodium sulfate, filtered and concentrated.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[F:10][C:11]([F:38])([C:28]([F:37])([F:36])[C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])[CH2:12][CH2:13][CH2:14][CH2:15]OC1(C)C=CC(S([O-])(=O)=O)=CC1>CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:15][CH2:14][CH2:13][CH2:12][C:11]([F:10])([F:38])[C:28]([F:36])([F:37])[C:29]([F:34])([F:35])[C:30]([F:31])([F:32])[F:33])=[C:4]([F:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: CC1(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C=CC(S(=O)(=O)[O-])=CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1cc(Br)ccc1OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 24 h

Procedure:
To a solution of commercially available 4-bromo-2-fluorophenol (25) (1 equi.) and 4-(5,5,6,6,7,7,8,8,8-nonafluoro-octyloxy)-tosylate (10) (1 equi.) in DMF (3 mL/mmole), cesium carbonate (1.25 equi.) was added at room temperature. The reaction mixture was stirred at that temperature for 24 h, quenched with water, extracted with ethyl acetate:hexane(1:1), washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by chromatography on silica gel (5% EtOAc/hexanes) and recrystallization from acetonitrile afforded 4-bromo-2-fluoro-1-(5,5,6,6,7,7,8,8,8-nonafluoro-octyloxy)-benzene (26) a colorless oil (87%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:34]([F:35])=[CH:33][C:32]([F:36])=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:37])=[CH:20][N:19]=1>>[Cl:37][C:21]1[C:22]([NH:24][C:25]2[C:34]([F:35])=[CH:33][C:32]([F:36])=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CNC(=O)c1cc(F)cc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cc(F)cc(F)c1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamino]-pyrimidin-4-ylamino}-3,5-difluoro-N-methyl-benzamide was prepared from 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3,5-difluoro-N-methyl-benzamide in an analogous manner to Example 1221d. Title compound was isolated as a white solid (91 mg, 58%). HPLC purity 99%, LCMS 517.14 (M+H), 1H-NMR (DMSO-D6, 400 MHZ) Δ 9.66 (s, 1H), 9.33 (s, 1H), 9.01 (s, 1H), 8.48 (d, J=4.9 Hz, 1H), 8.16 (s, 1H), 7.60-7.58 (m, 1H), 7.39 (d, J=8.6 Hz, 1H), 7.29 (s, 1H), 7.22 (d, J=8.8 Hz, 1H), 6.95 (8.1 Hz, 1H), 3.69-3.67 (m, 2H), 3.57-3.54 (m, 2H), 3.44-3.42 (m, 2H), 3.408 (s, 3H), 3.20-3.17 (m, 2H), 3.10-3.02 (m, 2H), 2.80 (s, 3H), 2.79-2.70 (m, 2H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20]([C@@H:22]1[CH2:30][C@H:29]2[C@H:24]([CH2:25][CH2:26][CH2:27][CH2:28]2)[NH:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:31][CH2:32][CH2:33][C@H:34]([NH:40][C@H:41]([C:43](O)=[O:44])[CH3:42])[C:35]([O:37][CH2:38][CH3:39])=[O:36].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.C(N(CC)CC)C>[CH2:38]([O:37][C:35]([C@@H:34]([NH:40][C@@H:41]([CH3:42])[C:43]([N:23]1[C@@H:24]2[C@@H:29]([CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:30][C@H:22]1[C:20]([O:19][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:21])=[O:44])[CH2:33][CH2:32][CH3:31])=[O:36])[CH3:39]
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H]2CCCC[C@@H]2N1
Reactant: CCC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCC[C@H](N[C@@H](C)C(=O)N1[C@H](C(=O)OCc2ccccc2)C[C@@H]2CCCC[C@@H]21)C(=O)OCC
Temperature: 0 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
There are introduced into a reactor, with stirring, 1 kg of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid benzyl ester para-toluenesulfonate, 0.06 kg of triethylamine, 4.6 liters of ethyl acetate and then, after stirring for 10 minutes at ambient temperature, 0.52 kg of N-[(S)-ethoxycarbonyl-1-butyl]-(S)-alanine, 0.15 kg of 1-hydroxybenzotriazole and 0.5 kg of dicylohexylcarbodiimide. The heterogeneous mixture is then brought to 30° C. for 3 hours while stirring well, and is subsequently cooled to 0° C. and filtered. The filtrate is then washed and subsequently evaporated to dryess to produce the expected product in a yield of 92%.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:12]O)[CH:3]=1.O=S(Cl)[Cl:16]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:12][Cl:16])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc2cc(Br)ccc12
Solvent: ClC(Cl)Cl
Product: ClCc1cccc2cc(Br)ccc12
Temperature: 25 °C
Yield: 100 %

Procedure:
A 39.5 g (0.167 mole) portion of 2-bromo-5-(hydroxymethyl)-naphthalene in 300 ml of chloroform was treated at 0°-5° over 0.3 hours with 75 ml (123 g, 1.03 mole) of SOCl2. The reaction mixture was allowed to warm to room temperature over 0.5 hours, heated to reflux over 0.2 hours, and allowed to cool slowly to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was taken up in 150 ml of benzene and again concentrated under reduced pressure to give 43 g (100%) of a light yellow oil which crystallized, m.p. 73°-76°.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.Br.Br.[Cl:15][C:16]1[CH:32]=[CH:31][C:19]2[N:20]=[C:21]([NH:23][CH2:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[S:22][C:18]=2[CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>O.CN(C)C(=O)C>[Cl:15][C:16]1[CH:32]=[CH:31][C:19]2[N:20]=[C:21]([NH:23][CH2:24][CH:25]3[CH2:26][CH2:27][N:28]([CH2:2][CH:3]4[O:8][C:7]5[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=5[O:5][CH2:4]4)[CH2:29][CH2:30]3)[S:22][C:18]=2[CH:17]=1
Reactant: BrCC1COc2ccccc2O1
Reactant: Clc1ccc2nc(NCC3CCNCC3)sc2c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Clc1ccc2nc(NCC3CCN(CC4COc5ccccc5O4)CC3)sc2c1
Temperature: 75 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
A mixture of 1.9 parts of 2-(bromomethyl)-2,3-dihydro-1,4-benzodioxin, 3.3 parts of 6-chloro-N-(4-piperidinylmethyl)-2-benzothiazolamine dihydrobromide, 5 parts of sodium carbonate, 0.1 parts of sodium iodide and 67.5 parts of N,N-dimethylacetamide was stirred overnight at about 75° C. Water was added to the reaction mixture and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The oily residue was crystallized from a mixture of 1,1'-oxybisethane and 2,2'-oxybispropane. The product was filtered off and dried, yielding 1.8 parts (59.8%) of 6-chloro-N-[[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]-methyl]-2-benzothiazolamine; mp. 155.8° C. (compound 16).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[O:3]1.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]=[C:25]=[O:26])[CH:19]=1>C(Cl)Cl>[F:17][C:18]1[CH:19]=[C:20]([NH:24][C:25]([NH:13][C:12]2[CH:14]=[CH:15][C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:10][CH:11]=2)=[O:26])[CH:21]=[CH:22][CH:23]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: O=C=Nc1cccc(F)c1
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(NC(=O)Nc3cccc(F)c3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1 g, 4.43 mmol) in CH2Cl2(30 ml) under argon was treated with 1-fluoro-3-isocyanatobenzene (0.515 ml, 4.43 mmol), added dropwise. The reaction was stirred at room temperature for 18 hours, and was concentrated to a solid. Methylene chloride and hexane were added to precipitate the product, which was collected and dried in vacuo to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Br-:14].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1>[Br:14][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)=[O:10]
Reactant: [Br-]
Reactant: CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(Cl)c([N+](=O)[O-])c1
Yield: 70.3 %

Procedure:
To a flask equipped with a magnetic stir bar and under an atmosphere of N2 was added 4′-chloro-3′-nitroacetophenone (10.0 g, 50.1 mmol) and THF (100 mL). To this stirring mixture was added portion-wise phenyltrimethylammonium tribromide (19.78 g, 52.6 mmol) over a 15 minutes time period. The resultant mixture was then stirred with monitoring every hour via LCMS. After 3 hr the mixture was then filtered and resulting solids washed with EtOAc. The organic solution was then concentrated, H2O and 10% aq. NaHCO3 added and washed with EtOAc (2×300 mL). The combined organic layers were then washed with Brine, dried (MgSO4), filtered and concentrated. The residue material was then subjected to purification via crystallization (dissolved material in 100 mL EtOAc and slowly added hexanes until cloudy—let stand for a few hours) to yield 9.81 g (70%) of 2-bromo-1-(4-chloro-3-nitrophenyl)ethanone as an off white colored solid product. 1H NMR (500 MHz, DMSO-D6) δ ppm 5.00 (s, 2H) 7.98 (d, J=8.54 Hz, 1H) 8.24 (dd, J=8.54, 2.14 Hz, 1H) 8.61 (d, J=1.98 Hz, 1H).