Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12](B2OC(C)(C)C(C)(C)O2)[CH:11]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=2)[CH:11]=1
Reactant: CC1(C)OB(c2cc(F)ccc2C#N)OC1(C)C
Reactant: Brc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(F)cc1-c1cccc(Br)n1
Temperature: 80 °C
Yield: 37.9 %

Procedure:
2,6-Dibromopyridine (0.94 g, 4.0 mmol), 4-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (1.48 g, 6.0 mmol) and potassium phosphate (1.70 g, 8.0 mmol) were dissolved in N,N-dimethylformamide (12 ml) and degassed with nitrogen for 15 min. Tetrakis(triphenylphosphine)palladium(0) (230 mg, 0.2 mmol) was added then the mixture heated at 80° C. for 16 h. The mixture was allowed to cool to ambient temperature, diluted with water (150 ml) and extracted into ethyl acetate (2×150 ml). The combined organics were washed with brine (100 ml), dried over anhydrous sodium sulfate and evaporated to give a yellow oil. Purification by flash column chromatography on silica eluting with isohexane on a gradient of ethyl acetate (10-15%) gave 4-fluoro-2-(6-bromopyridin-2-yl)benzonitrile (0.42 g, 38%) as a waxy solid: δH (360 MHz, CDCl3) 7.21-7.25 (1H, m), 7.59 (1H, d, J 8), 7.67 (1H, dd, J 9.3, 2.6), 7.72 (1H, t, J 7.7), 7.78-7.87 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[CH2:9][N:10]([C:11]([NH:13][NH2:14])=[O:12])[C:4]=2[CH:3]=1.CN(C1C=CC=CN=1)C.[Br:30][CH2:31][C:32](Br)=[O:33].CCOC(C)=O>CN(C=O)C.[Cl-].[Na+].O>[Br:30][CH2:31][C:32]([NH:14][NH:13][C:11]([N:10]1[CH2:9][C:8]2[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=2[O:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][C:4]1=2)=[O:12])=[O:33]
Reactant: O=C(Br)CBr
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: CN(C)c1ccccn1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CBr)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reaction time: 16 h

Procedure:
To an icebath-cooled stirring solution of 5.79 g (20 mmol) of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, hydrazide (1), prepared as described above in Example 1, 3.1 mL (22 mmol) of TEA, and 0.16 g (1 mmol) of dimethylaminopyridine in 50 mL of DMF Was added 4.44 g (22 mmol) of bromoacetyl bromide. After 16 hours of stirring, the reaction mixture was added to 250 mL of brine and 250 mL of EtOAc. The resulting layers were separated, and the organic layer was washed with 4×250 mL of brine. The organic layer was then dried and chromatographed. The yield of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-(bromoacetyl) hydrazide (19) was 3.75 g (45%). The product was employed immediately in the manner described in Example 20 below.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[C:14]1([CH2:20][O:21][C:22]([NH:24][C@H:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:27]O)=[O:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C[N+](CC(O)=O)(C)C>>[CH3:35][C:32]([CH3:33])([O:31][C:29](=[O:30])[CH:25]([NH:24][C:22]([O:21][CH2:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:23])[CH2:26][CH2:27][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1)[CH3:34]
Reactant: COC(=O)CCc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)[C@H](CCO)NC(=O)OCc1ccccc1
Agent: C[N+](C)(C)CC(=O)O
Product: COC(=O)CCc1cccc(OCCC(NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)c1
Yield: 67.9 %

Procedure:
The operation is carried out as in Preparation 1 (Method 2) starting from 270 mg of the phenol prepared in Stage A, 309 mg of 1,1-dimethyl-ethyl N-[(phenylmethoxy)carbonyl]-L-homoserinate and 616 mg of betaine. 320 mg of expected product is obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])CBr)=[CH:4][CH:3]=1.C([N:14](CC)CC)C.[I-].[Na+]>CN(C=O)C>[NH:14]1[C:6]2[C:5](=[CH:4][CH:3]=[CH:2][CH:7]=2)[CH:8]=[CH:11]1
Reactant: CC(CBr)c1ccc(F)cc1
Reactant: CCN(CC)CC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.6 %

Procedure:
A mixture of Intermediate 3 (0.31 g, 1.0 mmol), 2-(4-fluorophenyl)propyl bromide (0.228 g, 1.05 mmol), triethylamine (0.202 g, 2.0 mmol) and sodium iodide (0.165 g, 1.1 mmol), in DMF (20 ml) was heated at 90° C., with stirring, for 16 h. The mixture was cooled to room temperature and partitioned between dichloromethane and water. The CH2Cl2 layer was separated, dried (Na2SO4) and evaporated under vacuum. The crude product was chromatographed through silica gel eluting with CH2Cl2 /MeOH/NH3 (90:10:1) to give the title-indole (0.125 g, 28%). The 3.0 hydrogen oxalate monohydrate salt was prepared, mp 203-205° C., (Found: C, 52.11; H, 5.60; N, 11.45. C26H31N6F. 3.0 (C2H2O4) 1.0H2O requires C, 52.31; H, 5.35; N, 11.44%), δ(360 MHz, D6 -DMSO) 1.17 (3H, d, J=6.8 Hz, Me), 1.92-2.06 (2H, m, CH2), 2.44-3.26 (15H, m, 7 of CH2 and CH), 7.08-7.13 (2H, m, Ar--H), 7.26-7.33 (4H, m, Ar--H), 7.50 (1H, d, J=8.6 Hz, Ar--H), 7.78 (1H, d, J=1.5 Hz, Ar--H), 9.01 (2H, s, Ar--H), 11.16 (1H, s, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH:6]=[O:7].[C:13]([OH:23])(=[O:22])[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)O.[B]>CCOCC>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH:6]1[O:23][C:13](=[O:22])[CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:7]1
Reactant: O=CCOc1ccc(Cl)cc1Cl
Reactant: O=C(O)C(O)c1ccccc1
Agent: [B]
Solvent: CCOCC
Product: O=C1OC(COc2ccc(Cl)cc2Cl)OC1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
A solution containing 5.1 g (0.025 mole) of 2,4-dichlorophenoxyacetaldehyde, 4.25 g (0.028 mole) of mandelic acid, and 10.0 g (0.07 mole) of boron trifluoide etherate in 250 ml of ether was allowed to stir for 2 hours at ambient temperature, washed with aqueous sodium carbonate and water, dried and concentrated. The residual solid was purified by silica chromatography to give 2.7 g of 2-(2,4-dichloro-phenoxymethyl)-5-phenyl-1,3-dioxolan-4-one, trans isomer, having a melting point of 68°-71°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:33])=O>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:12]([C:13]([Cl:33])=[O:14])=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)O)cc(C(F)(F)F)c1OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)Cl)cc(C(F)(F)F)c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 4-benzyloxy-3-methoxy-5-trifluoromethylbenzoic acid (601 mg), toluene (6 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.16 mL) were added, and then the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (657 mg) as a yellow oily substance.
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]/[C:4]1[CH:15]=[C:12]([O:13][CH3:14])[C:9]([O:10][CH3:11])=[CH:8][C:5]=1[O:6][CH3:7].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:19]=1[CH2:28][CH2:29][CH3:30].C(C1C(=O)C(Cl)=C(Cl)C(=[O:36])C=1C#N)#N>>[CH3:1]/[CH:2]=[CH:3]/[C:4]1[CH:15]=[C:12]([O:13][CH3:14])[C:9]([O:10][CH3:11])=[CH:8][C:5]=1[O:6][CH3:7].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:19]=1/[CH:28]=[CH:29]/[CH:30]=[O:36]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: CCCc1cc(OC)c(OC)cc1OC
Agent: C/C=C/c1cc(OC)c(OC)cc1OC
Product: COc1cc(OC)c(OC)cc1/C=C/C=O

Procedure:
Preparation of α-asarone via dehydrogenation of 2,4,5-trimethoxyphenylpropane with DDQ containing little amount of silica gel: Addition of a catalytic amount of silica gel (0.2-0.6 g) drastically accelerated the rate of reaction as well as improved the yield of α-asarone when above dehydrogenation process (Example II-a) was conducted under the same condition resulting α-asarone in 72% yield and trans-2,4,5-trimethoxycinnamaldehyde in 18% yield.
Reaction SMILES: [OH:1][C:2]1([CH3:25])[CH2:8][CH:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[O:6][C:4](=[O:5])[CH2:3]1.C(N(CC)CC)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:33]([O:1][C:2]1([CH3:25])[CH2:8][CH:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:13][CH:12]=2)[O:6][C:4](=[O:5])[CH2:3]1)(=[O:35])[CH3:34]
Reactant: CC1(O)CC(=O)OC(CCc2ccc(OCc3ccccc3)cc2)C1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC1(C)CC(=O)OC(CCc2ccc(OCc3ccccc3)cc2)C1
Temperature: 0 °C

Procedure:
One hundred milligrams of 3-hydroxy-3-methyl-7-(p-benzyloxyphenyl)-5-heptanolide was dissolved in 0.1 ml of methylene chloride and 0.63 ml of acetic anhydride, 0.56 ml of triethylamine and 1.5 mg of N,N-dimethyl-4-pyridineamine were added thereto under cooling at 0° C. After allowing to stand under ice-cooling for 4 hours, the reaction mixture was poured into ice-water and the crystals thus precipitated were recrystallized from a mixture of ethyl acetate and n-hexane (1:10) affording 68 mg of the desired compound melting at 98°-101° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:23][CH3:24])=[CH:4][C:5]([CH2:14]O[Si](C(C)(C)C)(C)C)=[C:6]([CH:13]=1)[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].C1C[O:28][CH2:27][CH2:26]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:50]>CCOCC>[C:27]([O:1][C:2]1[C:3]([O:23][CH3:24])=[CH:4][C:5]([CH2:14][Br:50])=[C:6]([CH:13]=1)[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])(=[O:28])[CH3:26]
Reactant: COC(=O)CCc1cc(O)c(OC)cc1CO[Si](C)(C)C(C)(C)C
Reactant: C1CCOC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: COC(=O)CCc1cc(OC(C)=O)c(OC)cc1CBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 5-hydroxy-2-tert-butyldimethylsilyloxymethyl-4-methoxyhydrocinnamate (5.21 g) in carbon tetrabromide (12.35 g) in anhydrous ether (75 ml) and anhydrous THF (50 ml) is added portionwise triphenylphosphine (9.78 g) and the mixture stirred at room temperature for 60 minutes, diluted with ether, then filtered. The filtrate is concentrated in vacuo and the residue purified by filtration through silica gel in 50% ethyl acetate in hexanes followed by HPLC, eluting with 25% ethyl acetate in hexanes, to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:17]([O-])=O)=[CH:4][C:5]([CH3:16])=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])[CH:7]=1.O.O.Cl[Sn]Cl.[OH-].[Na+].C(Cl)Cl>C(O)C.O>[NH2:17][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])=[C:5]([CH3:16])[CH:4]=1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1C(=O)N1CCOCC1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(N)c(Cl)cc1C(=O)N1CCOCC1
Temperature: 65 °C
Yield: 92.7 %

Procedure:
To (5-chloro-2-methyl-4-nitrophenyl)(morpholino)methanone (244 mg, 0.86 mmol) in ethanol (6 mL) and water (0.6 mL) was added SnCl2.2H2O (776 mg, 3.44 mmol). The mixture was heated to 65° C. for 5 h and then 2 M aqueous sodium hydroxide solution (10 mL) and DCM (10 mL) were added. The organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo to give (4-amino-5-chloro-2-methylphenyl)(morpholino)methanone (203 mg, 93%) as an off-white solid. LCMS (10 cm_ESCI_Formic_MeCN): [M+H]+=255 at 2.84 min. 1H NMR (400 MHz, CDCl3): δ 7.07 (s, 1H), 6.60 (s, 1H), 4.10 (br s, 2H), 3.84-3.53 (br m, 6H), 3.36-3.24 (br m, 2H), 2.21 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]([C:13]1[CH:18]=[C:17]([O:19]C)[CH:16]=[CH:15][C:14]=1[CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:31]C)[CH:27]=2)[CH2:22]1)[C:4](=O)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:2].C(N(C1C=C(OC)C=CC=1C1CCC2C(=CC=C(OC)C=2)C1)CCN1CCCCC1)C>>[CH2:1]([N:3]([CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=1[CH:21]1[CH2:30][CH2:29][C:28]2[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:23]=2[CH2:22]1)[CH3:2]
Reactant: CCN(C(=O)CN1CCCCC1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: CCN(CCN1CCCCC1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Product: CCN(CCN1CCCCC1)c1cc(O)ccc1C1CCc2cc(O)ccc2C1

Procedure:
Synthesized from N-ethyl-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]-2-piperidin-1-ylacetamide according to an analogous synthetic method to Example 337 described below, the total amount of ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl](2-piperidin-1-ylethyl)amine (108 mg) was used according to an analogous synthetic method to Example 111 described below to provide the title compound (84 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:11][CH:12]=[C:13]([S:15][CH3:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C([Cl:30])C=C(C(OO)=[O:32])C=1.Cl>C(Cl)Cl.CCOCC>[ClH:30].[CH2:1]([O:8][C:9]1[C:10]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:11][CH:12]=[C:13]([S:15]([CH3:16])=[O:32])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1csc(Nc2ncc(S(C)=O)cc2OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
3-(Benzyloxy)-N-(4-methylthiazol-2-yl)-5-(methylthio)pyridin-2-amine (prepared according to Example 7; 0.057 g, 0.166 mmol) was placed in CH2Cl2 (5 mL) and cooled to 0° C. MCPBA (0.0398 g, 0.166 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours, then quenched with sodium bisulfite and extracted with CH2Cl2. The organic layer was washed with saturated sodium bicarbonate, dried, filtered, and concentrated. The residue was purified by silica gel (40-80% EtOAc in hexanes) to give the free base. The free base was dissolved in CH2Cl2, and 2M HCl in ether was added. The solution was concentrated to give 3-(benzyloxy)-5-(methylsulfinyl)-N-(4-methylthiazol-2-yl)pyridin-2-amine hydrochloride (0.037 g, 56.3% yield). 1H NMR (DMSO-d6) δ 8.18 (d, 1H), 7.81 (d, 1H), 7.62 (m, 2H), 7.43 (m, 2H), 7.37 (m, 1H), 6.83 (s, 1H), 5.39 (d, 2H), 2.82 (s, 3H), 2.30 (s, 3H). Mass spectrum (apci) m/z=360.0 (M+H-HCl).
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Br[C:16]1[CH:28]=[CH:27][C:19]2[N:20]=[C:21]([NH:23][C:24](=[O:26])[CH3:25])[S:22][C:18]=2[CH:17]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37].O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO.O>[F:29][C:30]1[CH:31]=[C:32]([C:2]2[C:10]3[S:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[N:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37].[F:29][C:30]1[CH:31]=[C:32]([C:16]2[CH:28]=[CH:27][C:19]3[N:20]=[C:21]([NH:23][C:24](=[O:26])[CH3:25])[S:22][C:18]=3[CH:17]=2)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: CC(=O)Nc1nc2ccc(Br)cc2s1
Reactant: CC(=O)Nc1nc2cccc(Br)c2s1
Reactant: COc1ccc(B(O)O)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: COc1ccc(-c2ccc3nc(NC(C)=O)sc3c2)cc1F
Product: COc1ccc(-c2cccc3nc(NC(C)=O)sc23)cc1F
Temperature: 85 °C
Reaction time: 1 h

Procedure:
The mixture (302.6 mg, 1.116 mmol) of N-(7-bromobenzo[d]thiazol-2-yl)acetamide and N-(6-bromobenzo[d]thiazol-2-yl)acetamide, 3-fluoro-4-methoxyphenylboronic acid (298 mg, 1.75 mmol), sodium carbonate monohydrate (0.247 mL, 4.48 mmol), and dichlorobis(triphenylphosphine)palladium (II) (168 mg, 0.239 mmol) were suspended in 1,2-dimethoxyethane (3.5 mL), water (1.5 mL) and EtOH (1.0 mL). The reaction flask was fit with a reflux condensor and placed in a preheated oil bath (85° C.) and stirred under argon for 1 hour. The reaction was cooled to room temperature and allowed to stand overnight. It was then filtered through a Celite® (diatomaceous earth) pad, and the solid was washed with MeOH, DCM, and DME. The filtrate was concentrated and treated with DCM. The resulting precipitate was collected by filtration and the crude was further purified by HPLC to provide N-(7-(3-Fluoro-4-methoxyphenyl)benzo[d]thiazol-2-yl)acetamide and N-(6-(3-Fluoro-4-methoxyphenyl)benzo[d]thiazol-2-yl)acetamide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[C:24]([NH2:42])=[CH:25][C:26]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH2:29][CH2:28][C:27]=2[CH:41]=1>>[Cl:20][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:42][C:24]2[C:23]([O:22][CH3:21])=[CH:41][C:27]3[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[CH2:31][CH2:32][C:26]=3[CH:25]=2)=[N:3][CH:4]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CCN1CCOCC1)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)CCN(CCN1CCOCC1)CC2
Yield: 19 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide and 8-Methoxy-3-(2-morpholin-4-yl-ethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamine. Product was isolated as a white foam (28 mg, 19%). MS (ESI+): 608 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.00 (s, 1H), 7.96 (s, 1H), 7.32 (s, 1H), 6.67 (s, 1H), 5.34 (d, J=8 Hz, 1H), 5.26 (d, 1H), 3.96 (m, 1H), 3.89 (s, 3H), 3.74 (t, 5 Hz, 4H), 3.27 (m, 1H), 2.90 9 m, 4H), 2.80 (s, 3H), 2.71 (m, 6H), 2.59 (m, 2H), 2.57 (br s, 4H), 2.25 (m, 2H), 2.39 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[OH:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][CH2:23][C:24](Cl)=[O:25].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1.CCCCCC>[Cl:22][CH2:23][C:24]([O:21][C@@H:16]1[CH2:17][CH2:18][CH2:19][CH2:20][C@H:15]1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:25]
Reactant: O=C(Cl)CCl
Reactant: O[C@@H]1CCCC[C@H]1c1ccccc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(CCl)O[C@@H]1CCCC[C@H]1c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 109 %

Procedure:
In a 1 L round bottom flask equipped with a magnetic stirrer, thermometer and condenser is placed 65 g (0.23 mol) of trans-2-(2'-benzyloxyphenyl)cyclohexanol. This is dissolved in 200 ml of methylenechloride, and then 28.5 g (0.25 mol) of chloroacetyl chloride is added followed by 0.14 g (0.001 mol) of 4-dimethylaminopyridine. The mixture is heated to reflux and monitored by TLC (silica gel: 20% ethyl acetate, hexane). After 4 hours TLC shows the reaction to be complete, it is cooled to room temperature and 200 ml of saturated sodium bicarbonate is added. The reaction mixture is stirred rapidly for another 3 hours. The organic phase is then separated, dried with anhydrous potassium carbonate, filtered and evaporated under reduced pressure to yield 90 g of an amber oil. This oil is dissolved in 100 ml of hexane from which it crystallizes to afford 74 g of off-white solid trans-2-(2'-benzyloxyphenyl)cyclohexyl chloroacetate, which is used directly in the next step.
Reaction SMILES: Cl[C:2]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][CH2:24][CH2:25][OH:26])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[CH3:27][N:28]([CH2:36][CH:37]=O)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[OH:26][CH2:25][CH2:24][N:23]([CH2:22][C:19]1[CH:20]=[CH:21][C:2]([CH3:39])=[C:3]([C:4]([NH:6][CH2:7][C:8]23[CH2:15][CH:14]4[CH2:16][CH:10]([CH2:11][CH:12]([CH2:13]4)[CH2:17]2)[CH2:9]3)=[O:5])[CH:18]=1)[CH2:37][CH2:36][N:28]([CH3:27])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CNCCO)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(CN(CCO)CCN(C)C(=O)OC(C)(C)C)cc1C(=O)NCC12CC3CC(CC(C3)C1)C2
Yield: 69.7 %

Procedure:
2-Chloro-5-[[(2-hydroxyethyl)amino]methyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.30 g, Example 71c), methyl(2-oxoethyl)-carbamic acid, 1,1-dimethylethyl ester (0.276 g), sodium triacetoxyborohydride (0.720 g) and dichloromethane (50 ml) were stirred together under nitrogen for 24 h. The mixture was poured into saturated aqueous sodium hydrogencarbonate solution, extracted into dichloromethane, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified on silica (eluting with 19:1 dichloromethane/methanol) to afford the subtitled compound (0.285 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[CH2:9][CH3:10].[ClH:11].[N:12]1([CH2:16][CH2:17][N:18]2[CH:22]=[C:21](C3C=CN=C(C(F)(F)F)C=3)[N:20]=[C:19]2[CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[N:12]1([CH2:16][CH2:17][N:18]2[CH:22]=[C:21]([C:35]3[CH:34]=[CH:33][CH:38]=[C:37]([Cl:11])[N:36]=3)[N:20]=[C:19]2[CH:33]2[CH2:38][CH2:37][N:36]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=3[CH2:9][CH3:10])[CH2:35][CH2:34]2)[CH2:13][CH2:14][CH2:15]1
Reactant: FC(F)(F)c1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccn1
Reactant: Cl
Reactant: CCc1c(N)ncnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCc1c(N)ncnc1N1CCC(c2nc(-c3cccc(Cl)n3)cn2CCN2CCC2)CC1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
A reaction mixture of 6-Chloro-5-ethyl-pyrimidin-4-ylamine (45.00 mg; 0.29 mmol; 1.00 eq.), 2-[1-(2-Azetidin-1-yl-ethyl)-2-piperidin-4-yl-1H-imidazol-4-yl]-6-chloropyridine hydrochloride (4) (140.40 mg; 0.29 mmol; 1.00 eq.), and Cs2CO3 (372.13 mg; 1.14 mmol; 4.00 eq.) in DMSO 1.0 ml was stirred at 120° C. for 2 days, purified by HPLC, collected title compound 36 mg. LC-MS (M+1=467, obsd.=467).
Reaction SMILES: [CH3:1][C:2]1[C:3](/[C:16](/[CH3:26])=[CH:17]/[C:18]2[S:22][C:21]([C:23]([OH:25])=[O:24])=[CH:20][CH:19]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH:27]1(N=C=NC2CCCCC2)CCCC[CH2:28]1>CCO.CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1[C:3](/[C:16](/[CH3:26])=[CH:17]/[C:18]2[S:22][C:21]([C:23]([O:25][CH2:27][CH3:28])=[O:24])=[CH:20][CH:19]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: C/C(=C\c1ccc(C(=O)O)s1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1ccc(/C=C(\C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)s1

Procedure:
A suspension of 0.161 g (0.437 mmol) of 5-((E)-2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl)propen-1-yl)-2-thiophenecarboxylic acid, (Compound 21, 0.03 g, 0.655 mmol) in EtOH, 0.099 g (0.48 mmol) of 1,3-dicyclohexylcarbodiimide, and 5.3 mg (0.044 mmol) of 4-dimethylaminopyridine in 10 mL of methylene chloride was stirred at room temperature for 16 hours. The reaction mixture was filtered and the filtrate washed with water and brine. The organic layers were combined and dried (MgSO4), The solvent was removed in-vacuo and the residue purified using flash chromatography (SiO2, 5% ethyl acetate in hexanes) to give the title compound as a clear oil.