Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][CH:10]=[C:7]([CH:8]=O)[C:6]=1[OH:13])([CH3:4])([CH3:3])[CH3:2].[I:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:12]=[CH:11][CH:10]=[C:7]([CH:8]=[N:19][C:18]2[CH:20]=[CH:21][C:15]([I:14])=[CH:16][CH:17]=2)[C:6]=1[OH:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cccc(C=O)c1O
Reactant: Nc1ccc(I)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cccc(C=Nc2ccc(I)cc2)c1O
Temperature: 25 °C
Yield: 96 %

Procedure:
An amount of 5.84 mmol of 3-tert-butyl salicylaldehyde (1) (1.04 g/1 ml) was dissolved in 150 ml of toluene. After addition of 4-iodoaniline (1.53 g/7 mmol/1.2 equivs.) and a few crystals of para-toluenesulfonic acid, the reaction mixture was stirred under reflux for three hours applying a Dean-Stark-trap. After cooling down to room temperature, sodium hydrogencarbonate solution (150 ml) was added. The organic phase was separated and filtered over sodium sulphate and silica. Removing the solvent and recrystallization from ethanol at −20° C. gave the title compound in a 96% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:33][CH2:34]CS([O-])(=O)=O)[CH2:15][CH2:14][N:13]([C:16](=[O:32])[C:17]3[CH:22]=[C:21]([O:23][CH2:24][CH3:25])[C:20]([O:26][CH2:27][CH3:28])=[C:19]([O:29][CH2:30][CH3:31])[CH:18]=3)[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[C:41]1([C:47]2([C:53]([NH2:55])=[O:54])[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:33][CH2:34][N:50]3[CH2:49][CH2:48][C:47]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)([C:53]([NH2:55])=[O:54])[CH2:52][CH2:51]3)[CH2:15][CH2:14][N:13]([C:16](=[O:32])[C:17]3[CH:18]=[C:19]([O:29][CH2:30][CH3:31])[C:20]([O:26][CH2:27][CH3:28])=[C:21]([O:23][CH2:24][CH3:25])[CH:22]=3)[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: CCOc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(OC)c(OC)c3)C2)cc(OCC)c1OCC
Agent: Cl
Product: CCOc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(OC)c(OC)c3)C2)cc(OCC)c1OCC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dimethoxy-phenyl)-1-(3,4,5-triethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (8 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (12 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=1.CCCCCC.C([Li])CCC.[C:32]1([N:38]=[C:39]=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(OCC)C>[C:32]1([NH:38][C:39]([C:2]2[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[N:3]=2)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Reactant: O=C=Nc1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)Nc2ccccc2)c1
Reaction time: 0.17 h

Procedure:
1.0 g (0.0029 mol) of 2-bromo-4-methoxy-6-{3-(trifluoromethyl)phenoxy} pyridine was dissolved in about 15 ml of diethyl ether. The solution was cooled in a dry ice-acetone bath in an argon atmosphere and mixed with 1.9 ml of a 1.69M-hexane solution of n-butyl lithium (0.0029×1.1 mol; hereinafter referred to merely as “BuLi”), followed by stirring for about 10 minutes. After 0.86 g (0.0029×2.5 mol) of phenyl isocyanate dissolved in about 5 ml of diethyl ether was added to the reaction solution, the solution was removed from the bath and stirred at room temperature for about 30 minutes. The reaction solution was mixed with about 5 ml of 1.2N aqueous hydrochloric acid solution, and then distributed in ethyl acetate-water, followed by washing with saturated sodium bicarbonate water and saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography (eluting solution: ethyl acetate/hexane) to separate a main fraction therefrom. The fraction was concentrated and then subjected to precipitation using hexane, thereby obtaining an aimed product.
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[N-:16]=[N+:17]=[N-:18].[Na+].[Cl-].[NH4+]>CN(C=O)C>[N:16]([CH2:15][CH:2]([OH:1])[CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14])=[N+:17]=[N-:18]
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(O)CN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 92.9 %

Procedure:
To DMF solution (400 ml) of N-(2,3-epoxypropyl)phthalimide 58.8 g (0.29 mol), sodium azide 37.6 g (0.58 mol) and ammonium chloride 18.5 g (0.35 mol) were added, and stirred at 90° C. for 3 hours. The reaction mixture was cooled to room temperature, and then filtered. The filtrate was evaporated to dryness. The residue was dissolved in benzene (800 ml), washed with water, brine and water sequentially and then dried over sodium sulfate. The solvent was removed in vacuo. The desired product was further purified by silica gel chromatography. 66.3 g of desired product was obtained. The NMR spectra were consistent with the desired title intermediate.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)=[O:3].[CH3:11][Mg+].[Br-]>C(OCC)C>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([OH:3])([CH3:11])[CH3:1])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: CC(C)(O)c1ccc(Br)cc1
Temperature: 0 °C

Procedure:
20.0 g (100 mmol) 4-bromoacetophenone are added to 300 mL diethylether and cooled down to 0° C. 35.2 mL MeMgBr (3M in diethylether) are added by a dropping funnel. Cooling is removed and the mixture is stirred at r.t. over night. The reaction quenched by careful addition of 150 mL sat. aq. NH4Cl solution and 150 mL water. The resulting mixture is stirred for 20 min. The layers are separated and the org. layer is washed with water (2×), dried with MgSO4 and the solvent is removed in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[C:4]([OH:10])[CH:3]=1.[CH:11]1(Br)[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[C:4]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1
Reactant: CSc1ccc(Br)cc1O
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(Br)cc1OC1CCCC1
Temperature: 60 °C

Procedure:
A stirred solution of 4-bromo-2-hydroxythioanisole (15.9 g) and cyclopentyl bromide (16.05 g) in dry dimethylformamide (170 mL) is treated with anhydrous potassium carbonate (14.7 g) and the mixture is heated at 60° C. for 1 day. After cooling, the solution is diluted with water (250 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts are dried over magnesium sulfate and concentrated. The residue is subjected to flash chromatography, eluting with a mixture of ethyl acetate and pentane (5:95 v/v), to give 4-bromo-2-cyclopentyloxy-1-(methylthio)benzene, in the form of an oil (17.2 g). [NMR (DMSO): 7.14-7.03(m,3H),4.93(m,1H), 2.33(s,3H),2.0-1.53(m,8H)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.C(Cl)Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([CH:34]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=3)[OH:35])[CH2:30][CH2:29]2)=[CH:23][CH:22]=1>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([O:35][CH:34]([CH:31]2[CH2:32][CH2:33][N:28]([CH2:27][C:24]3[CH:25]=[CH:26][C:21]([O:20][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=4)=[CH:22][CH:23]=3)[CH2:29][CH2:30]2)[C:36]2[CH:37]=[CH:38][C:39]([C:42]([F:44])([F:45])[F:43])=[CH:40][CH:41]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(C(F)(F)F)cc1)C1CCN(Cc2ccc(Oc3ccccn3)cc2)CC1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)cc1)OC(c1ccc(C(F)(F)F)cc1)C1CCN(Cc2ccc(Oc3ccccn3)cc2)CC1
Temperature: 35 °C
Reaction time: 16 h

Procedure:
A 0.06 gram (0.0004 mole) sample of 4-chlorophenylisocyanate was weighed into a two-dram vial, followed in turn by 1.2 mL of methylene chloride, 0.18 gram (0.0004 mole) of {1-[(4-(2-pyridyloxy)phenyl)methyl](4-piperidyl)}[4-(trifluoromethyl)phenyl]methanol, and 0.06 mL of triethylamine. The vial was tightly capped and gently shaken at 35° C. for 16 hours using a vortex mixer. After this time, the methylene chloride was removed under a nitrogen stream to provide a residue. The residue was purified with column chromatography on silica gel using mixtures of acetone and methylene chloride as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.2 gram of Compound 227. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]#[CH:10])(=O)=O.[C:11]1([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH2:6]([N:20]1[CH2:21][CH2:22][N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:18][CH2:19]1)[CH2:7][CH2:8][C:9]#[CH:10]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: C#CCCCOS(C)(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C#CCCCN1CCN(c2ccccc2)CC1
Yield: 71.7 %

Procedure:
A solution of pent-4-ynyl methanesulfonate (1.05 g), N-phenyl piperazine (1.02 g) and diisoproylethylamine (1.2 mL) in THF (5 mL) was heated to reflux overnight. The mixture was concentrated, diluted with aq. NaOH 2M (10 mL) and extracted with DCM (2×50 mL). Drying (Na2SO4) and silica gel flash chromatography (EtOAc/hexane 2:1→2:0) afforded 1-(pent-4-ynyl)-4-phenylpiperazine (1.03 g).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:13][CH2:14]Cl)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:27][CH2:26][N:25]([CH3:28])[C:24]2=[O:29])=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+].C(O)CCC>O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([N:4]2[CH2:13][CH2:14][N:16]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:27][CH2:26][N:25]([CH3:28])[C:24]4=[O:29])=[CH:21][CH:22]=3)[CH2:2][CH2:3]2)=[CH:6][CH:7]=1
Reactant: CN1CCN(c2ccc(N)cc2)C1=O
Reactant: COc1ccc(N(CCCl)CCCl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Product: COc1ccc(N2CCN(c3ccc(N4CCN(C)C4=O)cc3)CC2)cc1
Yield: 73 %

Procedure:
A mixture of 16.5 parts of N,N-bis(2-chloroethyl)-4-methoxybenzenamine, 12.5 parts of 1-(4-aminophenyl)-3-methyl-2-imidazolidinone, 11 parts of sodium hydrogen carbonate and 240 parts of 1-butanol was stirred and refluxed for 24 hours. After cooling, 100 parts of water were added and the whole was stirred. The precipitated product was filter off, washed with water and with 1-butanol and dried, yielding 17.5 parts (73%) of 1-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3-methyl-2-imidazolidinone; mp. 240.9°-241.0° C. (28).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].[Cl:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:38]=1[F:39]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:35]1[CH:36]=[CH:37][C:38]([F:39])=[C:33]([Cl:32])[CH:34]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: COC(=O)c1c(-c2ccc(F)c(Cl)c2)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1

Procedure:
The present compound was synthesized by a method similar to that in Example 272 and using 2-benzyl-6-chloro-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (100 mg) and 3-chloro-4-fluorophenylboronic acid. A colorless powder (80 mg).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C[O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[C:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:7]=1[OH:6])[NH:14][C:13](=[O:17])[CH2:12][CH2:11]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)NC(=O)CC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1cc2c(cc1O)NC(=O)CC2
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
Acetyl chloride (2.0 mL, 28.1 mmol) was added to a mixture of 3,4-dihydro-7-methoxy-2H-quinolin-2-one (1.99 g, 11.2 mmol) in 1,2-dichloroethane (30 mL). The mixture obtained was cooled to 0° C. and AlCl3 (6.0 g, 44.98 mmol) was added in portions. The mixture was heated to reflux for 2 hours. The reaction was cautiously poured over ice-H2O, stirred for a minimum of 1 hour (to overnight), and extracted with CH2Cl2. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated to give the title compound (1.89 g, 82%) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:12]=[C:13]([C:15](=[O:17])[CH3:16])[CH:14]=1)=[O:8])[CH3:5].CO[C:27](OC)([N:29]([CH3:31])[CH3:30])C>>[CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:12]=[C:13]([C:15](=[O:17])[CH:16]=[CH:27][N:29]([CH3:31])[CH3:30])[CH:14]=1)=[O:8])[CH3:5]
Reactant: COCC(C)NC(=O)c1cc(C(C)=O)cc(-c2ccc(C)cc2)c1
Reactant: COC(C)(OC)N(C)C
Product: COCC(C)NC(=O)c1cc(C(=O)C=CN(C)C)cc(-c2ccc(C)cc2)c1

Procedure:
A solution of 5-acetyl-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (648 mg, 2 mmol) in N,N-dimethylacetamide dimethyl acetal (0.8 mL) was heated to reflux for 18 hours. The reaction mixture was cooled and volatiles were removed in vacuo. The resulting 188 mg of crude 5-(3-dimethylamino-acryloyl)-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2(C(C3CCCCO3)=O)[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[N:23]=[CH:22][N:21](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:20]=4)[CH:17]=3)[NH:12][NH:11]2)=[CH:4][CH:3]=1>O1CCOCC1.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[N:23]=[CH:22][NH:21][N:20]=4)[CH:17]=3)[NH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(C1CCCCO1)C1(/C=C/c2ccc(Cl)cc2)NNc2ccc(-c3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc21
Agent: Cl
Solvent: C1COCCO1
Product: Clc1ccc(/C=C/c2n[nH]c3ccc(-c4nc[nH]n4)cc23)cc1
Reaction time: 6.5 h
Yield: 56.6 %

Procedure:
Hydrolysis was performed by stirring 2-{3-[(1E)-2-(4-chlorophenyl)vinyl]-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazoyl}perhydro-2H-pyran in 4 mL of 4.0 N commercial solution of HCl in dioxane and 2 mL of 6.0 N aqueous HCl, at room temperature for 6.5 hours. The title compound was purified by column chromatography (5% MeOH in dichloromethane) and was isolated as a 98:2 mixture of isomers (0.040 g, 56.6% yield): 1H NMR (DMSO-d6) δ 14.4, 14.0 (2s, 1H), 13.4, 13.3 (2s, 11H), 8.7 (m, 1H), 8.1 (m, 2H), 7.8-7.4 (m, 7H); ES-MS (m/z) 322 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[NH:12][C:13](=O)[C:14]([NH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]2C(C3CCCCC3)=[C:31]3[N:25]([CH2:26][CH2:27][O:28][C:29]4[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:30]=43)[C:24]=2[CH:45]=1)=[O:19])([CH3:16])[CH3:15].[C:47]1([CH3:53])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C(O)(=O)C>[CH:47]1([C:53]2[C:23]3[CH:22]=[CH:21][C:20]([C:18]([NH:17][C:14]([C:13]4[NH:12][C:3]5[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=5[N:1]=4)([CH3:16])[CH3:15])=[O:19])=[CH:45][C:24]=3[N:25]3[C:31]=2[C:30]2[CH:39]=[CH:40][C:41]([O:43][CH3:44])=[CH:42][C:29]=2[O:28][CH2:27][CH2:26]3)[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: Cc1ccccc1
Reactant: COC(=O)c1ccc(N)c(NC(=O)C(C)(C)NC(=O)c2ccc3c(C4CCCCC4)c4n(c3c2)CCOc2cc(OC)ccc2-4)c1
Solvent: CC(=O)O
Product: COC(=O)c1ccc2nc(C(C)(C)NC(=O)c3ccc4c(C5CCCCC5)c5n(c4c3)CCOc3cc(OC)ccc3-5)[nH]c2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Methyl 4-amino-3-{2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]-2-methylpropionylamino}benzoate (0.73 g, 1.16 mmol) was dissolved in acetic acid (14.0 ml), and the mixture was stirred at 100° C. for 2 hr. The mixture was allowed to cool to room temperature, toluene was added, and the solvent was evaporated under reduced pressure. To the obtained residue were added methanol and water. The precipitate was collected by filtration, washed with water, and dried in vacuo to give methyl 2-{1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]-1-methylethyl}-3H-benzimidazole-5-carboxylate (0.67 g, yield 95%).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[CH2:10])=[N:7][S:8][C:4]=2[CH:3]=1.[CH2:20]([NH2:23])[CH:21]=[CH2:22]>CN(C=O)C>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)[CH2:10][NH:23][CH2:20][CH:21]=[CH2:22])=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: C=CCN
Reactant: C=C(c1ccc(Cl)cc1)c1nsc2cc(Br)ccc12
Solvent: CN(C)C=O
Product: C=CCNCC(c1ccc(Cl)cc1)c1nsc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 66 %

Procedure:
A mixture of 6-bromo-3-(1-(4-chlorophenyl)vinyl)benzo[d]isothiazole (600 mg, 1.71 mmol), DMF (3 mL) and allylamine (3 mL) was stirred at room temperature for 3 days. The reaction was partitioned between EtOAc and water. The organic phase was washed with brine, dried and concentrated. The residue was purified by column chromatography (DCM:MeOH, 20:1) to give N-(2-(6-bromobenzo[d]isothiazol-3-yl)-2-(4-chlorophenyl)ethyl)prop-2-en-1-amine (464 mg, 66%). 1H NMR (CDCl3, 400 MHz) δ □8.06 (d, J=1.6 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.41 (dd, J=8.8 Hz, J=1.6 Hz, 1H), 7.25 (m, 4H), 5.86 (m, 1H), 5.16 (dd, J=17.2 Hz, J=1.6 Hz, 1H), 5.08 (d, J=10.4 Hz, 1H), 4.72 (t, J=7.2 Hz, 1H), 3.62 (dd, J=12.0 Hz, J=8.0 Hz, 1H), 3.31 (m, 2H), 3.20 (dd, J=12.0 Hz, J=6.8 Hz, 1H).
Reaction SMILES: [F:1][CH:2]([F:28])[CH2:3][N:4]1[CH2:9][C:8]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[O:7][CH:6]([C:22](=[O:27])[NH:23][CH2:24][CH:25]=O)[CH2:5]1>C1COCC1>[F:28][CH:2]([F:1])[CH2:3][N:4]1[CH2:9][C:8]2([CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:13][CH2:14]2)[O:7][CH:6]([C:22]2[O:27][CH:25]=[CH:24][N:23]=2)[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(CC(F)F)CC(C(=O)NCC=O)O2
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(CC(F)F)CC(c1ncco1)O2
Temperature: 70 °C
Yield: 38.1 %

Procedure:
To tert-butyl 4-(2,2-difluoroethyl)-2-((2-oxoethyl)carbamoyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (331 mg, 0.82 mmol) in THF (3 mL) was added Burgess' Salt (486 mg, 2.04 mmol). The reaction mixture was heated at 70° C. for 20 minutes under an atmosphere of nitrogen. The reaction mixture was cooled to room temperature, partitioned between EtOAc and saturated aq. NaHCO3, the layers separated and the aqueous layer was extracted once more with EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give an orange oil. The residue was purified by silica gel column chromatography using 0-30% EtOAc in DCM as eluent to yield tert-butyl 4-(2,2-difluoroethyl)-2-(oxazol-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (121 mg, 38%) as an off white foam. ESI-MS m/z calc. 387.2. found 388.3 (M+1)+; Retention time: 1.81 minutes (3 min run).
Reaction SMILES: [OH:1][C@@H:2]([C@H:6]([OH:10])[C:7]([OH:9])=O)[C:3]([OH:5])=O.[NH2:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]2[C:42]3[C:37](=[C:38]([Cl:44])[CH:39]=[C:40]([Cl:43])[CH:41]=3)[CH2:36][N:35]([CH3:45])[CH2:34]2)[CH:28]=1)(=[O:26])=[O:25]>>[Cl:43][C:40]1[CH:41]=[C:42]2[C:37](=[C:38]([Cl:44])[CH:39]=1)[CH2:36][N:35]([CH3:45])[CH2:34][CH:33]2[C:29]1[CH:28]=[C:27]([S:24]([NH:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][NH:11][C:3](=[O:5])[C@@H:2]([OH:1])[C@H:6]([OH:10])[C:7]([NH:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]3[C:42]4[C:37](=[C:38]([Cl:44])[CH:39]=[C:40]([Cl:43])[CH:41]=4)[CH2:36][N:35]([CH3:45])[CH2:34]3)[CH:28]=2)(=[O:26])=[O:25])=[O:9])(=[O:26])=[O:25])[CH:32]=[CH:31][CH:30]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN)c2)C1
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)[C@@H](O)[C@H](O)C(=O)NCCOCCOCCOCCNS(=O)(=O)c3cccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)c3)c2)C1
Yield: 32.1 %

Procedure:
Compound 222 was prepared following the procedure outlined in Example 215 using (2S,3S)-2,3-dihydroxysuccinic acid (15.5 mg, 0.103 mmol) and N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (Compound 28, 112 mg, 0.206 mmol). Purification by preparative HPLC gave the title compound (39.9 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): δ 7.87 (d, 2H), 7.77 (s, 2H), 7.63 (t, 2H), 7.54-7.50 (m, 4H), 6.82 (s, 2H), 4.34 (s, 2H), 3.90-3.85 (m, 1H), 3.62-3.30 (m, 47H), 3.14 (m, 8H), 3.05 (t, 4H). MS (m/z): 1206.95 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[O:16][CH2:15][CH2:14][NH:13][CH2:12]2)=[CH:7][CH:6]=1.[C:22]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[C:23]([CH3:25])=[CH2:24].N12CCCN=C1CCCCC2>CN(C=O)C>[C:28]([O:27][C:22](=[O:26])[CH:23]([CH3:25])[CH2:24][N:13]1[CH2:14][CH2:15][O:16][CH:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][C:3]3[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:2]=3[CH3:1])=[CH:10][CH:9]=2)[CH2:12]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: Cc1cccc(Oc2ccc(C3CNCCO3)cc2)c1C
Reactant: C=C(C)C(=O)OC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Cc1cccc(Oc2ccc(C3CN(CC(C)C(=O)OC(C)(C)C)CCO3)cc2)c1C
Temperature: 140 °C
Yield: 33.4 %

Procedure:
A mixture of 2-[4-(2,3-dimethyl-phenoxy)-phenyl]-morpholine (0.60 g; 1.9 mmol), tert-butyl methacrylate (0.61 ml; 3.8 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.84 ml; 5.6 mmol), and DMF (10 mL) was heated at 140° C., overnight, in a closed vessel. After cooling to room temperature, the mixture was partitioned between 5% aqueous NaHCO3 and EtOAc. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O/hexanes 1:9) to afford 3-{2-[4-(2,3-dimethyl-phenoxy)-phenyl]-morpholin-4-yl}-2-methyl-propionic acid tert-butyl ester (0.27 g).
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6](O)[C:5]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[CH2:2][CH3:3].P(Cl)(Cl)([Cl:24])=O>>[CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([Cl:24])[C:5]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc(C)nc(O)c1Cc1ccc([N+](=O)[O-])cc1
Reactant: O=P(Cl)(Cl)Cl
Product: CCCc1nc(C)nc(Cl)c1Cc1ccc([N+](=O)[O-])cc1

Procedure:
32 g of 6-n-propyl-2-methyl-5-(4-nitrobenzyl)-4-hydroxypyrimidine, prepared in Example 6, are suspended in 45 ml of phosphorus oxychloride. The mixture is brought to reflux for 6 hours and then concentrated under vacuum. The residue is taken up with water and extracted with dichloromethane. The organic phase is washed with potassium carbonate solution, then dried over magnesium sulphate and evaporated to dryness to give 24 g of 6-n-propyl-2-methyl-5-(4-nitrobenzyl)-4-chloropyrimidine in the form of crystals of melting point 65° C.