Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH2:22][CH3:23])[C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([O:18][C:19](=O)[CH3:20])=[CH:12][CH:11]=3)(=O)[CH3:2].[ClH:24].[N:25]1(CC[Cl:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C[O-].[Na+]>ClC1C=CC=CC=1>[ClH:33].[ClH:24].[CH2:22]([N:9]1[C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:1][CH2:2][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([O:18][CH2:19][CH2:20][N:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)[CH:14]=2)[CH3:23]
Reactant: CCn1c2ccc(OC(C)=O)cc2c2cc(OC(C)=O)ccc21
Reactant: ClCCN1CCCCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Clc1ccccc1
Product: CCn1c2ccc(OCCN3CCCCC3)cc2c2cc(OCCN3CCCCC3)ccc21

Procedure:
A mixture of 15.5 g (0.05 mole) of N-ethyl-3,6-carbazolediol diacetate, 18.4 g (0.1 mole) of 2-piperidinoethylchloride hydrochloride, 10.8 g (0.2 mole) of sodium methoxide and 400 ml of chlorobenzene is refluxed for 24 hours. Upon cooling, the reaction mixture is filtered, and the filtrate is washed with several portions of water, dried over anhydrous magnesium sulfate, diluted with ether and acidified with ethereal HCl. The resulting precipitate is collected and recrystallized from methanol-ethyl acetate to give N-ethyl-3,6-bis(2-piperidinoethoxy)carbazole dihydrochloride, M.P. 248°-250° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH:25]3[CH2:27][CH2:26]3)[CH3:24])=[CH:12][C:11]=2F)=O)=[CH:4][CH:3]=1.Cl.[NH2:30][OH:31].C([O-])(=O)C.[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH:25]4[CH2:27][CH2:26]4)[CH3:24])=[CH:12][C:11]=3[O:31][N:30]=2)=[CH:4][CH:3]=1
Reactant: CN(CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)c(F)c1)C1CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CN(CCCCCCOc1ccc2c(-c3ccc(Br)cc3)noc2c1)C1CC1
Temperature: 90 °C
Yield: 51.9 %

Procedure:
A mixture of 0.15 g of (4-bromo-phenyl)-[4-[6-(cyclopropyl-methyl-amino)-hexyloxy]-2-fluoro-phenyl]-methanone, 0.17 g of hydroxylamine.hydrochloride and 0.20 g of sodium acetate in 14 ml of ethanol is heated to 90° C. for 32 hrs. and then concentrated. The residue (containing the oxime corresponding to the starting ketone) is taken up in 50 ml of methylene chloride and washed with saturated aqueous sodium hydrogen carbonate solution and sodium chloride solution. The organic phase is dried and evaporated. The residue is dissolved in 15 ml of DMA and treated with 0.22 g of potassium carbonate. The mixture is heated at 130° C. for 5 hrs. For the working-up, the reaction mixture is filtered, the filtrate is concentrated and the residue is purified by chromatography (silica gel, toluene/acetone/triethylamine 92:7:1). There is obtained 0.077 g of [6-[3-(4-bromo-phenyl)-benzo[d]isoxazol-6-yloxy]hexyl]-cyclopropyl-methyl-amine which is converted into the fumarate, MS: m/e 443 (M+H+, 1 Br).
Reaction SMILES: [CH2:1]([O:3][P:4]([O-:6])[O-:5])[CH3:2].[CH2:7]([Sn+2:11]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH3:10].[CH2:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]CC>>[CH2:1]([O:3][P:4]([O-:6])[O-:5])[CH2:2][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].[CH2:16]([Sn+2:11]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:17][CH2:18][CH3:19]
Reactant: CCOP([O-])[O-]
Reactant: CCCCCCCCCCCCO
Agent: CCCC[Sn+2](CCCC)CCCC
Product: CCCCCCCCCCCCOP([O-])[O-]
Temperature: 140 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
In a 500 ml four-neck round-bottom flask equipped with a stirrer, thermometer, standard taper glass stopper, stillhead with condenser, cooled distillate receiver and cold trap, 133 g of tributyltin ethyl phosphite and 68.7 g of lauryl alcohol are heated with stirring for about 5 hours at 140° C, a vacuum of about 30 - 5 mm Hg being applied for 1 hour. Ethanol is initially distilled off and then the excess lauryl alcohol is distilled. 178 g tributyltin lauryl phosphite are obtained.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[C:8]([C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16]C(O)=C[CH:19]=3)[CH2:14][C:13]=2[CH:12]=1)(=[O:10])[CH3:9].N1C=CC=CC=1>C1COCC1>[C:8]([C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:19]=3)[CH2:14][C:13]=2[CH:12]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1ccc2c(c1)Cc1cc(O)ccc1-2
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc2c(c1)Cc1cc(C(C)=O)ccc1-2

Procedure:
Acetic anhydride (50 mL) was added to a mixture of 2-acetyl-7-hydroxyfluorene (50 g), pyridine (200 mL) and THF (200 mL) at 28° C. The temperature was elevated slowly up to 61° C. by exothermic heat to obtain a yellow transparent reaction mixture. An organic layer obtained by extracting the mixture with chloroform was washed well in order with 3M-hydrochloric acid, saturated sodium hydrogencarbonate and water, and then dried on anhydrous magnesium sulfate. The solvent was distilled off from this organic layer under reduced pressure, and the resulting residue was purified by means of column chromatography (silica gel, eluting solvent: toluene) and recrystallization (ethanol/ethyl acetate) to obtain 2-acetyl-7-acetoxyfluorene (47.3 g) of colorless crystal. Melting point: 125.5-127.6° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]([F:31])([F:30])[C:13]1([CH2:16][CH:17]([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=2)[CH2:18][NH2:19])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([C:20]1[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=1)[CH2:16][C:13]1([C:12]([F:11])([F:30])[F:31])[CH2:15][CH2:14]1)=[O:6]
Reactant: NCC(CC1(C(F)(F)F)CC1)c1cnc(C(F)(F)F)nc1
Reactant: O=C(O)c1ccccc1Cl
Product: O=C(NCC(CC1(C(F)(F)F)CC1)c1cnc(C(F)(F)F)nc1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and 3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine. LCMS (MH+): m/z=452.0, tR (minutes, Method F)=3.03
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[CH2:21]([Sn](CCCC)(CCCC)C=C)[CH2:22]CC>O1CCOCC1.CCOC(C)=O.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>[CH:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=3)[NH:3][C:2]=2[CH:21]=[CH2:22])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=Cc1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To a solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (from Example 1, Step 3) in dioxane (0.15 M) was added tri-n-butyl vinyl tin (1.1 eq.) followed by bis(triphenylphosphine)palladium(II) chloride (0.1 eq.). The reaction was stirred under nitrogen at 100° C. for 3 h and then cooled to RT. The mixture was then diluted with EtOAc and washed with brine (3×). The organic phase was then dried over Na2SO4 and evaporated to dryness. The residual material was purified by chromatography on silica gel (PE:EtOAc, 9:1). The product fractions were evaporated and the residual material re-crystallised from DCM with PE. The product was obtained as yellow crystalline material (60%).
Reaction SMILES: O.[NH2:2][NH2:3].[OH:4][C:5]1[C:10]([C:11]([O:13]C)=O)=[CH:9][CH:8]=[CH:7][N:6]=1>C(O)C>[O:4]=[C:5]1[C:10]([C:11]([NH:2][NH2:3])=[O:13])=[CH:9][CH:8]=[CH:7][NH:6]1
Reactant: NN
Reactant: COC(=O)c1cccnc1O
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc[nH]c1=O

Procedure:
Hydrazine hydrate (0.192 mL, 3.92 mmol) was added to a solution of the methyl 2-hydroxy-3-pyridinecarboxylate (400 mg, 2.61 mmol, commercially available from e.g. Apollo or Butt Park) in ethanol (10 mL) and the reaction was heated to reflux for 16 hrs. The reaction was cooled and the solvent was evaporated to afford an off-white solid in 395 mg.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[OH-].[Na+]>CO>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH:1]=[CH:17][C:16]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[CH:5][CH:6]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C=CC(=O)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a well-stirred solution of 4-hydroxy acetophenone, 1 (10 g, 73.5 mmol) and 4-methoxy benzaldehyde, 4 (8.9 mL, 73.5 mmol) in methanol (140 mL) was added 50% w/v aqueous sodium hydroxide solution (70 mL). The reaction mixture was stirred at room temperature for 12 h and then evaporated in vacuo. Water was added and acidified with hydrochloric acid (1N) and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over sodium sulphate, filtered and evaporated in vacuo. The residue yielded pure 7 after purification by column chromatography. Yield 16.8 g (90%); mp 184-185° C. MS (EI) m/z 254 (M+, 100%), 253 (34.7%), 239 (32.3%), 161 (36.8%), 121 (79.5%); IR (KBr) 3371, 1654; 1H NMR (200 MHz, CDCl3) δ 7.99 (d, J=8.6 Hz, 2H), 7.78 (d, J=15.6 Hz, 1H), 7.60 (d, J=8.6 Hz, 2H), 7.41 (d, J=15.6 Hz, 1H), 6.93 (d, J=7.2 Hz, 4H), 5.85 (s, 1H), 3.86 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:18])[CH:15]=2)[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:18])[CH:15]=2)[N:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CNc2ccc(Br)cc2C1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1Cc2cc(Br)ccc2N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.5 %

Procedure:
To a solution of 1B (1.636 g, 5 mmol) in DCE (16 mL) at RT was added benzaldehyde (1 mL, 10 mmol), followed by NaB(OAc)3H (2.97 g, 14 mmol) and AcOH (0.6 mL, 10 mmol). The reaction mixture was stirred at RT for 16 h, then quenched with aqueous NaHCO3 (40 mL) and extracted with CH2Cl2 (50 mL×3). The combined extracts were washed with brine, dried (Na2SO4), and concentrated. The resulting residue was chromatographed (silica gel) eluting with 0-20% of EtOAc in hexane to give the title compound (1.70 g, 81%) as a white foam.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[NH:6][N:5]=1)([CH3:3])[CH3:2].C1C(=O)N([Cl:19])C(=O)C1>CN(C=O)C>[Cl:19][C:8]1[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][NH:6][C:7]=1[CH:9]([CH3:11])[CH3:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)c1cc(C(C)C)[nH]n1
Solvent: CN(C)C=O
Product: CC(C)c1n[nH]c(C(C)C)c1Cl
Temperature: 80 °C

Procedure:
Following protocol L, a the solution of 3,5-diisopropyl-pyrazole (0.5 g, 3.57 mmol) in DMF (10 mL) was added NCS (0.72 g, 5.3 mmol) in portions under vigorous stirring. The reaction mixture was then heated at 80° C. for 14 h and then the reaction was quenched with water. It was then extracted with ethyl acetate (2×30 mL). The combined organics were washed with brine. The organic extracts were combined and dried with Na2SO4 and finally evaporated to give the title compound as colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](Cl)=[N:25][OH:26])=[CH:19][CH:18]=1.C(N(CC)CC)C>O1CCCC1>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]2[CH:2]=[C:1]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=3)[O:26][N:25]=2)=[CH:19][CH:18]=1
Reactant: ON=C(Cl)Cc1ccc(COc2ccccn2)cc1
Reactant: C#Cc1cccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: c1ccc(OCc2ccc(Cc3cc(-c4cccnc4)on3)cc2)nc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 24 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 3-ethynylpyridine (10 mg, 0.097 mmol) and (4-(pyridin-2-yloxymethyl)-phenyl)-acetohydroximoyl chloride (42.9 mg, 0.155 mmol) described in Manufacturing Example 2-1-5 was added triethylamine (54.1 μL, 0.388 mmol), which was stirred for 2.5 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:4 to 1:2, then 1:1) to obtain the title compound (8 mg, 24%).
Reaction SMILES: CO[CH:3]([O:11]C)[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[Mg].II.Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:7]1[CH:6]=[CH:5][C:4]([CH:3]=[O:11])=[CH:9][CH:8]=1
Reactant: COC(OC)c1ccc(Br)cc1
Reactant: Brc1ccccn1
Agent: II
Agent: [Mg]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(-c2ccccn2)cc1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
6.93 g (29.9 mmol) of 4-bromobenzaldehyde dimethyl acetal in 40 ml of THF are added dropwise to a warm (from 40° C. to 50° C.) suspension of 0.8 g (31.6 mmol) of magnesium turnings and a small amount of iodine in 10 ml of THF. The reaction mixture is heated to 65° C. and stirred at that temperature for about 30 min. The mixture is allowed to cool to room temperature and the Grignard reagent is added dropwise to a solution of 4.46 g (28.2 mmol) of 2-bromopyridine (Fluka, Buchs, Switzerland) and 0.4 g (0.74 mmol) of DPPP (Fluka, Buchs, Switzerland) in 100 ml of THF (slightly exothermic reaction). After the dropwise addition is complete, the reaction mixture is boiled under reflux for 4 hours and is then allowed to cool; 100 ml of water are added. The mixture is concentrated to about 50 ml using a rotary evaporator, diluted with ethyl acetate and extracted with 0.1N hydrochloric acid (3×). The combined HCl extracts are stirred at room temperature for 20 min, rendered basic with concentrated ammonia solution and extracted with methylene chloride. After removal of the solvent, the residue is chromatographed on silica gel (hexane/ethyl acetate 2:1). The product-containing fractions are concentrated, with the desired title compound crystallising out spontaneously. TLC: Rf =0.22 (hexane/ethyl acetate 2:1). HPLC20-100 : tRet =6.08. 1H-NMR (CDCl3 ; 200 MHz): 8.73/d, J=5 (2H); 8.16 and 7.97/each d (2×2H); 7.80/d, J=4 (2H); 7.3/m (1H).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][C:25]=5[O:27][C@H:28]([CH3:33])[C:29](OC)=[O:30])[N:20]=[CH:19][N:18]=4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)[N:3]=[CH:2]1.[CH3:34][NH:35][CH2:36][CH2:37][OH:38]>>[OH:38][CH2:37][CH2:36][N:35]([CH3:34])[C:29](=[O:30])[C@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:4]1[N:3]=[CH:2][S:1][CH:5]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[CH3:33]
Reactant: CNCCO
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12)C(=O)N(C)CCO
Yield: 73.9 %

Procedure:
Using the same procedure as in Example 26, methyl (2R)-2-[(4-{[1-(1,3-thiazol-4-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.43 mmol) was reacted with 2-(methylamino)ethanol (0.35 ml, 4.3 mmol) to give the title compound as a solid (160 mg, 73%), except that the mixture was heated at 45° C. for 20 hours and purified by chromatography on silica gel (eluant: 3% methanol in DCM). NMR Spectrum (2 rotamers) 1.60 (m, 3H), 3.18 and 2.93 (s, 3H), 3.65-3.40 (m, 4H), 5.00 and 4.73 (t, 1H), 5.79 (s, 2H), 5.90 and 5.81 (q, 1H), 7.35-7.30 (m, 2H), 7.51 (s, 1H), 7.85-7.70 (m, 3H), 8.11 (s, 1H), 8.51 (m, 2H), 9.04 (s, 1H), 11.09 (br s, 1H); Mass spectrum MH+ 504.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21](Br)=[C:20](CN(C(OC(C)(C)C)=O)C)[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35]([O:39][C:40]([N:42]1[CH2:46][CH2:45][CH2:44][CH:43]1[C:47]1[NH:48][C:49]([C:52]2[CH:57]=[CH:56][C:55](B3OC(C)(C)C(C)(C)O3)=[C:54](C(OC)=O)[CH:53]=2)=[CH:50][N:51]=1)=[O:41])([CH3:38])([CH3:37])[CH3:36].C(=O)(O)[O-].[Na+]>O.CCOC(C)=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>[C:35]([O:39][C:40]([N:42]1[CH2:46][CH2:45][CH2:44][CH:43]1[C:47]1[NH:48][C:49]([C:52]2[CH:57]=[CH:56][C:55]([C:21]3[CH:20]=[CH:19][C:18]([C:15]4[NH:14][C:13]([CH:9]5[CH2:10][CH2:11][CH2:12][N:8]5[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[N:17][CH:16]=4)=[CH:23][CH:22]=3)=[CH:54][CH:53]=2)=[CH:50][N:51]=1)=[O:41])([CH3:38])([CH3:36])[CH3:37]
Reactant: CN(Cc1cc(-c2cnc(C3CCCN3C(=O)OC(C)(C)C)[nH]2)ccc1Br)C(=O)OC(C)(C)C
Reactant: COC(=O)c1cc(-c2cnc(C3CCCN3C(=O)OC(C)(C)C)[nH]2)ccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)[nH]1
Temperature: 80 °C
Yield: 52.5 %

Procedure:
To the solution of 2-(5-{4-bromo-3-[(tert-butoxycarbonyl-methyl-amino)-methyl]-phenyl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (142 mg, 0.27 mmol) and 2-{5-[3-Methoxycarbonyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (125 mg, 0.25 mmol) in 1,2-dimethoxyether (2.3 ml) and water (0.7 ml) was added sodium bicarbonate (63 mg, 0.75 mmol), followed by Pd(PPh3)4 (12 mg) and PdCl2(dppf)CH2Cl2 (12 mg). The mixture was heated at 80° C. for 20 hours. The mixture was diluted with EtOAc, and was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave 4,4′-bis-[2-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-biphenyl-2-[(tert-butoxycarbonyl-methyl-amino)-2′-carboxylic acid dimethyl ester (82 mg). m/z: 826 (M+H)+, 413.6 (M+2H)+/2.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].C(N(CC)CC)C.Cl.[F:16][C:17]([F:51])([F:50])[C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[N:21]=[C:20]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([C:40]3[CH:41]=[C:42]([S:46](Cl)(=[O:48])=[O:47])[CH:43]=[CH:44][CH:45]=3)[CH:35]=2)[N:19]=1>C1COCC1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[S:46]([C:42]1[CH:43]=[CH:44][CH:45]=[C:40]([C:36]2[CH:35]=[C:34]([C:20]3[N:19]=[C:18]([C:17]([F:16])([F:50])[F:51])[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=4)[N:21]=3)[CH:39]=[CH:38][N:37]=2)[CH:41]=1)(=[O:47])=[O:48]
Reactant: OCCNCCO
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1)N(CCO)CCO
Temperature: 0 °C
Yield: 57.6 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of diethanolamine (0.114 g, 1.08 mmol), triethylamine (0.11 ml, 0.76 mmol) and THF (2 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.21 g, 0.36 mmol) in THF (3 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/hexane) and crystallization (diethyl ether/hexane) yielded the title compound as a white solid (0.127 g, 57%). MS (ISP) 613.2 [(M+H)+]; mp 186° C.
Reaction SMILES: [CH3:1][C:2]1([CH2:9][C:10]([OH:12])=O)[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].Cl.Cl.[CH3:15][C:16]1[CH:25]=[C:24]([CH2:26][O:27][C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.N1CC(=O)NC1=O>>[CH3:1][C:2]1([CH2:9][C:10]([NH:32][C:31]2[CH:30]=[CH:29][C:28]([O:27][CH2:26][C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:16]([CH3:15])[CH:25]=3)=[CH:34][CH:33]=2)=[O:12])[C:3](=[O:8])[NH:4][C:5](=[O:7])[NH:6]1
Reactant: Cc1cc(COc2ccc(N)cc2)c2ccccc2n1
Reactant: CC1(CC(=O)O)NC(=O)NC1=O
Agent: Cl
Agent: O=C1CNC(=O)N1
Product: Cc1cc(COc2ccc(NC(=O)CC3(C)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 15.9 %

Procedure:
5-methylhydantoin-5-acetic acid (50 mg, 0.30 mmol) and 4-[(2-methyl-4-quinolinyl)methoxy]-aniline bis-HCl salt (101 mg, 0.30 mmol) were coupled using general coupling method A to give 20 mg (13%) of the product hydantoin. MS found:(M+H)+=419.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:4]=1[CH:5]([OH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:18]([N:26]=[C:27]=[S:28])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO.C(N(CC)CC)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:3]([CH2:2][NH:1][C:27]([NH:26][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[S:28])=[C:4]([CH:5]([OH:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:13]=1
Reactant: S=C=NCCc1ccccc1
Reactant: NCc1ccc(Cl)cc1C(O)c1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: OC(c1ccccc1)c1cc(Cl)ccc1CNC(=S)NCCc1ccccc1

Procedure:
2-aminomethyl-5-chlorobenzhydrol (10 g; 0.04 mole) in 100 ml methanol and 2 ml triethylamine was treated dropwise with a solution of phenethyl isothiocyanate (8.6 g; 0.053 mole) in 25 ml of methanol. After 16 hours at room temperature the reaction mixture was evaporated and the residue was extracted with petroleum ether. The residual oil was recrystallized from diisopropyl ether to yield 1-(4-chloro-2-(α-hydroxybenzyl)benzyl)-3-phenethylthiourea as a white powder (M.Pt. 97° -- 101° ).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([NH2:11])=[C:5]([CH:12]2[CH2:17][C:16]([CH3:19])([CH3:18])[CH2:15][C:14]([CH3:21])([CH3:20])[CH2:13]2)[CH:4]=1.Cl.Cl[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]Cl>ClC1C=CC=CC=1Cl>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([N:11]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[C:5]([CH:12]2[CH2:17][C:16]([CH3:19])([CH3:18])[CH2:15][C:14]([CH3:21])([CH3:20])[CH2:13]2)[CH:4]=1
Reactant: COc1cc(N)c(C2CC(C)(C)CC(C)(C)C2)cc1OC
Reactant: ClCCNCCCl
Agent: Cl
Solvent: Clc1ccccc1Cl
Product: COc1cc(C2CC(C)(C)CC(C)(C)C2)c(N2CCNCC2)cc1OC
Temperature: 220 °C
Reaction time: 2 h

Procedure:
A mixture of the crude product of 4,5-dimethoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenylamine produced in Example (87c), bis(2-chloroethyl)amine hydrochloride (700 mg, 3.91 mmol) and 1,2-dichlorobenzene (10 ml) was stirred for 2 hours at an external temperature of 220° C. During the reaction, nitrogen gas was blown in several times to remove the excess hydrogen chloride gas from the reactor. The reaction mixture was cooled to room temperature, saturated aqueous solution of sodium hydrogencarbonate was added and extraction was performed with chloroform. The aqueous layer was again extracted with chloroform, and the organic layers were combined, washed with brine and then dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 490 mg of the title compound as a brown oil.