Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=O)[CH2:2][O:3][CH2:4][CH2:5][CH2:6][CH3:7].C(N(CC)CC)C.C(Cl)CCl.[NH2:21][C@@H:22]([CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[C@H:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[OH:24]>C(Cl)Cl>[C:1]([NH:21][C@@H:22]([CH2:31][N:32]1[CH2:33][CH2:34][O:35][CH2:36][CH2:37]1)[C@H:23]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[OH:24])(=[O:9])[CH2:2][O:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCOCC(=O)O
Reactant: N[C@@H](CN1CCOCC1)[C@@H](O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CCCCOCC(=O)N[C@@H](CN1CCOCC1)[C@@H](O)c1ccccc1
Reaction time: 8 h
Yield: 58.9 %

Procedure:
Methylene chloride (20 ml), 3-oxaheptanoic acid (529.0 mg, 4.0 mmol), triethylamine (1.40 ml, 10.0 mmol) and EDC (1.15 g, 6.0 mmol) were added to (1S,2S)-2-amino-3-morpholino-1-phenyl-1-propanol (944.0 mg, 4.0 mmol), followed by stirring overnight. Methylene chloride (100 ml) was added to the reaction solution. After washed with a saturated sodium hydrogen carbonate solution (50 ml), water (50 ml) and saturated brine (50 ml) successively, the organic layer was dried over sodium sulfate and filtered, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform:ethanol=30:1) to obtain the title compound (825 mg, yield 59%) as colorless oil.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[CH3:16][C:17]([CH3:24])([CH3:23])[CH2:18][S:19](Cl)(=[O:21])=[O:20].[CH2:25]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[CH3:26]>>[CH3:16][C:17]([CH3:24])([CH3:23])[CH2:18][S:19]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:31]([C:30]3[CH:32]=[CH:33][C:27]([CH2:25][CH3:26])=[CH:28][CH:29]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:21])=[O:20]
Reactant: CCc1ccc(N)cc1
Reactant: CC(C)(C)CS(=O)(=O)Cl
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: CCc1ccc(N2CCC3(CCN(S(=O)(=O)CC(C)(C)C)CC3)C2=O)cc1

Procedure:
Light brown solid. MS (ESI): 415.2 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2,2-dimethylpropane-1-sulfonyl chloride and 4-ethyl-aniline.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][Cl:6].[Mg].II.[Cl:11][C:12]1[C:17]2[CH:18]=[N:19][N:20]([CH2:21][CH3:22])[C:16]=2[N:15]=[C:14]2[C:23](=[O:32])[C:24]3[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=3[CH2:26][CH2:27][C:13]=12>C(I)C.O1CCCC1>[ClH:6].[Cl:11][C:12]1[C:17]2[CH:18]=[N:19][N:20]([CH2:21][CH3:22])[C:16]=2[N:15]=[C:14]2[C:23]([CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])([OH:32])[C:24]3[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=3[CH2:26][CH2:27][C:13]=12
Reactant: CN(C)CCCCl
Reactant: CCn1ncc2c(Cl)c3c(nc21)C(=O)c1ccccc1CC3
Agent: II
Agent: [Mg]
Solvent: CCI
Solvent: C1CCOC1
Product: CCn1ncc2c(Cl)c3c(nc21)C(O)(CCCN(C)C)c1ccccc1CC3
Product: Cl
Reaction time: 0.67 h

Procedure:
12.3 g. of freshly distilled and absolutely dry 3-(dimethylamino)propyl chloride (0.1 mol.) are added slowly with stirring and gentle heating to 2.4 g. of magnesium turnings in 70 ml. of dry tetrahydrofuran. A crystal of iodine and a few drops of ethyl iodide are employed as initiator. After all of the 3-(dimethylamino)propyl chloride is added, the reaction mixture is refluxed for two to three hours. To this Grignard reagent a solution of 10.8 g. of 4-chloro-1-ethyl-5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11(1H)-one (0.035 mol.), from example 1(e), in 70 ml. of dry tetrahydrofuran is added. The mixture is heated under reflux for 5 hours after which the solvent is evaporated and the residue treated with 150 ml. of water and 60 ml. of ammonium chloride solution (20%). The mixture is extracted with ether and the ethereal extract is washed with water and dried with Na2SO4. Then the etheral solution is allowed to stand over night in a refrigerator to separate unreacted starting material (2.6 g. of oil). The decanted solution is charcoaled, filtered and 8 ml. of ethereal hydrochloric acid (195 g./l.) are added. Stirring is continued for 40 minutes. The precipitated hydrochloride salt is filtered off, washed with ether, and recrystallized from ethyl acetate/ether (1:5) to yield 8.3 g. (55%) of 4-chloro-11-[3-(dimethylamino)propyl]-1-ethyl-1,5,6,11-tetrahydro[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11-ol, hydrochloride (1:1); m.p. 172°-176° (dec.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([CH2:8]O)[CH:5]=[CH:6][CH:7]=1.CN(C)C1C=CC=CC=1.S(Cl)([Cl:29])=O.Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][Cl:29])[C:3]=1[S:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1cccc(Cl)c1SCc1ccccc1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: ClC(Cl)Cl
Product: ClCc1cccc(Cl)c1SCc1ccccc1
Temperature: 15 °C
Reaction time: 1 h

Procedure:
To a mixture of 54 g of the compound of Example 2 in 200 mL of chloroform (ethanol-free) and of N,N-dimethylaniline, a solution of 30 g of thionyl chloride in 50 mL of chloroform (ethanol-free) was added while maintaining the reaction temperature at 15° C. with an ice-water bath. The mixture was stirred at 25° C. for 1 hour, then refluxed for 3 hours. The mixture was acidified with 1 N aqueous hydrochloric acid and the organic layer was collected. The organic layer was washed once with 1 N aqueous hydrochloric acid, dried over magnesium sulfate, and filtered. The filtrate was passed through a silica gel column, eluted with methylene chloride, and after evaporation of the eluant, 54 g subject compound was obtained as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH:21]=[CH2:22]>CC(C)=O>[CH2:22]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C(=O)OCC)cc1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a mixture of ethyl 4-hydroxybenzoate (10.0 g, 60.0 mmol) in acetone (100 mL) was added K2CO3 (33.0 g, 239.1 mmol) at 10° C.; stirred for 0.5 hour. Then 3-bromo-propene (8.0 g, 66.0 mmol) was added dropwise and the reaction mixture was stirred at 10° C. for 5 hours. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to give product (12.0 g, 96%).
Reaction SMILES: [C:1]1([CH2:7][S:8][C:9]2[N:10]=[C:11]([Cl:19])[C:12]3[S:17][C:16](Br)=[N:15][C:13]=3[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.C(N(CC)CC)C>C(#N)C>[C:30]([O:29][C:27]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:16]2[S:17][C:12]3[C:11]([Cl:19])=[N:10][C:9]([S:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[N:14][C:13]=3[N:15]=2)[CH2:22][CH2:23]1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1nc(SCc2ccccc2)nc2nc(Br)sc12
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc3nc(SCc4ccccc4)nc(Cl)c3s2)CC1
Temperature: 35 °C
Reaction time: 24 h
Yield: 57.5 %

Procedure:
5-Phenylmethylthio-2-bromo-7-chloro-thiazolo[4,5-d]pyrimidine (WO 00/09511) (525 mg, 1.4 mmol), 4-amino-1-N-Boc-piperidine (339 mg, 1.7 mmol) and triethylamine (196 μL, 1.4 mmol) were dissolved in anhydrous acetonitrile (15 mL) and the mixture was stirred under a nitrogen atmosphere at 35° C. for 24 hours. The mixture was filtered and the remaining solid was washed with acetonitrile. After drying in air for 48 hours, 396 mg (57% yield) of the title compound was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[NH2:12][C@H:13]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:14]([CH3:17])([OH:16])[CH3:15].C(N(C(C)C)CC)(C)C>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:12][C@H:13]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[C:14]([CH3:17])([OH:16])[CH3:15])[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Reactant: CC(C)(O)[C@H](N)c1ccc(F)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)[C@H](Nc1nc(Cl)nc2c1SCC2)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 28.5 %

Procedure:
533 mg 2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidine, 850 mg (R)-1-amino-1-(4-fluoro-phenyl)-2-methyl-propan-2-ol and 1.3 ml diisopropylethylamine are suspended in 9.8 ml dioxane. The reaction mixture is stirred for 2 hours in the microwave at 80° C. and then evaporated to dryness. The residue is mixed with water. The precipitate formed is suction filtered and purified by chromatography (silica gel, petroleum ether/ethyl acetate 100/0 to 60/40). 260 mg of the product are obtained as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:7](OC=C=O)=[C:6](OC)[C:5]([O:14][CH2:15][C:16]2[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[C:18]([F:24])[C:17]=2[F:25])=[CH:4][C:3]=1[N:26]1[C:34](=[O:35])[NH:33][C:32]2[C:27]1=[N:28][C:29]([CH3:38])=[N:30][C:31]=2[O:36][CH3:37].[O:39]1[CH2:43][CH2:42]CC1.[BH4-].[Na+].Cl.C([OH:49])C>>[Cl:1][C:2]1[CH:7]=[C:6]([O:49][CH2:42][CH2:43][OH:39])[C:5]([O:14][CH2:15][C:16]2[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[C:18]([F:24])[C:17]=2[F:25])=[CH:4][C:3]=1[N:26]1[C:34](=[O:35])[NH:33][C:32]2[C:27]1=[N:28][C:29]([CH3:38])=[N:30][C:31]=2[O:36][CH3:37]
Reactant: C1CCOC1
Reactant: CCO
Reactant: COc1ccc(F)c(F)c1COc1cc(-n2c(=O)[nH]c3c(OC)nc(C)nc32)c(Cl)c(OC=C=O)c1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(F)c(F)c1COc1cc(-n2c(=O)[nH]c3c(OC)nc(C)nc32)c(Cl)cc1OCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxy-carbonylmethoxyphenyl]-6-methoxy-2-methyl-7,9-dihydro-8H-purin-8-one (0.58 g) in ethanol (15 mL)-tetrahydrofuran (7.5 mL) was added sodium borohydride (0.2 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2−ethyl acetate) to give the title compound (0.52 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[CH:12](=O)[CH2:13][CH2:14][CH3:15]>>[CH2:12]([NH:6][C:5]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:13][CH2:14][CH3:15]
Reactant: COc1ccc(N)cc1OC
Reactant: CCCC=O
Product: CCCCNc1ccc(OC)c(OC)c1
Yield: 87.9 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 137, 3,4-dimethoxyaniline (500 mg, 3.26 mmol) and butyraldehyde (290 μL, 3.26 mmol) were converted to the title compound (600 mg, 83%). 1H NMR (CDCl3) δ 6.81-6.70 (m, 1H), 6.27-6.21 (m, 1H), 6.16 (dd, J=8.5, 2.5 Hz, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 3.08 (t, J=7.0 Hz, 2H), 1.56-1.40 (m, 4H), 0.99-0.93 (m, 3H); MS(ESI+) m/z 210.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:15][OH:16]>>[N:7]1([CH2:6][C:5]2[CH:13]=[CH:14][C:2]([NH:1][CH:2]3[CH2:3][CH2:4][O:16][CH2:15][CH2:14]3)=[CH:3][CH:4]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: Nc1ccc(CN2CCOCC2)cc1
Reactant: CO
Product: c1cc(NC2CCOCC2)ccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A flask containing 4-(4-aminobenzyl)morpholine from Preparation No. 22 (0.48 g) is treated with methanol (5 mL) and a few dozen dry molecular sieves (3 Å). The mixture is treated with acetic acid (1 mL) and terahydro-4H-pyran-4-one (0.24 mL). After 1 hour, the mixture is carefully treated with sodium cyanoborohydride (0.6 g) and heated to reflux under an argon atmosphere. After 1 hour, the mixture is cooled to room temperature and filtered with methanol washes. The filtrate is diluted with diethyl ether and washed with aqueous sodium hydroxide (2N). The aqueous is back-extracted with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue is flash column chromatographed on silica eluting with 2% to 5% methanol in dichloromethane. The product-containing fractions are combined and evaporated to afford 0.34 g of N-[4-(4-morpholinylmethyl)phenyl]tetrahydro-2H-pyran-4-amine as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])[CH2:13][CH2:12]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:30][C:31]1[C:32]([CH3:40])=[CH:33][C:34]2[N:35]([N:37]=[CH:38][N:39]=2)[N:36]=1>O1CCCC1>[ClH:30].[C:3]1([CH:9]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:31]3[C:32]([CH3:40])=[CH:33][C:34]4[N:35]([N:37]=[CH:38][N:39]=4)[N:36]=3)[CH2:13][CH2:12]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cc2ncnn2nc1Cl
Reactant: OCCCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc2ncnn2nc1OCCCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Product: Cl
Temperature: 0 °C
Yield: 38.7 %

Procedure:
160 mg of 60% sodium hydride in oil was suspended in 20 ml of tetrahydrofuran; 1.24 g of 4-(diphenylmethoxy)-1-piperidinehexanol was added, followed by heating and refluxing for 1 hour. After cooling, 570 mg of 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine was added, followed by heating and refluxing for 1 hour. After cooling, ice water was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. After the dry product was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol (10:1). The desired fraction was collected and dissolved in 5 ml of ethyl acetate; 0.54 ml of a 4 N hydrogen chloride solution in ethyl acetate was added; the crystal precipitated was collected by filtration, washed with ethyl ether and dried to yield 0.70 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)([CH3:4])([CH3:3])[CH3:2].[NH2:19][CH2:20][C@@H:21]([OH:39])[CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[C:31]=2[CH3:38])[CH2:25][CH2:24]1>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:11]([C:12]([NH:19][CH2:20][C@@H:21]([OH:39])[CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[C:31]=3[CH3:38])[CH2:25][CH2:24]2)=[O:14])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(OC2CCN(C[C@H](O)CN)CC2)ccc(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)COc1cccc(C(=O)O)c1
Product: Cc1c(OC2CCN(C[C@H](O)CNC(=O)c3cccc(OCC(=O)OC(C)(C)C)c3)CC2)ccc(Cl)c1Cl

Procedure:
Prepared as for Example 15 Step 2 using 3-(2-tert-butoxy-2-oxoethoxy)benzoic acid [WO 00/78317 A1] and (2R)-1-amino-3-[4-(3,4-dichloro-2-methylphenoxy)piperidin-1-yl]propan-2-ol to yield the subtitle compound as a white solid (0.11 g).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([CH:8]=[O:9])=[CH:5][CH:4]=1)[CH3:2].[N+:10]([CH:12](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:13])#[C-:11].C([O-])([O-])=O.[K+].[K+].O>CO>[CH2:1]([C:3]1[S:7][C:6]([C:8]2[O:9][CH:11]=[N:10][C:12]=2[CH3:13])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C=O)s1
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCc1ccc(-c2ocnc2C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.8 %

Procedure:
A mixture of 5-ethylthiophene-2-carbaldehyde (0.670 g, 4.78 mmol), 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (1.0 g, 4.8 mmol), and K2CO3 (0.859 g, 6.21 mmol) in MeOH (16 mL) was heated at reflux for 2 h, then cooled to room temperature and allowed to stand overnight. The mixture was poured into water and extracted with Et2O, and the combined extracts were concentrated in vacuo. The residue was chromatographed on silica gel (Analogix® SF40-115 column, 15% to 30% EtOAc/hexanes eluant, 18 minutes) to afford 0.94 g (102%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.26 (s, 1H), 7.15 (d, J=3.6, 1H), 6.91 (dt, J=3.7, 1.0 1H), 2.85 (qd, J=7.5, 0.8 2H), 2.29 (s, 3H), 1.26 (t, J=7.5, 3H). MS (DCI+) m/z 194 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:29]([O:31]CC)=[O:30])[CH:25]=4)[CH:20]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO>[CH3:1][C:2]1([CH3:34])[CH2:11][CH:10]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[C:8]2[CH:7]=[C:6]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:29]([OH:31])=[O:30])[CH:25]=4)[CH:20]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc2cc(-c3ccc4c(c3)C(c3ccc(C)cc3)=CCC4(C)C)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(-c4ccc5cc(C(=O)O)ccc5c4)cc32)cc1
Temperature: 0 °C
Yield: 19.4 %

Procedure:
A solution of ethyl 5′,6′-dihydro-5′,5′-dimethyl-8′-(4-methylphenyl)-[2,2′-binaphthalene]-6-carboxylate (Compound 64) 0.19 g, 0.43 mmol), EtOH (8 ml) and 1N aqueous NaOH (2 ml) was heated to 60° C. for 3 hours. The solution was cooled to 0° C. and acidified with 1N aqueous HCl. The product was extracted into ethyl acetate, and the organic layers combined, washed with water, brine, dried (MgSO,), filtered and the solvent removed in-vacuo. The residue was recrystalized from THF/ethyl acetate at 0° C. to give 35 mg of pure material. The mother liquor was concentrated under reduced pressure and the residue purified by silica gel chromatography (100% ethyl acetate) to give an additional 125 mg of the title compound (overall yield=160 mg, 90%) as a colorless solid. 1H NMR (DMSO-d6) δ8.57 (s, 1H), 8.11 (d, 1H, J=8.7 Hz), 7.96-7.82 (overlapping d's, 3H),7.65 (d, 2H, J=7.6 Hz), 7.50 (d, 1H, J=7.9 Hz), 7.28 (s, 1H), 7.26 (d, 2H, J=8.3 Hz), 7.21 (d, 2H, J=8.3 Hz), 6.01 (t, 1H, J 4.5 Hz), 3.34 (br s, 1H), 2.31 (s, 3H), 2.31 (d, 2H, J=4.5 Hz), 1.31 (s, 6H).
Reaction SMILES: [C:1]([NH:4][C:5]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[O:24][C:25]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:26]=3[N:27]=2)[CH2:19][CH2:18]1)([CH2:13][CH2:14][CH:15]=[CH2:16])[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].[CH3:33][C:34]1([CH3:41])[C:38]([CH3:40])([CH3:39])[O:37][BH:36][O:35]1.O>ClCCl.[Ir+].ClC1CCC=CCCC=1.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([NH:4][C:5]([CH:17]1[CH2:18][CH2:19][N:20]([C:23]2[O:24][C:25]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:26]=3[N:27]=2)[CH2:21][CH2:22]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:36]1[O:37][C:38]([CH3:40])([CH3:39])[C:34]([CH3:41])([CH3:33])[O:35]1)[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: C=CCCC(NC(C)=O)(C(=O)NC(C)(C)C)C1CCN(c2nc3ccc(Cl)cc3o2)CC1
Reactant: CC1(C)OBOC1(C)C
Agent: [Ir+]
Agent: ClC1=CCCC=CCC1
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1CCN(c2nc3ccc(Cl)cc3o2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
A solution of 2-acetamido-N-tert-butyl-2-(1-(6-chlorobenzo[d]oxazol-2-yl)piperidin-4-yl)hex-5-enamide (240 mg, 0.52 mmol) in dichloromethane (4 mL), was treated with chloro-1,5-cyclooctadiene iridium(I) dimer (10.4 mg, 3 mol %) and 1,2-bis(diphenylphosphino) ethane (12.2 mg, 6 mol %). The solution was stirred at room temperature for 30 minutes and then 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.152 mL, 1.04 mmol) was added dropwise, and the reaction was stirred overnight at room temperature. The next day, the reaction mixture was poured into water and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification of the crude product by flash column chromatography (silica gel, 30-100% ethyl acetate in heptane) gave 2-acetamido-N-tert-butyl-2-(1-(6-chlorobenzo[d]oxazol-2-yl)piperidin-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide as a colorless oil (212 mg, 69%). 1H NMR (CDCl3, 300 MHz) δ 7.24 (d, J=2 Hz, 1H), 7.20 (d, J=8.5 Hz, 1H), 7.12 (dd, J1=8.5 Hz, J2=2 Hz, 1H), 6.97 (s, NH, 1H), 5.48 (s, NH, 1H), 4.32 (m, 2H), 3.02 (m, 2H), 2.84 (m, 1H), 2.47 (tt, J1=12.5 Hz, J2=3 Hz, 1H), 2.01 (s, 3H), 1.86 (m, 2H), 1.30-1.55 (m, 6H), 1.34 (s, 9H), 1.24 (s, 12H), 1.02-1.22 (m, 1H), 0.75 (t, J=7.5 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=2[NH:10][C:9]1=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]([O:24][C:25](=[O:30])[CH:26](Br)[CH2:27][CH3:28])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=2[N:10]([CH:26]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:30])[CH2:27][CH3:28])[C:9]1=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC(Br)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2cc(C#N)ccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(C(=O)OC(C)(C)C)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.1 %

Procedure:
To a chilled solution of 5-cyano-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester (50 mg, 0.19 mmol) in dry DMF (1 mL) NaH (60% dispersion mineral oil, 8 mg, 0.20 mmol) was added under N2 atmosphere. The reaction was stirred at room temperature for 15 min. Then, a solution of tert-butyl-2-bromobutyrate (0.054 mL, 0.29 mmol) in DMF (2 mL) was added at 0° C. The reaction mixture was stirred at room temperature for 3 hours, diluted with ethyl acetate, washed with water, with a saturated NH4Cl aqueous solution, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography in silical gel using 15% ethyl acetate in n-heptane as eluent to afford 3-(1-tert-butoxycarbonyl-propyl)-5-cyano-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester (55 mg, 72%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[C:22]3[C:17](=[C:18]([Cl:24])[CH:19]=[C:20]([Cl:23])[CH:21]=3)[CH2:16][N:15]([CH3:25])[CH2:14]2)=[CH:9][CH:8]=1>>[ClH:23].[Cl:23][C:20]1[CH:21]=[C:22]2[C:17](=[C:18]([Cl:24])[CH:19]=1)[CH2:16][N:15]([CH3:25])[CH2:14][CH:13]2[C:10]1[CH:9]=[CH:8][C:7]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:12][CH:11]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(Br)cc2)C1
Reactant: C1CCNC1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(N3CCCC3)cc2)C1
Product: Cl

Procedure:
The reaction is carried out in analogy to the method described in example 10, starting from pyrrolidine and 4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline (example 5, intermediate 3). The product obtained after purification by chromatography is taken up in the DMSO/acetonitrile mixture, whereupon a precipitate separates out. This is filtered off, dissolved in 2 N HCl and freeze dried, resulting in the title compound of a colorless solid.