Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][C:15]3=[O:16])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH2:27](Br)[CH:28]=[C:29]([CH3:31])[CH3:30]>C(O)(C)C>[CH2:27]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][C:15]3=[O:16])[CH2:12][CH2:13]2)=[O:7])=[CH:25][CH:26]=1)[CH:28]=[C:29]([CH3:31])[CH3:30]
Reactant: O=C(c1ccc(O)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Reactant: CC(C)=CCBr
Solvent: CC(C)O
Product: CC(C)=CCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1

Procedure:
1-[1-(4-Hydroxybenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (500 mg), prenyl bromide (0.5 ml) and 1,8-diazabicyclo[5.4.0]-undecene-7 (0.65 ml) are dissolved in isopropanol (10 ml) and the mixture is refluxed with heating for 4 hours. The solvent is distilled off under reduced pressure and the residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=2:1) to give 1-{1-[4-(2-isopentenyloxy)benzoyl]-4-piperidinyl} -3,4-dihydrocarbostyril (0.159 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[F:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13](Cl)=[O:14]>>[OH:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[NH:1][C:13](=[O:14])[C:12]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:11]=1[F:10]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Reactant: Cc1ccc(O)c(N)c1
Product: Cc1ccc(O)c(NC(=O)c2cc([N+](=O)[O-])ccc2F)c1

Procedure:
Prepared by the method of Example 15a), from 2-amino-4-methylphenol (283 mg, 2.3 mmol) and 2-fluoro-5-nitrobenzoyl chloride (468 mg, 2.3 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][C:6]([CH3:19])([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH:16]([CH3:18])[CH3:17])[CH:10]=2)[CH2:5][CH2:4]1)C.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22].[OH-].[Na+]>C1(C)C=CC=CC=1>[C:24]1([O:23][C:21]([N:3]2[CH2:8][CH2:7][C:6]([CH3:19])([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH:16]([CH3:17])[CH3:18])[CH:10]=3)[CH2:5][CH2:4]2)=[O:22])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCN1CCC(C)(c2cccc(OC(C)C)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)Oc1cccc(C2(C)CCN(C(=O)Oc3ccccc3)CC2)c1
Temperature: 45 °C
Yield: 46.4 %

Procedure:
To N-ethyl-4-methyl-4-(3-(1-methylethoxy)phenyl)piperidine (Preparation 51, 3.98 g, 15.23 mmol) in toluene (30 ml) at 85° C. was slowly added phenyl chloroformate (2.1 ml, 16.75 mmol) and the mixture was then heated under reflux for 16 h. The solution was cooled to 45° C. and 50% w:v aqueous sodium hydroxide solution (2 ml) was added. Once the solution had cooled to room temperature the organic layer was separated and washed with methanol:1N aqueous hydrochloric acid (1:1, 3×10 ml), methanol:1N aqueous sodium hydroxide solution (1:1, 12 ml) and water (20 ml). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give the crude product. This was purified by silica column chromatography using ethyl acetate:hexane (20:80) to give the title compound as an oil (2.5 g, 45% over three steps).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:11][N:12]([CH:15]3[CH2:17][CH2:16]3)[C:13]=2[CH3:14])=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([Cl:33])[C:28](=[O:32])[N:29]([CH3:31])[CH:30]=1>C(Cl)Cl.CO>[Cl:33][C:27]1[C:28](=[O:32])[N:29]([CH3:31])[CH:30]=[C:25]([NH:24][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:11][N:12]([CH:15]3[CH2:17][CH2:16]3)[C:13]=2[CH3:14])[CH:26]=1
Reactant: CCOC(=O)c1nn(C2CC2)c(C)c1C(O)c1ccc(Cl)cc1
Reactant: Cn1cc(N)cc(Cl)c1=O
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1nn(C2CC2)c(C)c1C(Nc1cc(Cl)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-cyclopropyl-5-methyl-1H-pyrazole-3-carboxylate (Step 17.5) and 5-amino-3-chloro-1-methylpyridin-2(1H)-one (Step 5.2). tR: 4.81 min (HPLC 1); tR: 1.09 min (LC-MS 2); ESI-MS: 475/477 [M+H]+ (LC-MS 2); Rf=0.52 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].N1C=CC=CC=1.[Br:26]Br>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([Br:26])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccccc3c2c1C
Reactant: BrBr
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ncc2[nH]c3ccc(Br)cc3c2c1C
Reaction time: 1 h
Yield: 38 %

Procedure:
0.5 g of 4-methyl-β-carbolin-3-carboxylic acid ethyl ester (melting point 235°-239° C.) is dissolved in 25 ml of chloroform and 1.7 ml of pyridine and a solution of 1 ml of bromine in 21 ml of chloroform is added dropwise thereto at 0° C. After standing for one hour while cooling with ice and after dilution with 50 ml of the methylene chloride, the mixture is extracted by washing with sodium thiosulphate solution, dilute aqueous ammonia solution and water. After drying with sodium sulphate, filtering off and distilling off the solvent in vacuo, 6-bromo-4-methyl-β-carbolin-3-carboxylic acid ethyl ester is obtained in 38% yield, Melting point 231°-232° C. (from acetone).
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:7]([OH:8])[C@H:6]([OH:9])[C:5](=[O:10])[CH:4]=[CH:3]1.[H][H]>>[OH:8][C@H:7]1[C@H:6]([OH:9])[C@@H:5]([OH:10])[CH2:4][CH2:3][C:2]1=[O:1]
Reactant: [H][H]
Reactant: O=C1C=C[C@H](O)[C@@H](O)[C@@H]1O
Product: O=C1CC[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The method for producing catechol as described above, by reducing (4S,5R,6S)-4,5,6-trihydroxy-2-cyclohexene-1-one with hydrogen to produce (2S,3R,4S)-2,3,4-trihydroxycyclohexane-1-one represented by the following formula (3), and dehydrating the (2S,3R,4S)-2,3,4-trihydroxycyclohexane-1-one.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]([F:44])([F:43])[C:31]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:32]=1[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:33][C:32]3[CH:35]=[CH:36][C:37]([C:39]([F:42])([F:41])[F:40])=[CH:38][C:31]=3[C:30]([F:29])([F:43])[F:44])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Product: FC(F)(F)c1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c(C(F)(F)F)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2,4-bis-trifluoromethyl-benzaldehyde. MS (ESI) m/z 602.
Reaction SMILES: [Na].[CH3:2][O-:3].[Na+].CS[C:7]1[N:12]([NH2:13])[C:11](=[O:14])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:9][N:8]=1.CI>CO>[CH3:2][O:3][C:7]1[N:12]([NH2:13])[C:11](=[O:14])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:9][N:8]=1
Reactant: C[O-]
Reactant: CSc1nnc(-c2ccccc2)c(=O)n1N
Agent: [Na+]
Agent: [Na]
Solvent: CI
Solvent: CO
Product: COc1nnc(-c2ccccc2)c(=O)n1N
Reaction time: 1 h

Procedure:
2.3 g sodium are added to 500 ml methanol whereby a sodium methylate solution is formed. 23.4g 3-methylthio-4-amino-6-phenyl-1,2,4-triazine-5-one (1a) and 6.5 ml methyl iodide are added. The mixture is boiled for 1 hour. When cooling down the mixture, a crystalline precipitate separates. The crystals are removed by suction and recrystallized from methanol and optionally once more from acetic acid ester. The 3-methoxy-4-amino-6-phenyl-1,2,4-triazin-5one (33") thus obtained has a melting point of 167° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[N:9][CH:8]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)=[N:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC1(c2cnc(Cn3cc(N)cn3)s2)OCCO1
Product: CC(=O)c1cnc(Cn2cc(NC(=O)c3ncoc3-c3ccccc3)cn2)s1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 01: tR=0.9 min; [M+H]+=393.96.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[NH:10])[NH2:9].CC(C)([O-])C.[K+].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25](=[C:27]([C:33](OCC)=[O:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:26].Cl>CN(C)C=O>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25]1([CH3:26])[CH:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:33](=[O:34])[NH:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)=[N:10]1
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)c1ccc(F)cc1F
Reactant: N=C(N)c1ccccn1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1C(=O)NC(c2ccccn2)=NC1(C)c1ccc(F)cc1F
Temperature: 60 °C
Reaction time: 45 h
Yield: 32 %

Procedure:
Under a nitrogen atmosphere, a pressure tube was charged with a magnetic stirring bar, pyridine-2-carboximidamide hydrochloride (268 mg, 1.70 mmol), N,N-Dimethylformamide (13.2 mL), potassium tert-butoxide (382 mg, 3.41 mmol) and diethyl 2-(1-(2,4-difluorophenyl)ethylidene)malonate (508 mg, 1.70 mmol). The reaction mixture was sealed and stirred at 60° C. for 45 hours. After cooling to room temperature, the reaction mixture was poured into ice water (200 mL) and the resulting emulsion was neutralized (pH=7) using hydrochloric acid (1N). The mixture was extracted with dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. N,N-Dimethylformamide was co evaporated using toluene and the resulting yellow oil was purified using silica gel column chromatography with ethyl acetate in heptane in a gradient from 10 to 40%. The desired fractions were concentrated in vacuo yielding ethyl 4-(2,4-difluorophenyl)-4-methyl-6-oxo-2-(pyridin-2-yl)-1,4,5,6-tetrahydropyrimidine-5-carboxylate (203 mg). Under a nitrogen atmosphere, a tube was charged with a stirring bar, ethyl 4-(2,4-difluorophenyl)-4-methyl-6-oxo-2-(pyridin-2-yl)-1,4,5,6-tetrahydropyrimidine-5-carboxylate (137 mg, 0.367 mmol) and phosphorous oxychloride (0.509 mL, 5.48 mmol). The mixture was stirred and heated at reflux for 30 minutes. After cooling to room temperature, the reaction mixture was concentrated to dryness. The obtained residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate (3×10 mL), dried (isolute HM-N) and evaporated to resulting in ethyl 6-chloro-4-(2,4-difluorophenyl)-4-methyl-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (154 mg) as a yellow powder which was used as such in the next step.
Reaction SMILES: [CH:1]1([C@@:6]([OH:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([N:19]1[CH2:23][CH2:22][CH:21](O)[CH2:20]1)[CH3:18].O>CN(C=O)C>[CH2:17]([N:19]1[CH2:23][CH2:22][CH:21]([O:8][C:7](=[O:9])[C@:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)([OH:16])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:20]1)[CH3:18]
Reactant: O=C(O)[C@](O)(c1ccccc1)C1CCCC1
Reactant: CCN1CCC(O)C1
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCC(OC(=O)[C@](O)(c2ccccc2)C2CCCC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.7 %

Procedure:
0.655 g (0.00297 mol) of (2R)-2-Cyclopentyl-2-hydroxy-2-phenylacetic acid were dissolved in 8 ml of dry DMF. To this solution 0.580 g (0.0036 mol) of 1,1′-carbonildiimidazol were added and the mixture was stirred at room temperature for 1 h. After this time, the mixture obtained was added to a suspension (cooled at 0° C.) of 1-ethylpyrrolidin-3-ol (0.390 ml g, 0.0033 mol) and HNa (0.078 g, 0.0033 mol) in 4 ml of dry DMF. After stirring 15 h at room temperature the reaction mixture was treated with water and extracted three times with Et2O. The organic layers were combined, washed with water and dried. The residue was purified by silica gel column chromatography (eluent: CHCl3 plus isopropanol 0%→5%) to obtain 610 mg (65%) of the title product as an oil.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[CH3:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([CH3:30])[C:28]=1[OH:29])[CH:24]=O.Cl>C(Cl)Cl>[CH3:20][C:21]1[CH:22]=[C:23]([CH2:24][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:26]=[C:27]([CH3:30])[C:28]=1[OH:29]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(CN2CCCC2)cc(C)c1O
Yield: 82.2 %

Procedure:
NaB(OAc)3H (22.1 g, 0.104 mol) was added in portions for 15 min to a mixture of pyrrolidine (8.1 mL, 0.098 mol) and 3,5-dimethyl-4-hydroxybenzaldehyde (12.5 g, 0.083 mol) in CH2Cl2 (100 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon Ar. The mixture was stirred for 20 h and cooled with an ice bath. Concentrated HCl (19 mL) was added. The organic layer was separated and discarded. The aqueous one was alkalized with 10 N NaOH to pH 9 (30 mL) and extracted with chloroform (2×100 mL). The combined extracts were dried with Na2SO4, and evaporated to give the title compound (14 g, 82%) was obtained as white crystals. LCMS-data: 206.1 and 207.1 (M+H)+ (calculated for C13H19NO 205.1). 1H NMR (400 MHz)-data (DMSO-d6, J, Hz): 7.99 (br s, 1H, OH); 6.80 (s, 2H, ArH); 3.36 (s, 2H, CH2); 2.32-2.41 (m, 4H, CH2CH2CH2CH2); 2.13 (s, 6H, (CH3)2); 1.61-1.70 (m, 4H, CH2CH2CH2CH2).
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:20]([F:23])([F:22])[F:21])=[N:10][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:12][CH:13]=1)=[O:7].C(N(C(C)C)CC)(C)C.[F:34][C:35]([F:46])([F:45])[C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39]>ClCCl>[CH3:1][CH:2]([CH3:24])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:20]([F:23])([F:21])[F:22])=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:38](=[O:39])[C:37]3[CH:41]=[CH:42][CH:43]=[CH:44][C:36]=3[C:35]([F:34])([F:45])[F:46])[CH2:16][CH2:15]2)=[N:12][CH:13]=1)=[O:7]
Reactant: CC(C)CCNC(=O)c1cnc(N2CCNCC2)nc1C(F)(F)F
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CCNC(=O)c1cnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
To an ice-cold solution of 2-piperazin-1-yl-4-trifluoromethyl-pyrimidine-5-carboxylic acid (3-methylbutyl)amide (0.323 g, 0.935 mmol) in dichloromethane (20 mL) was added diisopropylethylamine (0.242 mL, 1.40 mmol). The mixture was stirred for 10 minutes before 2-trifluoromethylbenzoyl chloride (0.175 g, 0.842 mmol) in 5 mL dichloromethane was added. The stirring was continued for another 15 minutes. The reaction was quenched by the addition of saturated sodium bicarbonate solution, followed by water. The mixture was extracted with dichloromethane, and the organic layer was separated, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound in yield 76% (0.225 g, 0.435 mmol). 1H NMR (CDCl3) δ 8.59, 7.73-7.71, 7.64-7.51, 7.35-7.33, 5.76, 4.09-3.74, 3.44-3.37, 3.26-3.22, 1.68-1.59, 1.48-1.41, 0.09. MS (ES+) m/z 518.2 (M+1).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:26][C:17]3=[C:18]4[C:22](=[CH:23][CH:24]=[C:16]3[O:15][CH2:14]2)[NH:21][C:20](=[O:25])[CH2:19]4)(=O)=O)=CC=1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CS(C)=O>[CH2:27]([NH:34][CH2:12][C@@H:13]1[O:26][C:17]2=[C:18]3[C:22](=[CH:23][CH:24]=[C:16]2[O:15][CH2:14]1)[NH:21][C:20](=[O:25])[CH2:19]3)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Solvent: CS(C)=O
Product: O=C1Cc2c(ccc3c2O[C@@H](CNCc2ccccc2)CO3)N1
Reaction time: 18 h
Yield: 101.4 %

Procedure:
A 25 mL, flask is charged with [(2R)-8-oxo-2,3,8,9-tetrahydro-7H-[1,4]dioxino[2,3-e]indol-2-yl]methyl 4-methylbenzenesulfonate (1.00 g, 2.7 mmol) and DMSO (8.0 mL). Nitrogen gas is bubbled through the solution for 10 min, benzylamine (0.73 mL, 6.7 mmol) is added and nitrogen is bubbled through the mixture for another 15 min. The flask is immersed in an 85° C. oil bath and stirred for 18 h. The solution is cooled, water (24 mL) is added and the resulting solution is extracted with MTBE (3×15 mL). The combined organic extracts are washed successively with water (10 mL), saturated NH4Cl (10 mL) and saturated NaHCO3 (10 mL), and are evaporated to give the crude title compound (0.85 g, 101%) as a red syrup. LCMS (Basic Method): 1.84 min, 311 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 10.4 (br s, 1H), 7.35-7.27 (m, 5H), 6.73 (d, J=8.3 Hz, 1H), 6.36 (d, J=8.3 Hz, 1H), 4.37-4.35 (m, 1H), 4.25 (dd, J=2.2, 11.5 Hz, 1H), 4.03 (dd, J=7.3, 11.5 Hz, 1H), 3.88 (s, 2H), 3.44 (s, 2H), 2.97-2.88 (m, 2H), 8.9 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[C:22]([N+:33]#[C-:34])[S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:4]=1.[CH2:35](I)[CH3:36]>>[CH3:1][O:2][C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH:11]=[C:12]2[C:22]([N+:33]#[C-:34])([S:23]([C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH2:35][CH3:36])[CH:4]=1
Reactant: CCI
Reactant: [C-]#[N+]C(=C1CC[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)[C@H]3CC[C@]12C)S(=O)(=O)c1ccc(C)cc1
Product: [C-]#[N+]C(CC)(C1=CC[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)[C@H]3CC[C@]12C)S(=O)(=O)c1ccc(C)cc1

Procedure:
The title compound was prepared according to the method described in Example 8a starting from 3-methoxy-17-(isocyano-p-methylphenylsulfonylmethylene)-androsta-3,5-diene (954 mg, 2 mmol) and ethyl iodide (4.9 mmol). Yield: 900 mg (89%), m.p. 135°-150° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]2[O:10]C[N:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][C:6]=2[CH:15]=1.[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1B(O)O.C(=O)([O-])[O-].[K+].[K+]>COCCOCCOC.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>[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1[C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]([OH:10])=[C:6]([CH2:7][NH:8][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:15]=1
Reactant: CC(C)(C)N1COc2c(cc(Br)cc2-c2ccccc2)C1
Reactant: OB(O)c1cc2ccccc2o1
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: [K+]
Solvent: O
Solvent: COCCOCCOC
Product: CC(C)(C)NCc1cc(-c2cc3ccccc3o2)cc(-c2ccccc2)c1O
Temperature: 56.5 °C
Yield: 53 %

Procedure:
A mixture of 6-bromo-3-(tert-butyl)-8-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazine (from Example 42, Step 2) (0.552 g, 1.6 mmol), benzofuran-2-ylboronic acid (0.387 g, 1.5 equiv), and potassium carbonate (0.885 g, 4 equiv) in 2-methoxyethyl ether (10 mL) and water (2 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)Pd (0) (82 mg, 0.073 mmol, 4.5 mol %) was added and the resulting mixture was heated at 51-62° C. for 1.5 hours. To the reaction mixture, additional benzofuran-2-ylboronic acid (0.173 g, 1.07 mmol) was added. The resulting mixture was allowed to heat at 60-62° C. overnight. The cooled reaction mixture was concentrated and the resulting residue was purified by column chromatography to give 5-(benzofuran-2-yl)-3-((tert-butylamino)methyl)-[1,1′-biphenyl]-2-ol (0.315 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]O)=[CH:20][CH:19]=1.C(O)(=O)C(O)=O>C(O)(=O)C.O>[C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:15])=[C:7]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: COc1ccc(CO)cc1
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)cc1

Procedure:
4,6-Di-t-butyl-2-(4-methoxybenzyl)phenol was prepared as follows: A solution of 2,4-di-t-butylphenol (57.5 g), 4-methoxybenzyl alcohol (34.5 g) and oxalic acid (2 g) in acetic acid (80 ml) and water (2 ml) was refluxed for 7 hours, diluted with water, and extracted with chloroform. Distillation of the chloroform extract gave an oil (b.p. 200°-210° C. at 2 mm Hg) which crystallized (58 g; 71.4%). The product was recrystallized from methanol to give glistening colorless needles, m.p. 84°-85° (Found: C, 81.0; H, 8.21. Calc. for C22H30O2 : C, 80.9; H, 9.26%). The pmr spectrum exhibited the following: δ1.30, 9H, S; δ1.38, 9H, S; δ3.79, 3H, S; δ3.83, 2H, S; δ4.62, 1H, S; δ6.84, 2H, D (J=8 Hz); δ7.02, 1H, D (J=2 Hz); δ 7.14, 2H, D (J=8 Hz); δ7.23, 1H, D (J=Hz).
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10]CC)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C=CC=CC=1.[F:19][C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1[NH2:22]>>[F:19][C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1[NH:22][C:8](=[O:10])[CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: Nc1ccc(F)cc1F
Solvent: c1ccncc1
Product: CCOC(=O)C(C)C(=O)Nc1ccc(F)cc1F

Procedure:
The ester was prepared according to Procedure A using diethyl 2-methylmalonate (5.99 mL, 34.9 mmol), pyridine (3.76 mL, 46.5 mmol) and 2,4-difluoroaniline (2.34 mL, 23.2 mmol). The residue was purified by column chromatography on silica gel (0-30% EtOAc/hexanes) to give ethyl 3-(2,4-difluorophenylamino)-2-methyl-3-oxopropanoate as a red oil. Mass Spectrum (ESI) m/e=258.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9]1.[Li]CCCC.C(N(C(C)C)CC)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C1CCCC1
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: OC1(c2ccncc2Br)CCCC1
Yield: 33.8 %

Procedure:
Using analogous reaction condition and reagents as described in Example 20 for the preparation of I-20a above, 3-bromo pyridine solution (1.0 g, 6.36 mmol) was reacted with cyclopentanone solution (0.6 mL, 70 mmol) in dry THF (6 mL), n-BuLi solution (4.0 mL, 7.6 mmol) and diisopropylethyl amine (1.0 mL, 70 mmol) in dry THF (6 mL) to afford the crude product. The crude was purified by column chromatography on silica gel (20% ethyl acetate in hexane) afforded 520 mg of the product (34% yield).