Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[N-:16]=[N+:17]=[N-:18].[Na+].[Al]>O>[N:16]([CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]1=[O:15])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [Al]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NCCCN1C(=O)c2ccccc2C1=O
Yield: 72.4 %

Procedure:
A heavy-walled Pyrex tube was charged with a suspension of N-(3-bromopropyl)phthalimide (1.00 g, 3.72 mmol) and sodium azide (0.32 g, 4.84 mmol) in H2O (2 mL). The tube containing the resulting mixture was sealed with an aluminum crimp cap fitted with a silicon septum and then it was exposed to microwave irradiation for 30 min at a temperature of 120° C. After the irradiation, the reaction tube was cooled with high-pressure air until the temperature had fallen below 40° C. The product was extracted with ethyl acetate. The combined organic layers were dried with magnesium sulfate, filtered and concentrated in vacuo. The crude material (0.62 g, 72% yield) was used without further purification in the next step. 1H NMR (400 MHz, CDCl3) δ 7.86-7.83 (m, 2H), 7.73-7.70 (m, 2H), 3.77 (t, J=6.4 Hz, 2H), 3.36 (t, J=8.0 Hz, 2H), 1.94 (m, 2H).
Reaction SMILES: [C:1]([CH:4]([CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2]>O1CCOCC1.[H][H].[C].[Pd]>[C:5]([CH:4]([CH2:8][CH2:9][CH:10]([CH3:22])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:1](=[O:3])[CH3:2])(=[O:7])[CH3:6]
Reactant: CC(=O)C(CC=C(C)CCC=C(C)CCC=C(C)C)C(C)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: CC(=O)C(CCC(C)CCCC(C)CCCC(C)C)C(C)=O

Procedure:
10 Grams of 3-acetyl-6,10,14-trimethyl-5,9,13-pentadecatriene-2-on (Compound No. 2 in the Table) were dissolved in 10 g of dioxane, and one gram of 5% palladium-carbon was added to the solution. The mixture was catalytically reduced in hydrogen flow at an ordinary temperature under atmospheric pressure. After the reaction was completed, the palladium-carbon was filtered off, and the filtrate was subjected to distillation under the reduced pressure, to obtain 10 g of oily product. The product was purified by the column chromatography method as described in Example 1.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:17]/[OH:18])/[C:8]([O:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[O:9])[N:6]=1.Br[CH:20]([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:17]/[O:18][CH:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH3:28])/[C:8]([O:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:14])=[O:15])=[O:9])[N:6]=1
Reactant: CS(=O)(=O)CCOC(=O)/C(=N\O)c1csc(N)n1
Reactant: CC(Br)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(O/N=C(\C(=O)OCCS(C)(=O)=O)c1csc(N)n1)C(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 75.4 %

Procedure:
In 100 ml of acetone was suspended 5 g (0.017 mole) of methylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate and 5.33 g (0.0255 mole) of t-butyl 2-bromopropionate was added. After a serial addition of 0.3 ml of water and 9.4 g of anhydrous potassium carbonate, the mixture was stirred at 40° C. for about 2.5 hours. After completion of the reaction, the insoluble matter was filtered off. To the filtrate was added 100 ml of water and the mixture was extracted with 150 ml of ethyl acetate. The organic layer was washed with 50 ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated to dryness under reduced pressure. The concentrate was crystallized from ethyl acetate-isopropyl ether (1:5, v/v). After cooling to 0° C. or below, the crystalline precipitate was collected by filtration and dried under reduced pressrue to give 5.4 g (yield, 75.4%) of methylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-1-methylmethoxyimino)acetate as white crystals.
Reaction SMILES: C(O[C:6](=[O:34])[NH:7][C@H:8]([C:13](=[O:33])[NH:14][C@H:15]([B:20]1[O:28][C@H:27]2[C@:22]([CH3:32])([C@H:23]3[CH2:29][C@@H:25]([CH2:26]2)[C:24]3([CH3:31])[CH3:30])[O:21]1)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.[C:35]1([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:40]=[CH:39][CH:38]=[C:37]([NH:41][C@@H:42]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=2)C(O)=O)[CH:36]=1>>[CH3:18][CH:17]([CH3:19])[CH2:16][C@H:15]([NH:14][C:13](=[O:33])[C@@H:8]([NH:7][C:6](=[O:34])[C@@H:42]([NH:41][C:37]1[CH:36]=[C:35]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:40]=[CH:39][CH:38]=1)[CH2:46][C:47]1[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=1)[CH2:9][CH:10]([CH3:12])[CH3:11])[B:20]1[O:28][C@H:27]2[C@:22]([CH3:32])([C@H:23]3[CH2:29][C@@H:25]([CH2:26]2)[C:24]3([CH3:30])[CH3:31])[O:21]1
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Reactant: COc1ccc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)cc1
Product: COc1ccc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)B2O[C@@H]3C[C@@H]4C[C@@H](C4(C)C)[C@]3(C)O2)cc1

Procedure:
The title compound is prepared as described in example 1 but using {(S)-3-Methyl-1-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-butylcarbamoyl]-butyl}-carbamic acid tert-butyl ester and (S)-2-(Biphenyl-3-ylamino)-3-(4-methoxy-phenyl)-propionic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][OH:22])=[CH:15][C:14]=1[F:23].Cl([O-])=[O:25].[Na+].CC(=CC)C.P([O-])(O)(O)=O.[Na+]>O.C(O)(C)(C)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:25])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][OH:22])=[CH:15][C:14]=1[F:23]
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(OCCO)cc3F)cc12
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCO)cc3F)cc12
Temperature: 25 °C
Reaction time: 10 h
Yield: 33.4 %

Procedure:
To a solution of 6-chloro-5-[2-fluoro-4-(2-hydroxyethoxy)phenyl]-1H-indole-3-carbaldehyde (40 mg, 0.12 mmol) in water (1 mL) and t-butanol (1 mL) was added sodium chlorite (210 mg, 2.30 mmol), 2-methyl-2-butene (0.5 mL) and sodium dihydrogen phosphate (350 mg, 2.30 mmol). The reaction solution was stirred at room temperature for 10 hrs. The reaction was diluted with water (5 mL) and extracted with dichloromethane (20 mL×3). The combined organic phase was washed with water (20 mL), brine (20 mL) dried over sodium sulfate and concentrated to give a crude product. The crude was purified by reverse phase HPLC to give the title compound (14 mg, 59% yield) as an off-white solid. MS (ES−) 348.1 (M−H)−. 1H NMR (400 MHz, CD3OD) δ 8.04 (s, 2H), 7.63 (s, 1H), 7.28 (s, 1H), 6.91 (dd, 2H), 6.86 (dd, 2H), 4.16 (t, 2H), 3.96 (t, 2H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH2:16][O:17][CH3:18])[C:13](=[O:19])[CH2:12][N:11]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH2:16][O:17][CH3:18])[CH:13]([OH:19])[CH2:12][N:11]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: COCC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)CC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)CC1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-4-(methoxymethyl)-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate) (Intermediate 69, crude, 16.73 g, 43.39 mmol) was dissolved in MeOH (100 mL), cooled to 0° C. and CeCl3 (10.69 g, 43.39 mmol) was added to give a solution. Then NaBH4 (1.642 g, 43.39 mmol) was added slowly as solid, and the mixture was stirred from 0° C. to rt for 30 min. The volatile solvent was removed. The white solid was redissolved in 200 mL EtOAc and washed with sat. NaHCO3, brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column (0-100% EA/Hex) to afford 13.78 g, 82% as an colorless oil.
Reaction SMILES: N[C@H:2]([CH:7]=O)[CH2:3]CSC.[CH3:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[CH3:19])[C:15](=[O:20])[N:14]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH:13]2[CH2:27][CH2:28][O:29]S(C)(=O)=O.O>C(O)CC>[CH3:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[CH3:19])[C:15](=[O:20])[N:14]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH:13]2[CH2:27][CH2:28][O:29][CH2:3][CH2:2][CH3:7]
Reactant: CSCC[C@H](N)C=O
Reactant: Cc1cc2c(cc1C)C(CCOS(C)(=O)=O)N(c1cccnc1)C2=O
Solvent: O
Solvent: CCCO
Product: CCCOCCC1c2cc(C)c(C)cc2C(=O)N1c1cccnc1
Temperature: 90 °C
Yield: 26.4 %

Procedure:
Metal sodium (6.4 mg, 0.28 mmol) was stirred with heating in propanol (2 ml) at 110° C. for 1 hr, and 5,6-dimethyl-2-(3-pyridyl)-3-mesyloxyethylisoindolin-1-one (50 mg, 0.14 mmol) was added thereto, followed by stirring with heating at 90° C. for 3 hrs. To the reaction solution was added water, and extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:ethyl acetate=1:1) to give 12 mg of the title compound.
Reaction SMILES: [C:1]([C:3]1[C:4]2[CH:5]=[C:6](C#CC3C=CC(C(O)=O)=CC=3)[CH:7]=[CH:8][C:9]=2[C:10]([CH3:14])([CH3:13])[CH2:11][CH:12]=1)#[N:2].CC1(C)C2C=C([C:37]#[C:38][C:39]3[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][CH:40]=3)C=CC=2C(=O)CC1>>[C:1]([C:3]1[C:4]2[CH:5]=[CH:6][C:7]([C:37]#[C:38][C:39]3[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][CH:40]=3)=[CH:8][C:9]=2[C:10]([CH3:14])([CH3:13])[CH2:11][CH:12]=1)#[N:2]
Reactant: CC1(C)CCC(=O)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Reactant: CC1(C)CC=C(C#N)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Product: CC1(C)CC=C(C#N)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(8-cyano-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoic acid (Compound 129), 63 mg (0.26 mmol) of 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoic acid (Compound 7) was, converted into the title compound (yellow powder) using 0.06 ml (0.54 mmol) of cyanotrimethylsilane and 6 drops of boron trifluoride etherate.
Reaction SMILES: [NH2:1][CH2:2][C:3](=[O:5])[CH3:4].[C:6](Cl)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[N:9][CH:8]=1>ClCCl>[C:3]([CH2:2][NH:1][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[N:9][CH:8]=1)(=[O:5])[CH3:4]
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(=O)CN
Solvent: ClCCl
Product: CC(=O)CNC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 40 g (0.370 mol) of aminoacetone in 500 ml of dry dichloromethane, 50 g (0.350 mol) of nicotinoyl chloride was added dropwise at room temperature under a nitrogen atmosphere. The mixture was refluxed 5 h followed by stirring overnight at room temperature. The colorless precipitate was collected by filtration and dissolved in 400 ml of water. After basification with ammonia the aqueous solution was extracted with 3×400 ml of dichloromethane. The combined organic phases were treated with charcoal and dried over magnesium sulphate. Removal of the solvent in vacuo gave a colorless solid, 73. Yield: 30.0 g (0.170 mol, 48%).
Reaction SMILES: Cl[CH:2]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][C:8]=1[CH3:18])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][C:21]=1[CH3:30].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH3:30][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:20]=1[NH:19][CH:2]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][C:8]=1[CH3:18])[CH2:3][CH:4]([CH3:6])[CH3:5])[C:24]([OH:26])=[O:25]
Reactant: Cc1oc(-c2ccccc2)cc1C(Cl)CC(C)C
Reactant: COC(=O)c1ccc(N)c(C)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)O)ccc1NC(CC(C)C)c1cc(-c2ccccc2)oc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
A mixture of 3-(1-chloro-3-methylbutyl)-2-methyl-5-phenylfuran (1.1 g), methyl 4-amino-3-methylbenzoate (1.0 g), sodium carbonate (0.6 g) and sodium iodide (2.4 g) in N,N-dimethylacetamide (20 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), 2N lithium hydroxide (4 mL) was added, and the mixture was stirred at 70° C. for 6 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give the title compound (0.5 g, 31%) as an amorphous compound.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([O:36][C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=2)[CH2:32][CH2:31]1>>[CH2:1]([N:3]([CH2:41][C:40]1[CH:39]=[CH:38][C:37]([O:36][CH:33]2[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]2)=[CH:44][CH:43]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:15]2[CH:16]=[C:17]([OH:22])[CH:18]=[CH:19][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN1CCC(Oc2ccc(C=O)cc2)CC1
Product: CCN(Cc1ccc(OC2CCN(C)CC2)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 71.6 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (33 mg) and 4-(1-methylpiperidin-4-yloxy)benzaldehyde (94 mg) according to an analogous synthetic method to Example 264 described below and purified by LC-MS, the title compound (31 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH2:10][C:11](O)([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH:10]=[C:11]([C:13]([F:15])([F:16])[F:14])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2nc(C(F)(F)F)cn2-c2ccc(S(C)(=O)=O)cc2)cc1
Yield: 52.8 %

Procedure:
A mixture of 2-(4-methylphenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-4,5-dihydro-1H-imidazole (Step 2) (0.9 g, 2.3 mmol) and p-toluenesulfonic acid monohydrate (150 mg) in toluene (100 mL) was heated to reflux for 72 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude residue was redissolved in methylene chloride and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentration in vacuo, the crude mixture was purified by chromatography on silica gel using toluene/ethyl acetate (1/1) to give pure 2-(4-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole (462 mg, 54%) as a white solid: mp (DSC) 190° C. Anal. Calc'd for C18H15N2F3SO2: C, 56.84; H, 3.97; N, 7.36; S, 8.43. Found: C, 56.66; H, 3.82; N, 7.23; S, 8.45.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:22]=[CH:21][C:20](/[C:23](=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[F:34])/[C:24]#[N:25])=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:26]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[F:34])[C:23]([C:20]2[CH:19]=[CH:18][C:17]([Br:16])=[CH:22][CH:21]=2)([C:24]#[N:25])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Br)cc1
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Br)cc1
Yield: 55.6 %

Procedure:
In a manner similar to the method described in Example 1c, [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (1.1 g, 5 mmol) was reacted with (Z)-2-(4-bromo-phenyl)-3-(3-chloro-2-fluoro-phenyl)-acrylonitrile (1.2 g, 3.6 mmol) prepared in Example 54a, AgF (1.3 g, 10 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (100 mL) at room temperature for 3 h to give rac-(2R,3S,4R,5S)-4-(4-bromo-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.1 g, 56%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:43]=[CH:42][C:8]2[N:9]([CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[C:17]([C:22]3[C:27]([C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=5)=[CH:26][CH:25]=[C:24]([OH:35])[CH:23]=3)[CH:16]=[CH:15]4)=[N:11][C:7]=2[CH:6]=1)=[O:4].N1C=CC=CC=1.[O:50](S(C(F)(F)F)(=O)=O)[S:51]([C:54]([F:57])([F:56])[F:55])(=O)=[O:52]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([C:5]1[CH:43]=[CH:42][C:8]2[N:9]([CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[C:17]([C:22]3[C:27]([C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=5)=[CH:26][CH:25]=[C:24]([O:35][S:51]([C:54]([F:57])([F:56])[F:55])(=[O:52])=[O:50])[CH:23]=3)[CH:16]=[CH:15]4)=[N:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(O)ccc4-c4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OS(=O)(=O)C(F)(F)F)ccc4-c4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1 g (1.7 mmol) of Compound 475a in 20 mL of DCM, 550 μL (6.8 mmol) of pyridine, and 21 mg (0.17 mmol) of DMAP were added and the entire mixture was cooled to 0° C. Dropwise, 860 μL of Tf2O was added. The reaction was then stirred at room temperature for 1 h. Finally the reaction mixture was evaporated, and the product dissolved in ethyl acetate, washed with cold water (2×), brine (2×), dried with Na2SO4 and evaporated again to give the title intermediate as a white solid foam in quantitative yield.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C([N:14]1[CH2:19][CH2:18][O:17][CH:16]([CH:20]=[C:21]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH2:25][CH2:24][C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]2=3)[CH2:15]1)C1C=CC=CC=1>C1C=CC=CC=1>[CH2:5]([O:4][C:2]([N:14]1[CH2:19][CH2:18][O:17][CH:16]([CH:20]=[C:21]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH2:25][CH2:24][C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]2=3)[CH2:15]1)=[O:3])[CH3:6]
Reactant: C(=C1c2ccccc2CCc2ccccc21)C1CN(Cc2ccccc2)CCO1
Reactant: CCOC(=O)Cl
Solvent: c1ccccc1
Product: CCOC(=O)N1CCOC(C=C2c3ccccc3CCc3ccccc32)C1

Procedure:
Ethyl chloroformate (3.6 g) was added to 5-(4-benzylmorpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (3.13 g) in anhydrous benzene at room temperature, and the resulting mixture was heated under reflux for 5.5 hours. After cooling, the mixture was washed with a saturated aqueous sodium bicarbonate solution and water, dried and evaporated to afford 5-(4-ethoxycarbonylmorpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]-cycloheptene as oily material.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[CH:20][C:19]([C:22]([O:24]CC)=[O:23])=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[K+].C(O)C.Cl>O>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[CH:18][C:19]([C:22]([OH:24])=[O:23])=[CH:20][N:21]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(-c2ncc(C(=O)OCC)cn2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCOc1ccc(-c2ncc(C(=O)O)cn2)cc1

Procedure:
An eggplant type flask was charged with 2.6 g of the above Compound E, 0.8 g of potassium hydroxide, 45 ml of ethanol and 5 ml of water. The system was refluxed for one hour, and the resultant reaction liquid was poured into 100 ml of water, which was made acidic with hydrochloric acid and extracted with chloroform. The extract was dried over sodium sulfate, removed the solvent by distillation, and recrystallized with 50 ml of hexane. The crystalline product was recovered by filtration, and dried to provide 2.3 g of the object 2-(4-octyloxyphenyl)pyrimidine-5-carboxylic acid, which was the object product.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)([CH3:6])[CH:3]=[CH:4]I.C([Li])CCC.[CH3:19][Sn:20](Cl)([CH3:22])[CH3:21].O>O1CCCC1>[CH3:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)([CH3:6])[CH:3]=[CH:4][Sn:20]([CH3:22])([CH3:21])[CH3:19]
Reactant: C[Sn](C)(C)Cl
Reactant: CC(C)(C=CI)c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C=C[Sn](C)(C)C)c1ccc(Cl)cc1
Temperature: -90 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
A stirring solution of 4.8 grams (0.016 mole) of 3-methyl-3-(4-chlorophenyl)-1-iodo-1-butene in 50 mL of tetrahydrofuran is cooled to about -90° C., and 6.9 mL (0.018 mole) of n-butyllithium (2.5M in hexane) is added dropwise at a rate to maintain the reaction mixture temperature at about -85° to -90° C. Upon completion of the addition, the reaction mixture is stirred at -90° C. for 30 minutes. After this time, a solution of 3.7 grams (0.019 mole) of trimethyltin chloride in 10 mL of tetrahydrofuran is added dropwise at a rate sufficient to maintain the reaction mixture temperature at about -85° to -90° C. Upon completion of addition, the reaction mixture is again stirred at -90° C. for 30 minutes. After this time, the reaction mixture is allowed to warm to ambient temperature where it is stirred for about 18 hours. The reaction mixture is then poured into 150 mL of water and extracted with 150 mL of diethyl ether. The ether extract is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 4.8 grams of 3-methyl-3-(4-chlorophenyl)-1-trimethylstannyl-1-butene. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.[OH-].[Na+].[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[CH2:20]>O>[CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[N:6]([CH2:20][CH2:19][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:5]=2[CH2:4][CH2:3]1
Reactant: C=Cc1ccccn1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccccn2)CCN(C)CC1
Temperature: 80 °C
Yield: 35.8 %

Procedure:
The title compound was prepared by following general procedure 4. To a solution of 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (150 mg, 0.7 mmol) in 50% aq. NaOH solution (7 mL) tetra n-butyl ammonium chloride (9 mg, 0.03 mmol) followed by 2-vinylpyridine (80 mg, 0.77 mmol) was added and the reaction mixture was heated at 80° C. for 14 h. After completion of reaction, the reaction mixture was diluted with water, extracted with ethyl acetate; the organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography to afford 80 mg of 3,9-dimethyl-6-(2-(pyridin-2-yl)ethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole as the TFA salt.