Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)[C:15](=[O:29])[CH2:14][CH2:13][CH2:12]1.I[CH3:31]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:27])([F:26])[F:28])=[CH:20][CH:19]=2)[C:15](=[O:29])[CH:14]([CH3:31])[CH2:13][CH2:12]1
Reactant: CI
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Product: COc1cccc(OC)c1C1CCC(C)C(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 8 (GP8) by C-alkylation of 6-(2,6-dimethoxyphenyl)-1-(4-(trifluoromethoxy)benzyl)piperidin-2-one with commercially available iodomethane. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.84 min.; [M+H]+: 424.22 g/mol.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:22])[NH:6][C:7]2[C:12]([C:13]=1C)=[C:11](OS(O)(=O)=O)[C:10]([Cl:20])=[CH:9][C:8]=2[CH3:21])(=[O:3])[CH3:2].Cl.[F:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30][NH2:31])=[CH:27][CH:26]=1>>[C:1]([C:4]1[C:5](=[O:22])[NH:6][C:7]2[C:12]([C:13]=1[NH:31][CH2:30][CH2:29][C:28]1[CH:32]=[CH:33][C:25]([F:24])=[CH:26][CH:27]=1)=[CH:11][C:10]([Cl:20])=[CH:9][C:8]=2[CH3:21])(=[O:3])[CH3:2]
Reactant: NCCc1ccc(F)cc1
Reactant: CC(=O)c1c(C)c2c(OS(=O)(=O)O)c(Cl)cc(C)c2[nH]c1=O
Agent: Cl
Product: CC(=O)c1c(NCCc2ccc(F)cc2)c2cc(Cl)cc(C)c2[nH]c1=O
Yield: 77.8 %

Procedure:
3-Acetyl-6-chloro-8-methyl-4 -methylsulfoxy -2-quinolinone (2.98 g, 0.01 mol) and p-fluorophenethylamine hydrochloride (1.76g, 0.01 mol) were used, but the reaction was carried out as the above process of example 42 to obtain the desired product (2.9g, yield: 71%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[N:5]([C:6](=[O:9])[CH2:7][OH:8])[N:4]([CH:10]2[CH:17]3[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:19][CH:11]2[CH2:12]4)[CH2:16]3)[C:3]1=[O:20].[OH-].[Na+].[Br:24][C:25]1[CH:26]=[CH:27][C:28](F)=[N:29][CH:30]=1.O>CN(C)C=O>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([O:8][CH2:7][C:6]([N:5]2[C:2]([CH3:21])([CH3:1])[C:3](=[O:20])[N:4]2[CH:10]2[CH:11]3[CH2:12][CH:13]4[CH2:14][CH:15]([CH2:16][CH:17]2[CH2:18]4)[CH2:19]3)=[O:9])=[N:29][CH:30]=1
Reactant: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1C(=O)CO
Reactant: Fc1ccc(Br)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1C(=O)COc1ccc(Br)cn1
Reaction time: 1 h
Yield: 10.2 %

Procedure:
Under an argon atmosphere, a solution of 4,4-dimethyl-1-(hydroxyacetyl)-2-(adamantan-2-yl)-1,2-diazetidin-3-one (14.0 mg, 0.0480 mmol) in N,N-dimethylformamide (0.5 mL) was added with sodium hydroxide (excess amount) and 5-bromo-2-fluoropyridine (26.4 mg, 0.150 mmol) at room temperature, and the resultant was stirred at the same temperature for 1 hour. The reaction solution was added with water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, the obtained residue was purified using Preparatory Thin-Layer chromatography (hexane:ethyl acetate=2:1), and the title compound (2.20 mg, 10.2%) was obtained as a colorless oil.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[OH:25][CH2:26][C:27]([NH:31][S:32]([C:35]1[CH:36]=[N:37][CH:38]=[C:39](Br)[CH:40]=1)(=[O:34])=[O:33])([CH2:29][OH:30])[CH3:28]>>[OH:25][CH2:26][C:27]([NH:31][S:32]([C:35]1[CH:36]=[N:37][CH:38]=[C:39]([C:13]#[C:12][C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:24])=[CH:4][C:5]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)=[N:6][C:7]=23)[CH:40]=1)(=[O:34])=[O:33])([CH2:29][OH:30])[CH3:28]
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(CO)(CO)NS(=O)(=O)c1cncc(Br)c1
Product: CC(CO)(CO)NS(=O)(=O)c1cncc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2)(340 mg, 1.0 mmol) and 5-Bromo-pyridine-3-sulfonic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (example B.4) (295 mg, 1.0 mmol) according to general procedure II. Obtained as a light-brown solid (240 mg, 40%). MS (ISP) 582.2 [(M+H)+]; mp 204–206° C.
Reaction SMILES: C([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17](O)=O)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[NH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>ClCCl>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[CH2:23]([N:21]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:20])[S:12][CH:13]=1)[CH2:22][CH2:27][CH2:26][CH2:25][CH2:29][CH3:30]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)O)cs1
Reactant: Nc1cccnc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1cccnc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A compound obtained using {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}acetic acid synthesized in Example 3 and 3-aminopyridine as starting materials and by an operation similar to that of Example 293-1 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction solution was concentrated under reduced pressure, azeotroped with diethyl ether, and the precipitated solid was collected by filtration to give the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]([C:20](=[O:23])[CH2:21]Br)[CH2:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])(C)(C)C.FC(F)(F)C(O)=O.C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>CCO>[C:14]1([CH:12]([CH3:13])[CH2:11][N:10]2[CH2:9][CH2:8][NH:7][CH2:21][C:20]2=[O:23])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(CN(CCNC(=O)OC(C)(C)C)C(=O)CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(CN1CCNCC1=O)c1ccccc1
Yield: 74.5 %

Procedure:
In the same way as that described in Example 2, Step 3, using 2-[(bromoacetyl)(2-phenylpropyl)amino]ethyl carbamic acid tert-butyl ester (1.64 g, 4.11 mmol), trifluoroacetic acid (4 mL) and CH2Cl2 (40 mL), followed by K2CO3 (1.1 g, 8.2 mmol) and EtOH (100 mL). The piperazinone (668 mg, 75%) was isolated as a colourless oil. 1H NMR (250 MHz, CDCl3) δ1.28 (3H, d, J=6.8 Hz), 2.72-2.93 (3H, m), 3.04-3.26 (3H, m), 3.28 (1H, d, J=17.3 Hz), 3.52 (1H, d, J=17.3 Hz), 3.85-3.93 (1H, m), 7.19-7.35 (5H, m).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].CC(C)([O-])C.[K+].Cl[C:13]1[C:18]([C:19]#[N:20])=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([C:27]#[N:28])=[C:15]([S:29][CH2:30][C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=3)[S:34][CH:35]=2)[N:14]=1>CN(C=O)C>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C:33]2[S:34][CH:35]=[C:31]([CH2:30][S:29][C:15]3[C:16]([C:27]#[N:28])=[C:17]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:18]([C:19]#[N:20])=[C:13]([O:4][CH2:3][CH2:2][CH2:1][OH:5])[N:14]=3)[N:32]=2)=[CH:37][CH:38]=1
Reactant: OCCCO
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1c(OCCCO)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccccc1
Reaction time: 0.25 h

Procedure:
68 μl (0.939 mmol) of 1,3-propanediol are initially charged in 2 ml of DMF, 38 mg (0.344 mmol) of potassium tert-butoxide are added and the mixture is stirred for 15 minutes, after which 150 mg (0.313 mmol) of 2-chloro-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulphanyl)-4-phenylpyridine-3,5-dicarbonitrile, dissolved in 2 ml of DMF, are added. The reaction mixture is stirred at room temperature for 1 hour and then purified by preparative HPLC (acetonitrile/water: 10:90→95:5, with 0.1% TFA added). This gives 98 mg (59% of theory) of the target compound.
Reaction SMILES: [P:1]([Br:4])(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1>N1C=CC=CC=1>[Br:2][P:1]([Br:4])[C:10]1[CH:11]=[CH:12][C:7]([O:6][CH3:5])=[CH:8][C:9]=1[O:13][CH3:14]
Reactant: COc1cccc(OC)c1
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Product: COc1ccc(P(Br)Br)c(OC)c1

Procedure:
A solution of PBr3 (2.5 g, 9.2 mm) in 15 mL of pyridine was treated with 1,3-dimethoxybenzene (2.5 g, 18.1 mm) over a period of 5 min. The resulting mixture was then refluxed for 4 h. to give the crude 1-dibromophosphino-2,4dimethoxybenzene (31P NMR: δ159.2 ppm). This compound was used directly for the next step without further purification. Next, polymer-supported secondary amines from Example 1 (10.0 g, 1.1 mmol/g, 11.0 mmol) was slowly added into the mixture above while stirring at room temperature for a period of 10 min. The resulting suspension was stirred at room temperature overnight before the solution was filtered off. The resin was washed with THF (50 mL), hexane (3×50 mL), CH2Cl2 (4×50 mL), and hexane (2×50 mL). The resulting resin was dried in vacuum overnight to yield the polymer-supported 2-P(Br)-1,5-(MeO)2-C6H3. 31P NMR (122 MHz, CDCl3): δ153.8 ppm.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[C:12]([CH3:14])=[O:13].[Cl-].[NH4+]>O1CCCC1>[CH3:14][C:12]([C:6]1[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=1[CH3:4])([OH:13])[CH3:1]
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccc(O)cc1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(O)ccc1C(C)(C)O
Temperature: -40 °C
Reaction time: 5 h
Yield: 80.2 %

Procedure:
To a solution of methylmagnesium bromide (30 ml, 90 mmol, 3M solution) dissolved in tetrahydrofuran (15 ml), a solution of compound (16) (4.5 g, 30 mmol) dissolved in tetrahydrofuran (10 ml) was slowly added dropwise at −78° C. When the dropping was completed, was slowly heated to −40° C., and stirred for 5 hours. After heating to 0° C., the solution was stirred for one hour, and then, ammonium chloride (50 ml) was slowly added dropwise thereto. The reaction solution was extracted with organic solvent, washed, dried and purified by using column chromatography (eluent: hexane/ethyl acetate=10/1) to obtain 4.0 g (80%) of pure compound (17).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][CH:12]2[CH2:15][N:14]([C:16]3[S:17][C:18]4[C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:13]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].O>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][CH:12]2[CH2:15][N:14]([C:16]3[S:17][C:18]4[C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:13]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cccc2nc(N3CC(NC(=O)c4nc(Cl)c(CC)[nH]4)C3)sc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1[nH]c(C(=O)NC2CN(c3nc4cccc(C(=O)O)c4s3)C2)nc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.1 %

Procedure:
Ethyl 2-(3-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}azetidin-1-yl)-1,3-benzothiazole-7-carboxylate obtained in Example (224c) (350 mg, 0.81 mmol) was dissolved in methanol (8 mL). A 2 N aqueous lithium hydroxide solution (4.03 mL, 8.07 mmol) was added, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution, and then the mixture was washed with ethyl acetate. A 1 N aqueous hydrochloric acid solution (8 mL) was added to the aqueous layer, and then the solvent was evaporated under reduced pressure. The resulting residue was suspended and washed in methanol. Following filtration, the resulting solid was washed with water to obtain 191 mg of the title compound as a white solid (58%).
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH:10]=[CH:11][C@@H:12]2[OH:20])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:21][CH2:22][O:23][CH3:24])[CH:4]=[CH:5]2.[Cl-].[C:26]([O:34][CH3:35])(=[O:33])[CH2:27][CH2:28][CH2:29][C:30]([O-])=[O:31]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH:10]=[CH:11][C@@H:12]2[O:20][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C:26]([O:34][CH3:35])=[O:33])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:21][CH2:22][O:23][CH3:24])[CH:4]=[CH:5]2
Reactant: COC(=O)CCCC(=O)[O-]
Reactant: COCOc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: ClCCl
Product: COCOc1ccc2c3c1O[C@H]1[C@@H](OC(=O)CCCC(=O)OC)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Reaction time: 2 h

Procedure:
4,5α-Epoxy-3-methoxymethoxy-17-methyl-morphinan-7-en-6α-ol (2.0 g, 6.1 mmol) and 4-dimethylaminopyridine (0.8 g, 6.5 mmol) were dissolved in absolute CH2Cl2 (20 ml) and methyl glutarate chloride (1.0 g, 6.08 mmol) were added dropwise whilst cooling with ice and the mixture was stirred for 2 hours at this temperature. The reaction mixture was poured onto water (50 ml), the organic phase was washed twice more with 30 ml of water and dried over MgSO4. The solvent was evaporated off and the residue was separated off by flash chromatography (CH2Cl2 /MeOH 9/1).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]([O:8][CH2:9][CH3:10])=[CH2:7])CCC.Br[C:20]1[S:24][C:23]([C:25]2[S:26][C:27](Br)=[CH:28][N:29]=2)=[N:22][CH:21]=1.[F-].[K+]>CN(C)C=O.CCOCC.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>[CH2:9]([O:8][C:6]([C:20]1[S:24][C:23]([C:25]2[S:26][C:27]([C:6]([O:8][CH2:9][CH3:10])=[CH2:7])=[CH:28][N:29]=2)=[N:22][CH:21]=1)=[CH2:7])[CH3:10]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1cnc(-c2ncc(Br)s2)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=C(OCC)c1cnc(-c2ncc(C(=C)OCC)s2)s1
Temperature: 100 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
Tributyl(1-ethoxyvinyl)tin (0.425 mL, 1.26 mmol) and dichlorobis(triphenylphosphine)-palladium(II) (21.5 mg, 0.031 mmol) were added to a stirred solution of 5,5′-dibromo-2,2′-bithiazole (200 mg, 0.613 mmol) in dimethylformamide (4 mL) under nitrogen. The reaction mixture was heated at 100° C. for 2 h. The reaction was cooled, diluted with ether and aqueous potassium fluoride (0.5 g in 5 mL of water). The mixture was vigorously stirred for 1 h at room temperature, both phases were filtered through CELITE® and then separated. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (0 to 30% ethyl acetate in hexanes) to yield 5,5′-bis(1-ethoxyvinyl)-2,2′-bithiazole (181 mg, 0.587 mmol, 96% yield) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:12]=[CH:11][C:10]([NH:13][S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)(=[O:24])=[O:23])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2
Reactant: Nc1ccc(C(F)(F)F)c2cccnc12
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc(C(F)(F)F)c2cccnc12)c1ccccn1
Yield: 31.7 %

Procedure:
In a similar fashion using route 14 general procedure 27, 5-trifluoromethyl-quinolin-8-ylamine (Intermediate 45) (125 mg, 0.58 mmol), pyridine-2-sulfonyl chloride (Intermediate 18) (125 mg, 0.70 mmol), pyridine (0.09 ml, 1.17 mmol), DMAP (cat.) and DCM (5 ml) gave the title compound (65 mg, 31%) after purification by column chromatography with n-hexane/DCM (50:50) as the eluent.
Reaction SMILES: CO[N:3]=[CH:4][C:5]1[C:6]2[CH:7]=[CH:8][NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1.Cl>C(O)C.[Pd]>[NH:9]1[C:10]2[C:6](=[C:5]([CH2:4][NH2:3])[CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8]1
Reactant: CON=Cc1cccc2[nH]ccc12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1cccc2[nH]ccc12
Reaction time: 3 h
Yield: 95.8 %

Procedure:
An amount of 1H-Indole-4-carbaldehyde O-methyl-oxime (50 mg, 0.30 mmol) is dissolved in ethanol (5 mL). Then hydrogen chloride (0.217 mL) is added, followed by 10% Pd/C (5.0 mg). After hydrogenation at 35 psi for 3 h, the solution is filtered through Celite and evaporated to dryness. The residue is recrystallized from ethyl acetate to give 42 mg of crude product as an orange residue. MS (ESI) m/z 147.2 (M+1).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:12]2[CH2:13][C@@H:14]3[C:19]([CH3:21])([CH3:20])[C@:18]([CH3:22])([C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH2:17][CH2:16][N:15]3[C:23]([C:25]1[CH:29]=[CH:28][O:27][C:26]=1[CH3:30])=[O:24].O>ClCCl>[OH:6][C:7]1[C:12]2[CH2:13][C@@H:14]3[C:19]([CH3:21])([CH3:20])[C@:18]([CH3:22])([C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH2:17][CH2:16][N:15]3[C:23]([C:25]1[CH:29]=[CH:28][O:27][C:26]=1[CH3:30])=[O:24]
Reactant: COc1cccc2c1C[C@H]1N(C(=O)c3ccoc3C)CC[C@]2(C)C1(C)C
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1occc1C(=O)N1CC[C@@]2(C)c3cccc(O)c3C[C@@H]1C2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Boron tribromide (2 mL) is added to a solution of [(2R,6S)-10-methoxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(2-methyl-furan-3-yl)-methanone (0.22 g) in dichloromethane (10 mL). The resulting solution is stirred at ambient temperature for 2 h. Then, water is added and the mixture is stirred for another 10 min. The organic phase is separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with brine and dried (Na2SO4). The solvent is evaporated to give the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:12].[CH3:13][Si:14](Cl)([CH3:16])[CH3:15]>>[CH3:13][Si:14]([CH3:16])([CH3:15])[O:12][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][C:8]([O:11][Si:14]([CH3:16])([CH3:15])[CH3:13])=[CH:7][CH:6]=2)[CH:1]=1
Reactant: C[Si](C)(C)Cl
Reactant: Oc1ccc2ccc(O)cc2c1
Product: C[Si](C)(C)Oc1ccc2ccc(O[Si](C)(C)C)cc2c1

Procedure:
2,7-Bis(trimethylsilyloxy)naphthalene 5b was prepared from naphthalene-2,7-diol following the general procedure for the preparation of bis-silyl “BB” monomers, with substitution of tert-butyldimethylsilyl chloride with trimethylsilyl chloride. 5b was isolated as a yellow oil (13.1 g, 43.5 mmol, 99%): IR (neat) λmax 2958, 2856, 1630, 1604, 1507, 1460, 1427, 1365, 1250, 1211, 1151, 1110, 909, 833, 743, 697, 612, 489 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=8.9 Hz, 2H), 7.12 (d, J=2.3 Hz, 2H), 6.99 (dd, J=2.3, 8.8 Hz, 2H), 0.37 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 153.6, 136.2, 129.3, 125.4, 120.0, 114.0, −0.42; LRMS (EI) m/z=304.1 [M]+.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1.[ClH:14].[F:15][C:16]([F:30])([F:29])[C:17]1[CH:18]=[C:19]([C:23]2[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=2)[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[ClH:14].[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][CH2:2][N:26]1[CH2:25][CH:24]=[C:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:29])[F:30])[CH:18]=2)[CH2:28][CH2:27]1
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Reactant: BrCCc1ccc2ccccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)(F)c1cccc(C2=CCN(CCc3ccc4ccccc4c3)CC2)c1
Temperature: 25 °C
Yield: 70 %

Procedure:
A mixture of 6.25 g of 2-(2-bromoethyl)naphthalene, 7 g of 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride, 3.75 g of potassium carbonate and 100 ml of acetone is refluxed for 4 hours and the reaction mixture is then allowed to cool to room temperature. The salts formed are filtered off and discarded. The solvent is evaporated off and the residue is taken up with a solution of hydrochloric acid in ethanol to give 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride, which is recrystallized from ethanol. Yield: 70% of theory, relative to the starting 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride. The product obtained is in the form of a fine white crystalline powder having an HPLC purity of 99.9%.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].[CH2:7](O)[CH2:8][OH:9]>>[OH:9][CH2:8][CH2:7][O:5][C:4](=[O:6])[CH2:3][C:1]#[N:2]
Reactant: OCCO
Reactant: N#CCC(=O)O
Product: N#CCC(=O)OCCO
Yield: 74 %

Procedure:
Cyanoacetic acid was esterified with ethylene glycol according to U.S. Pat. No. 3,644,466 (Co. 7-8, Ex. 3) to give (2-hydroxyethyl)2-cyanoacetate in 74% yield.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][O:50][CH:51]4[CH2:53][CH2:52]4)=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C:10]1(CO)[CH2:54][OH:55])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@:12]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH2:49][O:50][CH:51]5[CH2:53][CH2:52]5)=[CH:45][CH:46]=4)[CH:34]=3)[O:11][C@@:10]1([CH2:54][OH:55])[CH2:32][O:31]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCCOC4CC4)cc3)c2)OC(CO)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCCOC5CC5)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
[(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol if (320 mg, 0.4 mmol) was dissolved in 10 mL methylene chloride and cooled to −10° C., followed by addition of trifluoroacetic acid (62 mL, 0.8 mmol). The mixture was stirred for 1 hour. Thereafter, the reaction mixture was partitioned after 10 mL saturated sodium bicarbonate solution were added. The aqueous phase was extracted with dichlormethane (10 mL) and the organic extract was washed with saturated sodium chloride solution (10 mL), combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound [(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 1g (230 mg, colorless oil), yield: 75.3%. MS m/z (ESI): 780.3 [M+18]. 1H NMR (400 MHz, CDCl3): δ 7.33 (m, 12H), 7.15 (m, 4H), 7.05 (m, 2H), 6.86 (d, 2H), 6.76 (d, 2H), 4.77 (m, 4H), 4.27 (m, 2H), 4.00 (m, 6H), 3.83 (m, 3H), 3.70 (m, 4H), 3.38 (m, 1H), 0.63 (m, 2H), 0.48 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH:14]=2)[N:11]=[C:10]([C:32]([C:38]([F:41])([F:40])[F:39])([C:34]([F:37])([F:36])[F:35])[OH:33])[CH2:9]1.Cl>C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)[CH:14]=2)[N:11]=[C:10]([C:32]([C:34]([F:36])([F:35])[F:37])([C:38]([F:41])([F:40])[F:39])[OH:33])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(N3N=C(C(O)(C(F)(F)F)C(F)(F)F)CC3c3ccccc3Cl)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: OC(C1=NN(c2cccc(N3CCNCC3)c2)C(c2ccccc2Cl)C1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 736.2 %

Procedure:
5-(2-Chloro-phenyl)-1-[3-(4-BOC-piperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (100.0 mg, 0.20 mmol) prepared in Example 436 was added to a saturated solution of hydrochloric acid in ethyl acetate (3.0 mL). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give 400.0 mg of 5-(2-chloro-phenyl)-1-[3-(piperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride as a yellow liquid.