Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C@@H]1C[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1O.[C:12](#[N:14])[CH3:13].S(=O)(=O)(O)[OH:16]>O>[NH2:14][C@@H:12]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@@H:13]1[OH:16]
Reactant: O=S(=O)(O)O
Reactant: CC#N
Reactant: O[C@@H]1c2ccccc2C[C@H]1Br
Solvent: O
Product: N[C@@H]1c2ccccc2C[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
Into a 10 ml eggplant-type flask, 1.07 g (5.0 mmol) of trans-(-)-2-bromo-1-indanol (I: X=OH, Y=Br; optical purity based on specific rotation: 42.5%) and 2.6 ml of acetonitrile were introduced. While this mixture was stirred with a magnetic stirrer, 0.76 g (7.5 mmol) of 97% sulfuric acid was dropwise added thereto in a period of 2 hours at room temperature. The resulting mixture was stirred at room temperature for 1 hour and then 6.5 ml of water was added thereto. After an acetonitrile/water azeotrope was distilled off under a reduced pressure of 200 mmHg at 40° C., the remaining mixture was stirred for 4.5 hours at 60° C. This reaction liquid was cooled to room temperature and then washed twice with 10 ml of dichloromethane. An aqueous solution of 25% sodium hydroxide was added to the water phase to attain a pH of 7. The resulting solution was washed twice with 10 ml of dichloromethane. Then, the pH of the water phase was adjusted to 11 by an addition of an aqueous solution of 25% sodium hydroxide. This phase was extracted with 10 ml of dichloromethane three times. The extracted phase was dried with sodium sulfate anhydride and then evaporated to dryness in vacuo to yield 0.47 g of cis-(+)-1-aminoindan-2-ol (V) as a white crystal (yield: 63.0%). According to an HPLC, its chemical purity and optical purity based on specific rotation were 98.8% and 42.0%, respectively.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:9][C:10]1[CH:25]=[CH:24][C:13]([CH2:14][N:15]2[C:20](=[O:21])[CH:19]=[CH:18][C:17]([CH:22]=O)=[CH:16]2)=[CH:12][CH:11]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:9][C:10]1[CH:25]=[CH:24][C:13]([CH2:14][N:15]2[CH:16]=[C:17]([CH2:22][N:2]([CH3:1])[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:18]=[CH:19][C:20]2=[O:21])=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(=O)n(Cc2ccc(Cl)cc2)c1
Reactant: CNc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(Cc1ccc(=O)n(Cc2ccc(Cl)cc2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
According to Scheme 7 Method A: A solution of N-methylbenzenamine (1 eq, 0.40 mmol, 0.04 mL) and 1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridine-3-carbaldehyde (1 eq, 0.40 mmol, 0.10 g) in CH2Cl2 (8 mL) was stirred for 10 min. at room temperature then AcOH (1 eq, 0.40 mmol, 0.02 mL) and NaBH(OAc)3 (1.5 eq, 0.60 mmol, 0.10 g) were added. The reaction mixture was stirred 3 hours at room temperature, was quenched with water and the aqueous phase was extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column 25 g SiO2) using CH2Cl2/MeOH 95/5 followed by crystallization in pentane/diisopropyl ether to afford 1-(4-chlorobenzyl)-5-((methyl(phenyl)amino)methyl)pyridin-2(1H)-one (0.12 mmol, 0.04 g, 29%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CC(C)=O>[Br-:1].[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][P+:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Product: Brc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 23 h
Yield: 195.2 %

Procedure:
25.2 g (101 mmol) of 4-bromobenzylbromide and 100 mL of acetone were put into a 200 mL conical flask, and then 29.1 g (111 mmol) of triphenylphosphine was added thereto. Thereafter, this mixture was stirred at room temperature for 23 hours to be reacted. After the reaction, a precipitate in the reaction mixture was collected by suction filtration. Then, 50.5 g of objective 4-bromobenzyltriphenylphosphonium bromide was obtained as a white powdered solid in a yield of 98%. Synthetic scheme of 4-bromobenzyltriphenylphosphonium bromide is illustrated below (synthetic scheme a-1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=2)[N:7]=1.[NH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH3:18][O:17][C:12]1[C:11]([C:8]2[N:6]3[N:7]=[C:2]([NH:19][C@@H:20]4[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: COc1ncccc1-c1cnc2ccc(Cl)nn12
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ncccc1-c1cnc2ccc(N[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)nn12
Temperature: 110 °C
Yield: 42.6 %

Procedure:
A mixture of 6-chloro-3-(2-methoxypyridin-3-yl)imidazo[1,2-b]pyridazine (Preparation 2, 0.15 g, 0.58 mmol), tert-butyl (3R)-3-aminopiperidine-1-carboxylate (0.23 g, 1.15 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (0.03 g, 0.09 mmol), sodium tert-butoxide (0.08 g, 0.81 mmol) and toluene (4 mL) in a Schlenk vial was subjected to three cycles of evacuation backfilling with argon. Tris(dibenzylidene acetone)dipalladium(0) (0.04 g, 0.04 mmol) was then added and the resulting mixture was subjected to three further cycles of evacuation backfilling before being heated at 110° C. for 20 hours. Subsequently, the reaction was cooled down, filtered through Celite® eluting with ethyl acetate and dichloromethane, and the filtrate was evaporated to dryness. The crude was purified by flash chromatography (1:1 hexanes/ethyl acetate to 100% ethyl acetate) to give the title compound (0.105 g, 42%) as a solid.
Reaction SMILES: [C:1]([O:5][C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(CO)C(=CCCC1)CC3)(=[O:4])[CH2:2][CH3:3].C(O)(=O)CC.[OH:31][C@H:32]1[CH2:37][CH2:36][C@H:35]2[C@H:38]3[C@H:49]([CH2:50][CH2:51][C@:33]12[CH3:34])[C@:46]1([CH:47]=[O:48])[C:41](=[CH:42][CH2:43][CH2:44][C@@H:45]1C)[CH2:40][CH2:39]3>>[C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].[OH:31][C@H:32]1[CH2:37][CH2:36][C@H:35]2[C@H:38]3[C@H:49]([CH2:50][CH2:51][C@:33]12[CH3:34])[C@:46]1([CH:47]=[O:48])[C:41](=[CH:42][CH2:43][CH2:44][CH2:45]1)[CH2:40][CH2:39]3
Reactant: CCC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CCCC[C@]4(CO)[C@H]3CC[C@]12C
Reactant: C[C@H]1CCC=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21C=O
Solvent: CCC(=O)O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CCCC[C@@]43C=O)[C@@H]1CC[C@@H]2O

Procedure:
Substituting 4-androstene-17β,19-diol 17-propionate for the 17β-hydroxy-1α-methyl-4-androsten-19-one propionate above results in the preparation of 17β-hydroxy-4-androsten-19-one propionate.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.[CH:21]1([CH2:24][C@H:25]([NH2:31])[C:26]2[S:27][CH:28]=[CH:29][N:30]=2)[CH2:23][CH2:22]1>>[CH:21]1([CH2:24][C@H:25]([NH:31][C:12]([C:10]2[CH:9]=[CH:8][C:7]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[C:26]2[S:27][CH:28]=[CH:29][N:30]=2)[CH2:23][CH2:22]1
Reactant: O=C(O)c1ccc(C2CCOCC2)c(OCC2CC2)n1
Reactant: N[C@@H](CC1CC1)c1nccs1
Product: O=C(N[C@@H](CC1CC1)c1nccs1)c1ccc(C2CCOCC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid (Example 9 f) and (S)-2-cyclopropyl-1-thiazol-2-yl-ethylamine as starting materials, MS (LC/MS): 428.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:13][CH:14]=O>C(O)C.O.N>[N:1]1[CH:13]=[CH:14][N:11]2[CH:10]=[CH:9][CH:8]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]=12
Reactant: O=CCCl
Reactant: COC(=O)c1cccnc1N
Agent: N
Solvent: O
Solvent: CCO
Product: COC(=O)c1cccn2ccnc12

Procedure:
A mixture of methyl 2-aminonicotinate (WO 89/01488 pg33, prep 17) (1 g, 6.56 mmol), and chloroacetaldehyde (1.05 mL, 6.56 mmol) in ethanol (5 mL) was heated under reflux for 18 hours. The cooled mixture was diluted with water (10 mL), 0.88 ammonia (1 mL) added and the solution concentrated in vacuo. The residue was dissolved in methanol and the dark solution treated with charcoal, the mixture filtered and the filtrate concentrated in vacuo. The residue was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (97:2.5:0.5) as eluant, and the product triturated with ether, to afford the title compound, 768 mg.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[F:18])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.Cl[CH2:20][C:21]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:22]=1[O:23][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:20][C:21]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:22]=3[O:23][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:13][C:12]=2[F:18])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: COC(=O)C(C)Oc1cc(Cl)ccc1CCl
Reactant: Oc1ccc(-n2nc3c(c2Cl)CCCC3)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(Cl)ccc1COc1ccc(-n2nc3c(c2Cl)CCCC3)c(F)c1
Yield: 81.1 %

Procedure:
By the method of Example 1, Step I, 0.49 g (0.0016 mole) of 3-chloro-2-(2-fluoro-4-hydroxyphenyl)-4,5,6,7-tetrahydroindazole and 0.52 g (0.002 mole) of methyl 2-(2-chloromethyl-5-chlorophenoxy)propionate (Example 2, Step E) were reacted in the presence of 0.41 g (0.003 mole) of anhydrous potassium carbonate in 30 mL of N,N-dimethylformamide, yielding 0.64 g of methyl 2-[2-[4-(3-chloro-4,5,6,7-tetrahydroindazol-2-yl)-3-fluorophenoxymethyl]-5-chlorophenoxy]propionate as a syrup. The NMR and IR spectra were consistent with the proposed structure. NMR: 1.64 (d, 3H, JHH =8.0 Hz); 1.82 (m, 4H); 2.50 (t, 2H, JHH =4.0 Hz); 2.68 (t, 2H, JHH =4.0 Hz); 3.76 (s, 3H); 4.82 (q, 1H, JHH =8 Hz); 5.18 (s, 2H,); 6.78-7.40 (m, 6H) .
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:24][CH3:25])=[C:8]([C:10]#[C:11][CH2:12][NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=1)(=O)[CH3:2].[CH:26]1([NH2:29])[CH2:28][CH2:27]1>>[CH:26]1([NH:29][CH:1]([C:4]2[CH:5]=[CH:6][C:7]([O:24][CH3:25])=[C:8]([C:10]#[C:11][CH2:12][NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[CH3:2])[CH2:28][CH2:27]1
Reactant: COc1ccc(C(C)=O)cc1C#CCNC(=O)OCc1ccccc1
Reactant: NC1CC1
Product: COc1ccc(C(C)NC2CC2)cc1C#CCNC(=O)OCc1ccccc1

Procedure:
Benzyl [3-(5-acetyl-2-methoxyphenyl)prop-2-yn-1-yl]carbamate and cyclopropylamine were treated in the similar manner to Reference Example 6(6) to give benzyl (3-{5-[1-(cyclopropylamino)ethyl]-2-methoxyphenyl}prop-2-yn-1-yl)carbamate [Ex(295-2)] as a yellow oil.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:39])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:10](=[O:32])[C:9]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[CH:8]2)=[O:4].[NH2:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:25]([N:11]1[C:12]2[C:7](=[C:6]([OH:39])[C:5]([C:3]([NH:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:10]1=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2ccc(C(F)(F)F)nc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2ccc(C(F)(F)F)nc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 41.8 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-(6-trifluoromethyl-pyridin-3-yl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (67 mg, 0.13 mmol), β-alanine (674 mg, 7.6 mmol) and NaOMe solution (11 mL, 5.7 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration. The crude solid was purified by silica gel chromatography (5-50% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 32 mg of the title compound as an off-white solid. MS: (+) m/z 589.30 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][S:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])=[CH:5][CH:4]=1.[F:18][S:19]([O:22][CH3:23])(=[O:21])=[O:20]>C(Cl)Cl>[F:18][S:19]([O-:22])(=[O:21])=[O:20].[CH3:15][N+:11]1([CH3:23])[CH2:12][CH2:13][CH2:14][C@H:10]1[CH2:9][S:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=1
Reactant: COc1ccc(CSC[C@@H]2CCCN2C)cc1
Reactant: COS(=O)(=O)F
Solvent: ClCCl
Product: COc1ccc(CSC[C@@H]2CCC[N+]2(C)C)cc1
Product: O=S(=O)([O-])F

Procedure:
The procedure described in preparation 5-(5) was repeated, but using 740 mg of (2S)-2-(4-methoxybenzyl-thiomethyl)-1-methylpyrrolidine and 243 μl of methyl fluorosulfonate in the presence of 22 ml of methylene chloride, to afford 1.0 g of the title compound as crystals, melting at 150°-153° C.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21](/[CH:23]=[CH:24]/[C:25](O)=[O:26])[N:22]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21](/[CH:23]=[CH:24]/[C:25]([NH:28][CH2:29][CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:26])[N:22]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1ccc(-c2c(-c3nc(/C=C/C(=O)O)cs3)cnn2C(C)(C)C)cc1
Reactant: NCC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2c(-c3nc(/C=C/C(=O)NCC4CCOCC4)cs3)cnn2C(C)(C)C)cc1
Yield: 47.8 %

Procedure:
A solution of the compound (90 mg, 0.23 mmol) obtained in step 5, 4-(aminomethyl)tetrahydropyran (0.029 mL, 0.26 mmol), DIEA (0.049 mL, 0.28 mmol) and HATU (107 mg, 0.28 mmol) in DMF (2.0 mL) was stirred at room temperature for 14 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (solvent gradient; 50→80% ethyl acetate/hexane) and crystallized from ethyl acetate and hexane to give the title compound (52.7 mg, 0.110 mmol, 46.7%) as a white powder.
Reaction SMILES: C(OC([N:8]1[C:12]([C:13]2[C:14](=[O:26])[N:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:16]([CH3:19])[C:17]=2[CH3:18])=[CH:11][C:10]([CH3:27])=[N:9]1)=O)(C)(C)C.C(OC(N1C(C)=CC(C2C(=O)N(C3C=CC=CC=3)N(C)C=2C)=N1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:27][C:10]1[CH:11]=[C:12]([C:13]2[C:14](=[O:26])[N:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:16]([CH3:19])[C:17]=2[CH3:18])[NH:8][N:9]=1
Reactant: Cc1cc(-c2c(C)n(C)n(-c3ccccc3)c2=O)n(C(=O)OC(C)(C)C)n1
Agent: Cc1cc(-c2c(C)n(C)n(-c3ccccc3)c2=O)nn1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2c(C)n(C)n(-c3ccccc3)c2=O)[nH]n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the mixture of the N-methyl isomers (E) and (F) of Example 26 (0.012 g, 0.035 mmol) in dichloromethane (1 ml) add trifluoroacetic acid (1 ml). Stir this mixture at room temperature for 1 hour, and then evaporate the mixture to dryness. Dilute the residue with dichloromethane, wash sequentially with water, aqueous sodium bicarbonate solution, and water. Dry the organic layer (sodium sulfate) and concentrate to give 0.009 g (0.035 mmol) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].Br[CH2:11][CH2:12][CH2:13]Cl.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:15]1([CH2:16][CH2:17][CH2:18][O:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])[CH2:20][CH2:19][CH2:13][CH2:12][CH2:11]1
Reactant: N#Cc1ccccc1O
Reactant: ClCCCBr
Reactant: C1CCNCC1
Product: N#Cc1ccccc1OCCCN1CCCCC1
Yield: 77 %

Procedure:
According to a similar manner as that in Reference Example 36 except that 2-cyanophenol, 1-bromo-3-chloropropane, and piperidine were used, 2-(3-piperidinopropoxy)benzonitrile (77%) was obtained as a crude product.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11](O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](=[O:18])([O-])[O-].[K+].[K+].[Br:21][C:22]1[S:23][CH:24]=[C:25](CCl)[CH:26]=1.C(OCC)(=O)C>CN(C)C=O>[Br:21][C:22]1[S:23][CH:24]=[C:25]([CH2:15][O:18][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:1][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:26]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: ClCc1csc(Br)c1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1cc(COc2ccccc2Oc2ccccc2)cs1
Temperature: 80 °C
Reaction time: 12 h
Yield: 113.5 %

Procedure:
7.44 g of 4-phenoxyphenol and 5.52 g of potassium carbonate are stirred in 50 ml of anhydrous dimethylformamide for 1 hour at 70° C. 5.52 g of 2-bromo-4-chloromethylthiophene is then dripped in, and the mixture is stirred for a further 12 hours at 80° C., and at room temperature (approx. 20° C.) overnight. The mixture is then stirred into 500 ml of ethyl acetate and washed three times with water. After drying over sodium sulfate and removal of the solvent, the residue is recrystallized from n-hexane. There is obtained 10.7 g of 2-bromo-4-[(phenoxyphenoxy)-methyl]-thiophene; colorless powder; m.p.: 90° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4].C(N(CC)CC)C.[Br:19][CH2:20][C:21](Br)=[O:22]>C1COCC1>[Br:19][CH2:20][C:21]([NH:1][C@H:2]([CH2:3][OH:4])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:22]
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: O=C(Br)CBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CBr)N[C@H](CO)Cc1ccccc1
Reaction time: 1.25 h
Yield: 88.4 %

Procedure:
To a solution of (S)-2-amino-3-phenyl-1-propanol (1.00 g, 6.61 mmol) and triethylamine (1 mL, 7.17 mmol) in THF (70 mL) at −78° C. was added dropwise bromoactyl bromide (0.60 mL, 6.9 mmol). After 1.25 hours at −78° C., the resultant mixture was partitioned between 1M pH7 phosphate buffer (100 mL) and hexanes (100 mL). The aqueous layer was extracted with EtOAc:hex (2:1, 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give 1.59 g (85%) of 2-bromo-N-(1(S)-hydroxymethyl-2-phenylethyl)acetamide as a solid, mp 83-5° C.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:20])([CH:17]([CH3:19])[CH3:18])[C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])=[O:5].C1C[O:24][CH2:23][CH2:22]1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:23]([NH:2][C:3]([CH3:20])([CH:17]([CH3:18])[CH3:19])[C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])=[O:5])(=[O:24])[CH3:22]
Reactant: Cc1ccc(S(=O)(=O)NC(=O)C(C)(N)C(C)C)cc1
Reactant: C1CCOC1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NC(C)(C(=O)NS(=O)(=O)c1ccc(C)cc1)C(C)C

Procedure:
2-Amino-2,3-dimethyl-N-(p-tolylsulfonyl)butyramide hydrochloride (45 g ~0.4 mols) is completely dissolved in 160 mL of pyridine and 500 mL of THF is added. Acetic anhydride (45 mL) is then poured into the solution and the reaction mixture is heated at reflux for one hour. The solvents are removed under reduced pressure, and the oily residue is crystallized from EtOH/water affording 33.09 g of the title product having m.p. 198°-199° C.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].C(OC([N:14]1[CH2:21][CH2:20][C@:19]2([CH3:24])[C@H:22]([CH3:23])[C@H:15]1[CH2:16][C:17]1[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][C:18]=12)=O)(C)(C)C.Cl[C:39]1[N:40]=[N:41][C:42]([CH3:45])=[CH:43][CH:44]=1>CN(C)C=O>[CH3:24][C@:19]12[C@H:22]([CH3:23])[C@H:15]([NH:14][CH2:21][CH2:20]1)[CH2:16][C:17]1[CH:28]=[CH:27][C:26]([C:39]3[N:40]=[N:41][C:42]([CH3:45])=[CH:43][CH:44]=3)=[CH:25][C:18]2=1
Reactant: Cc1ccc(Cl)nn1
Reactant: C[C@@H]1[C@H]2Cc3ccc(B4OC(C)(C)C(C)(C)O4)cc3[C@]1(C)CCN2C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)[C@]2(C)CCN[C@H](C3)[C@H]2C)nn1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2 M Aqueous Na2CO3 solution (1.13 mL) is added to a mixture of (2R,6R,11S)-6,11-dimethyl-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester (483 mg) and 3-chloro-6-methyl-pyridazine (218 mg) in dimethylformamide (2 mL). The resulting mixture is flushed with argon and then 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane complex (73 mg) is added. The mixture is heated to 100° C. and stirred at this temperature overnight. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are washed with water and brine and dried (MgSO4). The solvent is removed under reduced pressure and the residue is taken up in CH2Cl2 (3 mL) and treated with F3CCOO2H (0.5 mL) for 1 h. Then, the solution is concentrated and the residue is purified by HPLC on reversed phase (MeCN/H2O/NH3) to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[CH2:6][CH2:5]2.[O:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH2:27]OS(C)(=O)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][C:13](=[O:21])[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:27][C@@H:23]3[CH2:24][CH2:25][CH2:26][O:22]3)=[CH:18][CH:19]=1)[CH2:6][CH2:5]2
Reactant: CS(=O)(=O)OC[C@@H]1CCCO1
Reactant: O=C(N[C@H]1CCc2cc(Br)ccc2C1)c1ccc(O)cc1
Product: O=C(N[C@H]1CCc2cc(Br)ccc2C1)c1ccc(OC[C@@H]2CCCO2)cc1

Procedure:
According to method F, N-((S)-6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)-4-hydroxybenzamide was reacted with methanesulfonic acid (S)-1-(tetrahydrofuran-2-yl)methyl ester. The product was thus obtained with the molecular weight of 430.35 (C22H24BrNO3); MS (ESI): 430 (M+H+).