Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1.Br[CH2:15][CH2:16][CH:17]=[CH2:18].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:18]([NH:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:12])([F:13])[F:1])=[CH:10][CH:9]=1)[CH2:17][CH:16]=[CH2:15]
Reactant: Nc1ccc(OCC(F)(F)F)cc1
Reactant: C=CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCCNc1ccc(OCC(F)(F)F)cc1
Yield: 22 %

Procedure:
The mixture of 4-(2,2,2-Trifluoro-ethoxy)-phenylamine (2.5 g, 13 mmol), 4-bromobut-1-ene (3.54 g, 26 mmol) and Cs2CO3 (6.41 g, 20 mmol) was stirred in 30 mL of DMF at ambient temperature for 72 h. And then the mixture was filtered and washed with water. The filtrate was extracted with EtOAc (30 mL×3). The combined organic layers was washed with brine and dried with anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica-gel column chromatography (eluting with petroleum ether/ethyl acetate=30:1). The title compound (0.7 g, 22%) as brown oil was obtained. LC-MS: 246.1 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:18]=[CH:17][C:12]([O:13][CH2:14][CH2:15][OH:16])=[CH:11][CH:10]=2)[O:3]1.C(N(CC)CC)C.[S:27](Cl)([C:30]1[CH:36]=[CH:35][C:33](C)=[CH:32][CH:31]=1)(=[O:29])=[O:28]>CN(C)C1C=CN=CC=1.ClCCl>[C:30]1([S:27]([O:16][CH2:15][CH2:14][O:13][C:12]2[CH:17]=[CH:18][C:9]([B:4]3[O:3][C:2]([CH3:19])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:10][CH:11]=2)(=[O:29])=[O:28])[CH:36]=[CH:35][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)OB(c2ccc(OCCO)cc2)OC1(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(OCCOS(=O)(=O)c3ccccc3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
Into dichloromethane 100 ml, 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethanol (4.4 g, 16.7 mmol) synthesized in Example 2 (2b) was dissolved, to which triethylamine (4.6 ml, 33.2 mmol), 4-dimethylaminopyridine (400 mg, 3.3 mmol), tosyl chloride (4.8 g, 25.2 mmol) were sequentially added while cooling with ice. The resulting mixture was warmed back to room temperature, followed by further stirring for two hours. The resulting reaction liquid was sequentially washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate, 100:0-70:30, V/V) to give the desired title compound (6.1 g, yield 88%).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=O)[C:15]=4[N:14]=3)=[C:9]([C:25]([F:28])([F:27])[F:26])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:29]1([CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1>>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([NH:39][C:38]5[CH:37]=[CH:36][C:35]([CH2:34][N:29]6[CH2:33][CH2:32][CH2:31][CH2:30]6)=[CH:41][CH:40]=5)=[O:24])[C:15]=4[N:14]=3)=[C:9]([C:25]([F:27])([F:26])[F:28])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cccc2[nH]c(-c3ccc(CN4CCCC4)cc3C(F)(F)F)nc12
Reactant: Nc1ccc(CN2CCCC2)cc1
Product: O=C(Nc1ccc(CN2CCCC2)cc1)c1cccc2[nH]c(-c3ccc(CN4CCCC4)cc3C(F)(F)F)nc12

Procedure:
2-(4-(pyrrolidin-1-ylmethyl)-2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxylic acid 159 was coupled with 4-(pyrrolidin-1-ylmethyl)aniline 160 to produce 2-(4-(pyrrolidin-1-ylmethyl)-2-(trifluoromethyl)phenyl)-N-(4-(pyrrolidin-1-ylmethyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide (Compound 869) using the same general procedure outlined in Example 39. MS (ESI) calcd for C31H32F3N5O: 547.26; found: 548 [M+H].
Reaction SMILES: [CH3:1][N:2]([CH3:39])[CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][C:16]2[CH:17]=[C:18]([N:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)[CH:19]=[CH:20][C:21]=2[C:22]([O:24][CH3:25])=[O:23])[NH:8][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:39][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][C:16]2[CH:17]=[C:18]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:19]=[CH:20][C:21]=2[C:22]([O:24][CH3:25])=[O:23])[NH:8][CH:7]=1
Reactant: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1Oc1cccc2[nH]cc(CCCN(C)C)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(N2CCNCC2)cc1Oc1cccc2[nH]cc(CCCN(C)C)c12
Reaction time: 2 h

Procedure:
A solution of EXAMPLE 339F (484 mg) in dichloromethane (22 mL) was cooled in an ice bath and 2,2,2-trifluoroacetic acid (11 mL) was added. The reaction was stirred for 2 hours, concentrated and the crude product was chromatographed on silica gel with 7N-methanolic ammonia in methylene chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=O)[NH:8][CH:7]=[C:6]2[C:16]#[N:17].P(Br)(Br)([Br:20])=O.C1(OC)C=CC=CC=1>>[Br:20][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2)[C:6]([C:16]#[N:17])=[CH:7][N:8]=1
Reactant: COc1cc2c(C#N)c[nH]c(=O)c2cc1OC
Reactant: O=P(Br)(Br)Br
Solvent: COc1ccccc1
Product: COc1cc2c(C#N)cnc(Br)c2cc1OC
Temperature: 110 °C
Yield: 22.7 %

Procedure:
To a mixture of 6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carbonitrile. (3.5 g, 15.2 mmol) and phosphorus oxybromide (30 g, 105 mmol) was added anisole (3.2 mL, 30.4 mmol). The reaction mixture was heated at 110° C. for 1 h. The excess phosphorus oxybromide was removed in vacuo. The mixture was then neutralized to pH=7 by addition of saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane (3×200 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (100 mL), dried with anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product was recrystallized from chloroform and diethyl ether to afford product 1-bromo-6,7-dimethoxy-isoquinoline-4-carbonitrile (1 g, 22.7% yield) as a white solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:8]1[CH:3]([N:2]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4][CH2:5][CH:6]([OH:9])[CH2:7]1
Reactant: BrCc1ccccc1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OC1CCC(N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
trans-4-Aminocyclohexanol hydrochloride (25 g, 217 mmol) was suspended in acetonitrile (500 mL). Benzyl bromide (54.2 mL, 456 mmol) and potassium carbonate (120 g, 868 mmol) were added to the suspension and the resulting mixture was stirred vigorously overnight at room temperature. The reaction mixture was filtered through a plug of celite and the plug was washed thoroughly with acetonitrile. The filtrate was condensed to give a white solid. The crude solids were purified by silica gel chromatography (0-60% ethyl acetate in hexanes). Pure product containing fractions were combined and concentrated to afford (1r,4r)-4-(dibenzylamino)cyclohexanol (25 g, 85 mmol, 39.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.26-7.36 (m, 8H), 7.16-7.22 (m, 2H), 4.43 (d, J=4.69 Hz, 1H), 3.55 (s, 4H), 3.27-3.33 (m, 1H), 2.28-2.40 (m, 1H), 1.69-1.88 (m, 4H), 1.40 (qd, J=12.56, 2.93 Hz, 2H), 0.89-1.05 (m, 2H); MS (ESI) m/z 296.3 [M+1]+.
Reaction SMILES: [NH:1]1[C@H:3]([C:4](OCC)=[O:5])[C@H:2]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].CCO.[BH4-].[Na+]>CCOC(C)=O>[CH2:12]([O:11][C:9]([C@@H:2]1[C@@H:3]([CH2:4][OH:5])[NH:1]1)=[O:10])[CH3:13]
Reactant: CCOC(=O)[C@H]1N[C@@H]1C(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)[C@H]1N[C@@H]1CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
In a round bottom flask equipped with a magnetic stirring bar and a septum was placed (S,S) diethyl aziridine-2,3-dicarboxylate (1.87 g, 10 mmol) dissolved into 30 ml of EtOH. The vessel was cooled to 0° C. and NaBH4 (302.6 mg, 8 mmol) was added slowly. The reaction mixture was allowed to stir at 0° C. until the reaction was complete according to TLC (EtOAc, Rf=0.66), which was approximately 2 hours. The reaction was quenched by the addition of pH 7 phosphate buffer, and extracted three times with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; gradient 8:2 EtOAc/hexanes—100% EtOAc) to afford the title compound in 84% yield as a pale yellow oil. 1H NMR (CDCl3, 200 MHz) δ: 4.22 (q, J=7.0 Hz, 2H), 3.82 (dd, J=12.4 Hz, 2.8 Hz, 1H), 3.48 (dd, J=12 Hz, 4.8 Hz, 1H), 2.46 (m, 2H), 1.50 (bs, 1H), 1.31 (t, J=7.0 Hz, 3H) ppm. 13C NMR (CDCl3, 50 MHz) δ: 172.2, 62.0, 61.5, 39.8, 32.7, 14.3 ppm. HRMS (ESI) [M+H]+ calcd. for C6H12NO3 146.0817, found 146.0820.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9]/[CH:10]=[CH:11]/[C:12]1[C:21]2[C:20]([NH2:22])=[N:19][S:18](=[O:24])(=[O:23])[NH:17][C:16]=2[CH:15]=[CH:14][CH:13]=1.CC(O)=O.O>C1COCC1>[NH2:22][C:20]1[C:21]2[C:12](/[CH:11]=[CH:10]/[CH2:9][CH2:8][OH:7])=[CH:13][CH:14]=[CH:15][C:16]=2[NH:17][S:18](=[O:24])(=[O:23])[N:19]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(/C=C/CCOC3CCCCO3)c21
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: NC1=NS(=O)(=O)Nc2cccc(/C=C/CCO)c21
Temperature: 45 °C
Yield: 0.1 %

Procedure:
To a solution of (E)-5-(4-(tetrahydro-2H-pyran-2-yloxy)but-1-enyl)-1H-benzo[c][1,2,6]thiadiazin-4-amine-2,2-dioxide (322 mmol, 43 mg) (Example 273) in THF (860 μL) was added AcOH (1.7 mL) and water (430 μL) and the solution heated overnight at 45° C. The solution was cooled to room temperature and the solvent evaporated. The residue was triturated with boiling water then cooled to room temperature. The resulting solid was collected and washed with water to give the desired product (69 mg, 80%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 2.365 (q, J=6 Hz, 2H), 3.568 (q, J=6 Hz, 2H), 4.681 (t, J=6 Hz, 1H), 6.186 (d of t, J=7 Hz, 16 Hz, 1H), 6.786 (d, J=16 Hz, 1H), 6.922 (d, J=8 Hz, 1H), 7.022 (br. s, 1H), 7.088 (d, J=8 Hz, 1H), 7.468 (t, J=8 Hz, 1H), 8.388 (br. s, 1H), 10.935 (s, 1H). MS 268 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([N:12]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:8]=[CH:7]2.CCCCCC.C([Li])CCC.[CH3:38][N:39]1[CH2:44][CH2:43][C:42](=[O:45])[CH2:41][CH2:40]1>O1CCCC1>[CH2:20]([N:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][CH:3]=[C:2]2[C:42]2([OH:45])[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]2)=[CH:7][CH:8]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CN1CCC(=O)CC1
Reactant: Brc1cccc2ccc(N(Cc3ccccc3)Cc3ccccc3)cc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN1CCC(O)(c2cccc3ccc(N(Cc4ccccc4)Cc4ccccc4)cc23)CC1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 138.8 %

Procedure:
The following reaction was run in two side by side reactions and the crude products were combined for work up and purification. A mechanically stirred solution of 8-bromo-2-(dibenzylamino)-naphthalene (10.0 g, 24.9 mmol from Preparation 4) in tetrahydrofuran (200 mL) was cooled to -95° C. (hexane/liquid nitrogen) and butyllithium (10.39 mL, 24.9 mmol, 2.4 M) was added dropwise. The orange solution was stirred 7 min, then 1-methyl-4-piperidone (2.82 g, 24.9 mmol) was added dropwise over 10 minutes with a 10 mL tetrahydrofuran rinse. The orange color faded while stirring was continued 20 minutes at -100° C. The reaction was allowed to warm to room temperature and quenched with water. The solvent was removed and the residue was partitioned between methylene chloride and water (at this point the two reactions were combined). The phases were separated and the organic layer was washed with brine, dried, and concentrated onto silica gel. Flash chromatography (4×4 inches silica gel) proceeded as follows: methylene chloride (1 L) and 2% methanol/methylene chloride (1.6 L) unweighed white solid 7-dibenzylaminonaphthalene; 15% methanol / methylene chloride (1 L), 25% methanol/methylene chloride (1 L) and 30% methanol/methylene chloride/0.2% ammonium hydroxide (4 L) product contaminated with water. The combined eluents were concentrated and redissolved in methylene chloride. The solution was dried and concentrated to afford 15.09 g (69%) of 7-dibenzylamino-1-(4-hydroxy-1-methyl-4-piperidinyl)-naphthalene as a light tan foam. A sample recrystallized from ethyl acetate had mp 173°-174° C. Analysis calculated for C30H32N2O: C, 82.53; H, 7.39; N, 6.42. Found: C, 82.42; H, 7.44; N, 6.38.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:21]([O-])=O.[CH:24]1([C:27]2[N:32]=[C:31]([CH:33]=O)[CH:30]=[CH:29][CH:28]=2)[CH2:26][CH2:25]1.S(S([O-])=O)([O-])=O.[Na+].[Na+].O>C(O)C>[CH:24]1([C:27]2[N:32]=[C:31]([C:33]3[NH:1][C:2]4=[N:7][C:6]([N:8]5[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]6[CH2:20][CH2:19][CH2:18][CH2:17]6)=[O:15])[CH2:9]5)=[CH:5][CH:4]=[C:3]4[N:21]=3)[CH:30]=[CH:29][CH:28]=2)[CH2:26][CH2:25]1
Reactant: O=Cc1cccc(C2CC2)n1
Reactant: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C([C@@H]1CCCN(c2ccc3nc(-c4cccc(C5CC5)n4)[nH]c3n2)C1)N1CCCC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 18.6 %

Procedure:
To a solution of (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (250 mg, 0.711 mmol) in ethanol (15 mL) was added 6-cyclopropylpicolinaldehyde (0.137 g, 0.974 mmol), sodium dithionite (536 mg, 2.96 mmol) and water (2 mL). The reaction mixture was stirred for 16 h at 100° C. in a sealed tube. The mixture was cooled, and the solvent was removed under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via preparative TLC eluting with 4% methanol in dichloromethane to afford the title compound (55 mg, 17%). MS (ES+APCI) (M+H) 417.2; LCMS retention time 1.944 (Method F). 1H NMR (300 MHz, CDCl3) δ 1.00-1.09 (m, 2H), 1.09-1.16 (m, 2H), 1.63-1.74 (m, 1H), 1.81-2.14 (m, 7H), 2.62-2.76 (m, 1H), 2.99 (dd, 1H), 3.08-3.21 (m, 1H), 3.44-3.55 (m, 3H), 3.58-3.70 (m, 1H), 4.35 (d, 1H), 4.48 (d, 1H), 6.71 (d, 1H), 7.19 (d, 1H), 7.66 (t, 1H), 7.87 (d, 1H), 8.04 (d, 1H), 10.18 (br s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:12]([CH2:18]OC)[CH2:13][Si](C)(C)C)([CH3:11])([CH3:10])[CH3:9].[F:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([O:32][CH3:33])=[O:31])=[CH:24][CH:23]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:8]([N:12]1[CH2:13][C@@H:28]([C:25]2[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=2)[C@H:29]([C:30]([O:32][CH3:33])=[O:31])[CH2:18]1)([CH3:9])([CH3:10])[CH3:11]
Reactant: COCN(C[Si](C)(C)C)C(C)(C)C
Reactant: COC(=O)/C=C/c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CN(C(C)(C)C)C[C@H]1c1ccc(F)cc1
Reaction time: 18 h
Yield: 75.1 %

Procedure:
Trifluoroacetic acid (38.9 mL, 0.505 mmol) was added to a solution of the product of step B (1.03 g, 5.05 mmol) and methyl (2E)-3-(4-fluorophenyl)prop-2-enoate (1.00 g, 5.05 mmol) in methylene chloride (10 mL) at ambient temperature. After 18 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted three times with methylene chloride. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification of the crude residue by medium pressure liquid chromatography on silica gel (gradient elution; 0–9% methanol (containing 10% v/v ammonium hydroxide)/methylene chloride as eluent) furnished the title compound as a colorless liquid (1.06 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.Cl[P:16]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCCC1>[CH:22]1([P:16]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: ClP(C1CCCC1)C1CCCC1
Reactant: COc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccccc1P(C1CCCC1)C1CCCC1
Yield: 88.5 %

Procedure:
Under a nitrogen atmosphere, into a reaction vessel equipped with a dropping funnel were added 0.91 g of 2-bromoanisole and 20 mL of tetrahydrofuran. The resultant solution was cooled down to −78° C., then, 3.4 ml of n-butyllithium (1.62 M/hexane solution) was dropped. The resultant mixture was stirred at the same temperature for 2 hours, then, a solution obtained by dissolving 1.00 g of chlorodicyclopentylphosphine in 13 ml of tetrahydrofuran was dropped at −78° C. The resultant mixture was stirred at room temperature for 3 hours. The resultant reaction mixture was concentrated, and purified by silica gel column chromatography, to obtain 1.19 g of dicyclopentyl(2-methoxyphenyl)phosphine in the form of viscous liquid.
Reaction SMILES: [C@H:1]12[CH2:7][C@@H:6]([OH:8])[C@H:5]1[CH2:4][NH:3][CH2:2]2.[CH:9]([C:11]1[C:12]([F:23])=[CH:13][N:14]=[C:15]2[C:20]=1[N:19]=[C:18]([O:21][CH3:22])[CH:17]=[CH:16]2)=[CH2:10]>CCO>[F:23][C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:11]=1[CH2:9][CH2:10][N:3]1[CH2:4][C@H:5]3[C@H:1]([CH2:7][C@H:6]3[OH:8])[CH2:2]1)=[N:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2
Reactant: O[C@@H]1C[C@@H]2CNC[C@@H]21
Reactant: C=Cc1c(F)cnc2ccc(OC)nc12
Solvent: CCO
Product: COc1ccc2ncc(F)c(CCN3C[C@H]4C[C@@H](O)[C@H]4C3)c2n1
Reaction time: 12 h
Yield: 23.4 %

Procedure:
A solution of (±)-(1S,5R,6R)-3-azabicyclo[3.2.0]heptan-6-ol (700 mg, 6.2 mmol) and 8-ethenyl-7-fluoro-2-(methyloxy)-1,5-naphthyridine (1.3 g, 6.2 mmol) in EtOH (4 mL) were heated at 85° C. After 12 h, the solution was concentrated and the residue purified via column chromatography (silica, 1% MeOH in DCM (1% NH4OH)) yielding the title compound (460 mg, 23%) as a yellow oil: LC/MS (ES) m/e 318 (M+H)+.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[F:5][C:6]1[C:11]([O:12][CH2:13]CO)=[CH:10][C:9]([O:16][CH3:17])=[CH:8][C:7]=1[C@H:18]([NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[NH:37])=[CH:34][CH:33]=1)[C:19]1[NH:23][C:22](=[O:24])[N:21]([C:25]2[N:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[N:20]=1.BrC[CH2:43][CH2:44][O:45][Si](C(C)(C)C)(C)C>>[C:1]([OH:4])(=[O:3])[CH3:2].[F:5][C:6]1[C:11]([O:12][CH2:13][CH2:43][CH2:44][OH:45])=[CH:10][C:9]([O:16][CH3:17])=[CH:8][C:7]=1[C@H:18]([NH:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([NH2:38])=[NH:37])=[CH:39][CH:40]=1)[C:19]1[NH:23][C:22](=[O:24])[N:21]([C:25]2[N:26]=[CH:27][CH:28]=[CH:29][N:30]=2)[N:20]=1
Reactant: COc1cc(OCCO)c(F)c([C@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Solvent: CC(=O)O
Product: COc1cc(OCCCO)c(F)c([C@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1

Procedure:
The same procedure was carried out as in Examples (153a) to (153b), except that (3-bromopropoxy)-t-butyldimethylsilane was used instead of 2-(2-bromoethoxy)tetrahydro-2H-pyran in Example (153a), to give the first eluting enantiomer of the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][CH2:9][C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]1([CH:25]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.Cl>C(Cl)Cl.O>[C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][CH2:9][C:10]([N:27]2[CH2:28][CH2:29][CH2:30][CH:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26]2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2CCCNC2)cc1
Reactant: O=C(Cl)COC(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(COC(c1ccccc1)c1ccccc1)N1CCCC(c2ccccc2)C1
Reaction time: 8 h
Yield: 64.9 %

Procedure:
A solution of 4.5 g (17.2 mmole) of (diphenylmethoxy) acetyl chloride in 50 cm3 of methylene chloride was added drop-wise at room temperature to a solution of 2.8 g (17.2 mmole) of 3-phenylpiperidine [prepared according to M. Julia et al., Bull. Soc. Chim. Fr. 1968, 987] and 3.5 g (34.4 mmole) of triethylamine in 100 cm3 of methylene chloride. The reaction mixture was heated to reflux for 4 hours; it was allowed to stand overnight and was then poured into a solution of 10 cm3 of concentrated hydrochloric acid in 300 cm3 of water. The mixture was extracted with methylene chloride, washed with water and dried on sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel filtration (eluent, hexaneethyl acetate, 1/1), then by recrystallization from a hexane-ethyl acetate mixture. There was obtained 4.3 g (yield: 65%) of 1-[(diphenylmethoxy)acetyl]-3-phenylpiperidine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][S:14]([NH:17][CH3:18])(=[O:16])=[O:15])[CH:11]=2)[NH:6][CH:5]=1.[C:19]1([N:25]=[CH:26]OCC)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[C:19]1([NH:25][CH:26]=[N:1][CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][S:14]([NH:17][CH3:18])(=[O:15])=[O:16])[CH:11]=3)[NH:6][CH:5]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC=Nc1ccccc1
Reactant: CNS(=O)(=O)Cc1ccc2[nH]cc(CCN)c2c1
Solvent: CC(C)=O
Product: CNS(=O)(=O)Cc1ccc2[nH]cc(CCN=CNc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.6 %

Procedure:
2.67 g (0.01 m) of 3-(2-aminoethyl)-1H-indole-5-yl-N-methyl methane sulphonamide and 10 mL of acetone were charged in a 25 mL round bottom flask. 1.64g (0.01 m) of ethyl N-phenylformimidate were added and the mixture was stirred at room temperature for 24 hours. When the reaction was deemed to have terminated, as per the TLC control (eluant: butanol/acetic acid/H2O 65/13/22) the acetone was concentrated to dryness and the oil obtained was crystallized from toluene. It was filtered, was washed with 10 mL of toluene and dried in a current of air at 50° C. to give 2.5 g of 3-[2-(N-phenylaminomethyleneamino)ethyl]-1H-indole-5-yl-N-methyl methane sulphonamide, in the form of a cream colored solid, representing a 67% yield. M.p.=72°-73° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:21])[CH2:9]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:5]=[CH:6][CH:7]=1.[N-:22]=[N+:23]=[N-:24].[Na+].CS(C)=O>O>[N:22]([CH2:9][C@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:21])=[N+:23]=[N-:24]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)c2cccc(Cl)c2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NC[C@@H](O)c1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of toluene-4-sulfonic acid (S)-2-(3-chlorophenyl)-2-hydroxyethyl ester (16.34 g, 0.050 mol), sodium azide (6.50 g, 0.10 mol) and DMSO (50 mL) was stirred for 2 h at 80° C. Water (100 mL) was added, extracted with hexane-ether (1:1) mixture (2×150 mL). Combined extract was dried over Na2SO4, evaporated. The residue was separated on SiO2 (100 g), hexane-EtOAc, 0 to 20%. Colorless oil, 7.0 g, (0.035 mol, 71%).