Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[N:14]=[CH:15][CH:16]=[CH:17][N:18]=2)[C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1c(OC)cccc1-c1ncccn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cccc(-c2ncccn2)c1C(=O)O
Temperature: 50 °C

Procedure:
To a solution of the title compound of Step A (265 mg, 1.09 mmol) in THF (4 mL) was added 2 M NaOH (2 mL). The mixture was heated at 50° C. for 72 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to remove THF. Then, 1 M HCl(aq) was added and the aqueous was extracted with 10:1 DCM/2,2,2-trifluoroethanol (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated to give intermediate A-24, which was used without further purification in subsequent steps. MS (ESI) mass calcd. for C12H10N2O3, 230.1. m/z found 231.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.86 (d, J=4.9 Hz, 2H), 7.77 (dd, J=7.9, 1.0 Hz, 1H), 7.51 (t, J=8.1 Hz, 1H), 7.45 (t, J=4.9 Hz, 1H), 7.25 (dd, J=8.4, 1.0 Hz, 1H), 3.83 (s, 3H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[CH3:19][C:20]([O:23][C:24](=[O:31])[C@H:25]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH2:26])([CH3:22])[CH3:21]>>[C:20]([O:23][C:24](=[O:31])[C@@H:25]([NH:26][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH2:27][CH:28]([CH3:29])[CH3:30])([CH3:21])([CH3:19])[CH3:22]
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: CC(C)C[C@H](NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(=O)OC(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and L-leucine 1,1-dimethylethyl ester hydrochloride (1:1) (CAN 2748-02-9) as starting materials; LC-MS (UV peak area/ESI) 98.7%, 403.2599 (M+H)+.
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([C:7]2[S:11][C:10]([C:12]3C=CC=CC=3C(OC)=O)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH2:29].[OH-].[Na+]>C1COCC1>[C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([C:7]2[S:11][C:10]([CH2:12][OH:29])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: O
Reactant: COC(=O)c1ccccc1-c1ccc(-c2ccc(C)cc2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(CO)s2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl (5-p-tolylthiophen-2-yl)benzoate (5.0 mmol) in THF (20 mL) at 0° C. was slowly added LAH (1.0 M in THF, 6.0 mL). The reaction was then stirred at room temperature for 3 hours, and water (0.24 mL), 15% aqueous NaOH (0.24 mL), and water (0.72 mL) were added to the reaction mixture. After 30 minutes, the reaction mixture was filtered through celite and concentrated to give the pure product 13.1 (0.95 g). MS ESI (pos.) m/e 205.0 (M+H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH:11]([F:13])[F:12])[S:8][CH:7]=1)=[O:5])C>C(O)C.O1CCCC1.[OH-].[Na+]>[F:13][CH:11]([F:12])[C:9]1[S:8][CH:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1
Reactant: CCOC(=O)c1csc(C(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1csc(C(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Bromo-3-thiophenecarboxylic acid (4.14 g) was dissolved in tetrahydrofuran (50 ml), and the mixture was cooled to -78° C. n-Butyllithium (1.6M in hexane, 27.5 ml) was slowly added dropwise. The resulting mixture was stirred at the same temperature for 1 hour, and N,N-dimethylformamide (3.1 ml) was added. The mixture was warmed slowly to room temperature and concentrated under reduced pressure. The concentrate was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of 5-formyl-3-thiophenecarboxylic acid (3.12 g). 5-Formyl-3-thiophenecarboxylic acid (3.12 g) was dissolved in N,N-dimethylformamide (50 ml), and iodoethane (1.58 ml) and potassium carbonate (2.76 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water and extracted with ethyl acetate. The extract was washed with 5 % potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-formyl-3-thiophenecarboxylic acid ethyl ester (0.71 g). 5-Formyl-3-thiophenecarboxylic acid ethyl ester (1.47 g) synthesized in this manner in methylene chloride (10 ml) was slowly added dropwise to diethylaminosulfur trifluoride (DAST) (1.2 ml) in methylene chloride (10 ml) at room temperature. The mixture was stirred at room temperature for 15 hours, and saturated aqueous sodium bicarbonate was added. The organic layer was collected, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-difluoromethyl-3-thiophenecarboxylic acid ethyl ester (0.7 g). 5-Difluoromethyl-3-thiophenecarboxylic acid ethyl ester was dissolved in a mixture of ethanol (5 ml) and tetrahydrofuran (5 ml), and 1N aqueous sodium hydroxide (5 ml) was added. The mixture was stirred at room temperature for 1 hour and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-difluoromethyl-3-thiophenecarboxylic acid (0.58 g) as crystals.
Reaction SMILES: [N+](C1C=CC(N2CCCCC2)=CC=1C1N=CN=C(NCC2C=CC=C(C(F)(F)F)C=2)C=1)([O-])=O.NC1C=CC(N2CCCCC2)=CC=1C1N=CN=C(NCC2C=CC=C(C(F)(F)F)C=2)C=1.[NH2:65][C:66]1[CH:71]=[CH:70][C:69]([N:72]2[CH2:77][CH2:76][CH2:75][CH2:74][CH2:73]2)=[CH:68][C:67]=1[C:78]1[CH:83]=[C:82]([C:84](=[O:93])[CH2:85][CH2:86][C:87]2[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=2)[CH:81]=[CH:80][N:79]=1>>[NH2:65][C:66]1[CH:71]=[CH:70][C:69]([N:72]2[CH2:77][CH2:76][CH2:75][CH2:74][CH2:73]2)=[CH:68][C:67]=1[C:78]1[CH:83]=[C:82]([CH:84]([OH:93])[CH2:85][CH2:86][C:87]2[CH:88]=[CH:89][CH:90]=[CH:91][CH:92]=2)[CH:81]=[CH:80][N:79]=1
Reactant: Nc1ccc(N2CCCCC2)cc1-c1cc(C(=O)CCc2ccccc2)ccn1
Agent: Nc1ccc(N2CCCCC2)cc1-c1cc(NCc2cccc(C(F)(F)F)c2)ncn1
Agent: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(NCc2cccc(C(F)(F)F)c2)ncn1
Product: Nc1ccc(N2CCCCC2)cc1-c1cc(C(O)CCc2ccccc2)ccn1

Procedure:
This mixture was prepared using the procedure described for the conversion of 6-(2-nitro-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)pyrimidin-4-amine 3.1c to 6-(2-amino-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)pyrimidin-4-amine 3.1d. After chromatography on silica gel, mg of a mixture of starting material, 1-(2-(2-amino-5-(piperidin-1-yl)phenyl)pyridin-4-yl)-3-phenylpropan-1-one and 1-(2-(2-amino-5-(piperidin-1-yl)phenyl)pyridin-4-yl)-3-phenylpropan-1-ol was obtained.
Reaction SMILES: [N+](C1C=CC(C([O:10][C@H:11]2[CH2:16][CH2:15][C@@H:14]([N:17]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])[CH2:13][CH2:12]2)=O)=CC=1)([O-])=O.C[O-].[Na+].S([O-])(O)(=O)=O.[K+]>CO.O1CCCC1>[OH:10][C@@H:11]1[CH2:12][CH2:13][C@H:14]([N:17]2[C:18](=[O:27])[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]2=[O:26])[CH2:15][CH2:16]1
Reactant: O=C(O[C@H]1CC[C@@H](N2C(=O)c3ccccc3C2=O)CC1)c1ccc([N+](=O)[O-])cc1
Agent: C[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@@H](O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of cis-4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)cyclohexyl 4-nitrobenzoate (2.0 g, 5.07 mmol) in a mixture of methanol (40 ml) and tetrahydrofuran (40 ml) was added 28%-sodium methoxide (1.04 ml, 5.07 mmol) at 0° C., and stirred at 0° C. for 30 minutes and then at room temperature for 3.5 hours. The reaction solution was adjusted to pH 4 with a 0.5M-aqueous potassium hydrogensulfate solution and distilled under reduced pressure to remove the solvent. The residue was added to water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=3/1) to obtain cis-2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione (932 mg, 75%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:22]=[CH:21][C:6]2[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C@H:16]([CH2:18][CH:19]=[CH2:20])[NH2:17])=[N:8][O:9][C:5]=2[CH:4]=1>CO>[ClH:2].[O:9]1[C:5]2[CH:4]=[CH:3][CH:22]=[CH:21][C:6]=2[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C@H:16]([CH2:18][CH:19]=[CH2:20])[NH2:17])=[N:8]1
Reactant: C=CC[C@H](N)c1ccccc1-c1noc2cc(Cl)ccc12
Agent: Cl
Solvent: CO
Product: C=CC[C@H](N)c1ccccc1-c1noc2ccccc12

Procedure:
(S)-(-)-2-(6-chloro-1,2-benzisoxazol-3-yl)-a-2-propenyl-benzenemethanamine hydrochloride, melting at 169-178° C., a (c=0.9 in methanol) -7.8.
Reaction SMILES: CO[C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH:5]=1.[C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH3:17].[Li].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(O)(C(F)(F)F)=O.CC(C)=O>[C:20]([O:19][C:16](=[O:18])[CH2:17][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH:5]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(-n2cncn2)c1
Agent: [Li]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cncn2)c1

Procedure:
The 3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionic acid tert.-butyl ester was prepared from 3-[1,2,4]triazol-1-yl-benzoic acid methyl ester [CAS-No. 167626-27-9] by treatment with lithium tert.-butyl acetate according to general procedure H (method b). Prepared from (Example H6) by stirring in TFA/acetone with TFAA according to general procedure J (method b). Obtained as a yellow solid (539 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([N:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:35][CH2:34]2)=[CH:31][CH:32]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: Cc1ccc(N2CCNCC2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(N2CCN(CCCN3c4cccc5cccc(c45)S3(=O)=O)CC2)cc1
Temperature: 20 °C
Yield: 43 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (7 g), triethylamine (3.5 cc) and 4-(4-methylphenyl)piperazine (4.4 g) in toluene (100 cc). The mixture is heated for 6 hours at boiling point, then cooled to a temperature of about 20° C. After purification, flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with a mixture of dichloromethane and ethyl acetate (80-20 vol) as eluant, and recrystallization from boiling acetonitrile (40 cc), 2-{3-[4-(4-methylphenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (4.5 g) is obtained, m.p. 136° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.[CH2:9]([O:11][CH2:12][CH2:13][N:14]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[N:16]=[C:15]1[CH2:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]=[C:33]=[S:34])[CH2:26][CH2:25]1)[CH3:10]>>[NH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][C:3]=1[NH:8][C:33]([NH:32][CH2:31][CH2:30][N:27]1[CH2:28][CH2:29][N:24]([CH2:23][C:15]2[N:14]([CH2:13][CH2:12][O:11][CH2:9][CH3:10])[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH2:25][CH2:26]1)=[S:34]
Reactant: Nc1ccncc1N
Reactant: CCOCCn1c(CN2CCN(CCN=C=S)CC2)nc2cccnc21
Product: CCOCCn1c(CN2CCN(CCNC(=S)Nc3cnccc3N)CC2)nc2cccnc21
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 3.8 parts of 3,4-pyridinediamine, 13.1 parts of 3-(2-ethoxyethyl)-2-[[4-(2-isothiocyanatoethyl)-1-piperazinyl]methyl]-3H-imidazo[4,5-b]-pyridine and 135 parts stirred overnight at reflux temperature. The whole was evaporated, yielding 16.9 parts (100%) of N-(4-amino-3-pyridinyl)-N'-[2-[4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperazinyl]ethyl]thiourea as a residue (compound 121)
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]=[N+:20]=[N-:21])=[CH:15][C:14]=2[C:22]([F:25])([F:24])[F:23])(=[O:12])=[O:11])[CH2:7][C@@H:6]1[O:26][CH3:27])=[O:4].[CH2:28]([O:31][CH3:32])[C:29]#[CH:30]>C(Cl)Cl.[Cu]I>[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:30]=[C:29]([CH2:28][O:31][CH3:32])[N:21]=[N:20]3)=[CH:15][C:14]=2[C:22]([F:23])([F:24])[F:25])(=[O:12])=[O:11])[CH2:7][C@@H:6]1[O:26][CH3:27])=[O:4]
Reactant: C#CCOC
Reactant: COC(=O)[C@H]1C[C@H](S(=O)(=O)c2ccc(N=[N+]=[N-])cc2C(F)(F)F)C[C@@H]1OC
Agent: [Cu]I
Solvent: ClCCl
Product: COCc1cn(-c2ccc(S(=O)(=O)[C@@H]3C[C@H](OC)[C@@H](C(=O)OC)C3)c(C(F)(F)F)c2)nn1
Yield: 53 %

Procedure:
To a solution of (1R,2R,4R) and (1S,2S,4S)-4-(4-azido-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid methyl ester (100 mg, 0.245 mmol) in DCM (5 ml) was added methyl propargyl ether (26 mg, 0.371 mmol) and CuI (20 mg, immobilized on Amberlyst A-21, loading 1.2 mmol CuI/g, prepared according to Org. Letters 2006, 8, 1689) and the mixture was placed on a shaker over night. The mixture was then filtered and concentrated and the remaining oil was purified by silica gel chromatography (DCM/MeOH 98:2) to obtain the title compound (62 mg, 53%) as colorless oil. MS (EI): 478.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)=[O:3].[OH-].[K+]>ClCCl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Cl-].[Ru+2]>[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH:2]([OH:3])[CH3:1]
Reactant: CC(=O)c1ccc2ccccc2c1
Agent: [Ru+2]
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Product: CC(O)c1ccc2ccccc2c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Tris(triphenylphosphine)ruthenium(II) chloride (3.8 mg, 4 μmol, 1 mol %) and a chiral ligand (M=Ru, R=t-Bu, Ar=3,5-t-Bu2C6H3—, 2.6 μmol, 0.65 mol %) were dissolved in dichloromethane (3 mL) under nitrogen atmosphere, and then heated and stirred for 0.5 h at 40° C. After the mixture was cooled to room temperature, 2-acetonaphthone (0.4 mmol), dichloromethane (2 mL) and an aqueous solution of potassium hydroxide (0.2 mL, 0.2 M) were added thereto. Thereafter, the reaction system was placed in an autoclave, and stirred for 24 h under H2 (10 atm) at 50° C. The solvent was removed under reduced pressure, and the resultants were separated by column chromatography (silica gel column; eluent: ethyl acetate/petroleum ether=1/5). Accordingly, pure 1-(2-naphthyl)ethanol was obtained and the ee value (ee=98%) was measured by GC analysis.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[Cl:16][CH2:17][CH2:18][CH2:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH2:1]([NH:8][S:20]([CH2:19][CH2:18][CH2:17][Cl:16])(=[O:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(CCCCl)NCc1ccccc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 87 %

Procedure:
Benzylamine (1 eq.) was dissolved in anhydrous DCM (0.5 M) and Et3N (1.1 eq.) was added; after cooling at 0° C., 1-chloro-3-propanesulfonyl chloride was slowly added and the mixture was stirred at RT for 20 h. All volatiles were evaporated in vacuo and the residue taken up with Et2O; the precipitate was filtered off and the filtrate was concentrated; addition of PE afforded N-benzyl-3-chloropropane-1-sulfonamide as a white solid (87%). (ES+) m/z 248 (M+H+). Di-tert-butyl dicarbonate (1.5 eq.) was slowly added to an ice-cooled 0.45 M THF solution of N-benzyl-3-chloropropane-1-sulfonamide. DMAP (0.1 eq.) was then added and the reaction stirred overnight at RT. All volatiles were removed in vacuo and the crude diluted with EtOAc, washed with HCl, sat. aq. NaHCO3 and brine. After drying over Na2SO4, all volatiles were evaporated in vacuo and the residual material used in the next step without purification. (ES+) m/z 348, 350 (M+H+).
Reaction SMILES: Cl.[O:2]=[C:3]1[C:12]2[C:7]3[C:8](=[CH:13][CH:14]=[CH:15][C:6]=3[C:5](=[O:16])[N:4]1[CH2:17]CCCN1CCC(N(C3C=CC=CC=3)C(=O)CC)CC1)[CH:9]=[CH:10][CH:11]=2.[Br:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]CBr.BrCCCCBr>>[Br:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:17][N:4]1[C:5](=[O:16])[C:6]2[CH:15]=[CH:14][CH:13]=[C:8]3[C:7]=2[C:12](=[CH:11][CH:10]=[CH:9]3)[C:3]1=[O:2]
Reactant: BrCCCCCCBr
Reactant: CCC(=O)N(c1ccccc1)C1CCN(CCCCN2C(=O)c3cccc4cccc(c34)C2=O)CC1
Agent: Cl
Solvent: BrCCCCBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCCBr

Procedure:
Following the procedure of part (a) of example 31 but substituting 1,6-dibromohexane for the 1,4-dibromobutane, one obtains 2-(6-bromohexyl)-1H-benz[de]isoquinoline-1,3(2H)-dione; m.p. 95°-96°.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[N:7]2[CH:10]=[CH:11][NH:12][C:6]2=[N:5][C:4]=1[CH3:13])[CH3:2].[Si]([O:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1)(C(C)(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>CN(C=O)C>[CH2:1]([C:3]1[C:8](=[O:9])[N:7]2[CH:10]=[CH:11][N:12]([CH2:32][C:31]3[CH:30]=[CH:29][C:28]([C:26](=[O:27])[C:25]4[CH:36]=[CH:37][C:22]([OH:21])=[CH:23][CH:24]=4)=[CH:35][CH:34]=3)[C:6]2=[N:5][C:4]=1[CH3:13])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Reactant: CCc1c(C)nc2[nH]ccn2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CCc1c(C)nc2n(Cc3ccc(C(=O)c4ccc(O)cc4)cc3)ccn2c1=O
Yield: 10.6 %

Procedure:
A solution of 6-ethyl-7-methylimidazo[1,2-a]-pyrimidin-5(1H)-one (3.93 g), 4-(4-t-butyldimethylsilyloxybenzoyl)benzyl bromide (14.79 g) and potassium carbonate (5.97 g) in DMF (25 ml)-dimethyl sulfoxide (25 ml) was stirred at room temperature for 20 hours. This reaction mixture was concentrated and the residue was extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane: methanol =9:1) and recrystallized from ethanol-ethyl acetate to provide the title compound as colorless solid (909 mg).
Reaction SMILES: [PH2:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[O:23]S(C(F)(F)F)(=O)=O)=O.Cl[SiH](Cl)Cl>C(N(CC)CC)C>[C:3]1([P:1]([C:13]2[CH:22]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]2[CH:12]=[CH:11][C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[C:4]=2[C:13]2[C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[CH:16]=[CH:15][C:14]=2[OH:23])[CH:12]=[CH:11][CH:10]=[CH:5][CH:4]=1
Reactant: O=[PH2]c1ccc2ccccc2c1-c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Agent: Cl[SiH](Cl)Cl
Solvent: CCN(CC)CC
Product: Oc1ccc2c(c1-c1c(P(c3ccccc3)c3ccccc3)ccc3c1CCCC3)CCCC2

Procedure:
In detail, 2,2'-dihydroxy-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthyl (3), which is obtained by hydrogenation of 1,1'-bi-2-naphthol in the presence of a platinum oxide catalyst, is reacted with trifluoromethanesulfonic acid anhydride (4) in accordance with the process described in Tetrahedron Letters, Vol. 31, pp. 6321-6324 (1990) to obtain 2,2'-bis(trifluoromethanesulfonyloxy)-5,5',6,6',7,7',8,8-octahydro-1,1'-binaphthyl (5). Compound (5) is reacted with phosphine oxide (6) in the presence of a palladium catalyst to obtain compound (7). Compound (7) is first reduced by trichlorosilane in the presence of triethylamine and then hydrolyzed or first hydrolyzed and then reduced to obtain 2- diphenylphosphino-2'-hydroxy-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthyl (8). Compound (8) is reacted with a chlorophosphite derivative (9) in the presence of triethylamine to obtain an optically active phosphine compound of formula (II).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[CH2:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.C([O-])([O-])=O.[K+].[K+].[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1>CC#N.O>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][N:9]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[CH2:32][C:31]1[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COc1ccc(NCc2c(Cl)cncc2Cl)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(N(Cc2ccc(F)cc2)Cc2c(Cl)cncc2Cl)cc1OC
Temperature: 120 °C

Procedure:
Intermediate B1 (480 mg, 1.5 mmoles) was dissolved in CH3CN (7.5 mL). Solid K2CO3 (518 mg, 3.75 mmoles), solid KI (250 mg, 1.5 mmoles) and neat 4-fluoro-benzyl-bromide (0.191 mL, 1.5 mmoles) were added, and the mixture was heated in a sealed vial in a microwave oven at 120° C. for 30+30 minutes. The reaction mixture was diluted with water (40 mL) and extracted with AcOEt (3×40 mL). The organic layer was washed with brine, dried over Na2SO4, and evaporated to dryness. The crude was purified by flash chromatography (SiO2, petroleum ether/AcOEt from 9/1 to 7/3). The title compound was obtained as a light-yellow solid in amount of 407 mg.
Reaction SMILES: [CH:1]([Si:4]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[O:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)([CH3:3])[CH3:2].[C:22](C1C2C(=CC=C(OC(F)(F)F)C=2)N(CC(O)=O)C=1)(=[O:24])[CH3:23]>>[CH:19]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:16]([CH3:18])[CH3:17])[O:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[C:22](=[O:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)[Si](OCc1ccc2[nH]ccc2c1)(C(C)C)C(C)C
Reactant: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Product: CC(=O)c1c[nH]c2ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc12

Procedure:
The title compound was prepared from 5-triisopropylsilanyloxymethyl-1H-indole in a similar manner as described in step A of Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)-acetic acid. Brown solid. MS: 346 [M+H]+; tR (HPLC conditions c): 6.86 min.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH:5]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)[CH2:6][NH:7][C:8]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)=[O:9])C.[OH-].[Na+]>C(O)C>[CH3:30][O:29][C:23]1[CH:22]=[C:21]([CH:5]([CH2:6][NH:7][C:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)=[O:9])[C:4]([OH:31])=[O:3])[CH:26]=[CH:25][C:24]=1[O:27][CH3:28]
Reactant: CCOC(=O)C(CNC(=O)Cc1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CC(=O)NCC(C(=O)O)c2ccc(OC)c(OC)c2)cc1OC
Yield: 63.4 %

Procedure:
A mixture of 18.4 g of 2-(3,4-dimethoxyphenyl)-3-{{[(3,4-dimethoxyphenyl)methyl]carbonyl}amino}propanoic acid ethyl ester, 50 ml of ethanol, and 65 ml of 10% sodium hydroxide was refluxed for 2 hours, concentrated to remove ethanol, and diluted with water. The aqueous layer was washed with ethyl acetate, acidified with excess 6N hydrochloric acid, and the product was extracted with ethyl acetate, dried, and evaporated. Trituration of the residue with ether provided 10.9 g of insoluble 2-(3,4-dimethoxyphenyl)-3-{{[(3,4-dimethoxyphenyl)methyl]carbonyl}amino}propanoic acid, mp 151°-153°. Crystallization from ethyl acetate gave the analytical sample, mp 150°-152°.