Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH2:7][CH2:6][CH2:5]1)(=O)[CH3:2].Cl.[NH2:17][OH:18].O.O.O.C([O-])(=O)C.[Na+]>O>[C:1](=[N:17][OH:18])([C:4]1([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH2:7][CH2:6][CH2:5]1)[CH3:2]
Reactant: NO
Reactant: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(=NO)C1(c2ccc(Cl)c(Cl)c2)CCC1

Procedure:
A mixture of 1-acetyl-1-(3,4-dichlorophenyl)cyclobutane (4.86 g) prepared as described in Example 1, hydroxylamine hydrochloride (1.6 g), sodium acetate trihydrate (3.3 g), industrial methylated spirit (15 ml) and water (2 ml) was heated under reflux for twenty hours. The cooled reaction mixture was poured into water and the oil which separated was cooled to give a solid which was recrystallised from industrial methylated spirit to give 1-acetyl-1-(3,4-dichlorophenyl)cyclobutane oxime (m.p. 120°-121° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][CH:16]3[CH2:25][CH2:24][C:19]4(OCC[O:20]4)[CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl>O1CCCC1.C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][CH:16]3[CH2:25][CH2:24][C:19](=[O:20])[CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2ccc(C#CC3CCC4(CC3)OCCO4)cc2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1CCC(C#Cc2ccc(-c3ccc(F)cc3)cc2)CC1
Yield: 98.3 %

Procedure:
A solution of 1.30 g of 8-[(4'-fluoro-4-biphenylyl)ethynyl]-1,4-dioxaspiro[4.5]decane in 30 ml of tetrahydrofuran was stirred with 3.5 ml of 3N hydrochloric acid for 2.4 hours. The reaction mixture was diluted with diethyl ether, washed with saturated sodium hydrogen carbonate solution and with saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated. 1.11 g of 4-[(4'-fluoro-4-biphenylyl)ethynyl]cyclohexanone were obtained.
Reaction SMILES: [CH:1]1[CH2:5][CH2:4][CH2:3][C:2]=1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:9]2[C:29]1[CH:34]=[CH:33][CH:32]=[C:31](OCC2CC2)[CH:30]=1>C(OCC)(=O)C.[Pd].CCO>[C:2]([C:32]1[CH:33]=[CH:34][C:29]([C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([CH:2]4[CH2:1][CH2:5][CH2:4][CH2:3]4)[CH:7]=3)[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)[C:10]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:30][CH:31]=1)([CH3:6])([CH3:3])[CH3:1]
Reactant: CCOC(=O)c1c(-c2cccc(OCC3CC3)c2)c2cc(C3=CCCC3)ccc2n1Cc1cccc(OC)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cc(C3CCCC3)ccc2n1Cc1cccc(OC)c1
Reaction time: 16 h
Yield: 187.3 %

Procedure:
A solution of ethyl 5-(1-cyclopenten-2-yl)-3-[3-(cyclopropylmethoxy)phenyl]-1-(3-methoxybenzyl)-1H-indole-2-carboxylate (Example 128, 225 mg, 0.44 mmol) in ethyl acetate (3 mL) and ETOH (3 mL) was added to a slurry of 10% palladium on charcoal (100 mg) in ethyl acetate (2 mL) and EtOH (2 mL). The reaction was placed under hydrogen (1 atm) and stirred for 16 h. The mixture was filtered through a pad of Celite using ethyl acetate to rinse. Evaporation of the filtrate gave 210 mg (93%) of the product. The product had: 1H NMR (300 MHz, acetone-D6) δ 7.37-7.53 (m, 6 H), 7.28 (dd, 1 H), 7.19 (dd, 1 H), 6.67-6.82 (m, 3 H), 5.83 (s, 3 H), 4.08 (q, 2 H), 3.75 (s, 3 H), 3.06 (p, 1 H), 1.99-2.06 (m, 2 H), 1.47-1.83 (m, 6 H), 1.40 (s, 9 H), 0.98 (t, 3 H).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[NH:29]1[CH2:34][CH2:33][CH2:32][CH:31]([C:35]([OH:38])([CH3:37])[CH3:36])[CH2:30]1>>[CH3:28][N:4]1[C:3]([CH2:2][N:29]2[CH2:34][CH2:33][CH2:32][CH:31]([C:35]([OH:38])([CH3:37])[CH3:36])[CH2:30]2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: CC(C)(O)C1CCCNC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCCC(C(C)(C)O)C3)n(C)c2n1

Procedure:
Following General Procedure E of amine alkylation, 4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and 2-(piperidin-3-yl)propan-2-ol were reacted to give 265. M+H+=505.3
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1Cl

Procedure:
A mixture of 3-chloro-4-nitrophenol (10 g, 0.058 mole), benzyl bromide (11.8 g, 0.069 mole), and potassium carbonate (16 g, 0.116 mole) in acetone is stirred, heated at reflux temperature for 17 hours, cooled and filtered. The filtrate is concentrated in vacuo to give a solid residue which is recrystallized from absolute ethanol to give the title compound, mp 82°-84.5° C., identified by elemental and NMR analyses.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=O.[Br:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27].C1(C)C(C)=CC=CC=1>C1(C)C=CC=CC=1>[Br:23][C:24]1[CH:25]=[C:26]([NH:27][C:3]([C:5]2[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][C:9]=3[C:10]=2[OH:11])=[O:2])[CH:28]=[CH:29][CH:30]=1
Reactant: Nc1cccc(Br)c1
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: CN1C(C(=O)Nc2cccc(Br)c2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Yield: 77 %

Procedure:
N-(3-Bromophenyl)-4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 1 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide and 3-bromoaniline in toluene. Yield: 77% of theory; m.p.268°-269° C (decomp.; from xylene).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[N:26]1([CH2:2][C:3]([NH:5][C:6]2[CH:25]=[CH:24][C:9]3[N:10]=[C:11]([NH:14][CH2:15][CH2:16][O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[O:12][CH2:13][C:8]=3[CH:7]=2)=[O:4])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: C1COCCN1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(NCCOc1ccccc1)=N2
Product: O=C(CN1CCOCC1)Nc1ccc2c(c1)COC(NCCOc1ccccc1)=N2
Yield: 100.4 %

Procedure:
Prepared from 2-chloro-N-[2-(2-phenoxy-ethylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 122, step A) (180 mg, 0.50 mmol; HPLC 1.096 min) and morpholine (0.87 ml, 10 mmol) according to the procedure described for Example 3 step B. Obtained the title compound as a white solid (206 mg, 100%; HPLC 0.588 min), MS (ISP) m/e=411.2 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].C(=O)([O-])[O-].[K+].[K+].[Cl:16][CH2:17][CH2:18]Cl.CN(C)C=O>O>[Cl:16][CH2:17][CH2:18][N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: ClCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)NC(=O)N(CCCl)C1=O

Procedure:
A mixture of 1,664 g of 5,5-dimethyl-hydantoin (13.0 mols), 897 g of anhydrous potassium carbonate (6.5 mols), 5,148 g of 1,2-dichloroethane (52 mols) and 1,485 ml of dimethylformamide is reacted for 18 hours and 20 minutes at 90° C to 100° C internal temperature (external temperature 155° C), the water of reaction produced being removed continuously by azeotropic circulatory distillation. Water of reaction split off: 110 g (94.0% of theory). Thereafter, the reaction mixture, whilst still hot, is separated by filtration from the potassium chloride produced, the filtrate is concentrated on a rotary evaporator at 100° C in a water pump vacuum and the residue is dried to constant weight at 100° C and 10-1 mm Hg.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([O:25][CH3:26])=[O:24])=[CH:13][CH:12]=2)[C:8]([CH2:27][CH2:28][CH2:29][CH3:30])=[N:7][C:6]=1[Cl:31])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([O:25][CH3:26])=[O:24])=[CH:15][CH:16]=2)[C:8]([CH2:27][CH2:28][CH2:29][CH3:30])=[N:7][C:6]=1[Cl:31]
Reactant: CCCCc1nc(Cl)c(CN=[N+]=[N-])n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Pd]
Solvent: CO
Product: CCCCc1nc(Cl)c(CN)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reaction time: 1 h
Yield: 85.5 %

Procedure:
5-Azidomethyl-2-butyl-1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-4-chloroimidazole (3.48 g) was hydrogenated at 1 atm in methanol (100 mL) over 10% palladium/carbon (0.5 g). After 1 hour, the mixture was filtered through Celite® and the solvent removed in vacuo to give product (2.80 g) as an oil. NMR (200 MHz, CDCl3) δ 7.84 (d, 1H, J=7 Hz); 7.52 (t, 1H, J=7 Hz); 7.40 (t, 1H, J=7 Hz); 7.30 (d, 1H, J=7 Hz); 7.26 (d, 2H, J=8 Hz); 7.02 (d, 2H, J=8 Hz); 5.27 (s, 2H); 3.74 (s, 2H); 3.65 (s, 3H); 2.60 (t, 2H, J=7 Hz); 1.67 (t of t, 2H, J=7,7 Hz); 1.36 (t of q, 2H, J=7,7 Hz); 0.86 (t, 3H, J=7 Hz). Anal. Calcd. for C23H26ClN3O2.(DMSO)0.5 : C, 63.91; H, 6.48; N, 9.32. Found: C, 63.78; H, 6.30; N, 9.14.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([Cl:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][CH2:25][C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])[CH:6]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:41])C=1>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16]([CH2:17][C:18]([Cl:21])([F:20])[F:19])=[O:41])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][CH2:25][C:26]([F:32])([F:31])[C:27]([F:29])([F:30])[F:28])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)Nc1cc(OCC(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)Cl)c(C)cc1F
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc(OCC(F)(F)C(F)(F)F)nn1-c1cc(S(=O)CC(F)(F)Cl)c(C)cc1F
Reaction time: 0.5 h
Yield: 97 %

Procedure:
0.6 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2-chloro-2,2-difluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole was dissolved in 20mL of chloroform, and 0.3 g of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for 30 minutes under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous potassium carbonate solution, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.6 g of the title compound.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[CH:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)=O.[OH-].[Na+].Cl>O1CCCC1.O>[CH3:13][Si:2]([CH3:12])([CH3:1])[C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH:10]=[CH:14][C:16]2[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)c1cccc([Si](C)(C)C)c1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cccc(C(=O)C=Cc2ccc(C(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
To a solution of 130 mg (0.676 mmol) of 3'-trimethylsilylacetophenone and 127 mg (0.774 mmol) of methyl 4-formylbenzoate in 4.5 ml of tetrahydrofuran (THF) were added 128 mg (3.20 mmol) of NaOH and 3 ml of hot water, and the mixture was stirred at room temperature overnight. The reaction mixture was adjusted with 7 ml of 0.5N-HCl to pH6, and then the aqueous solution was extracted with ethyl acetate. The extract was washed with 0.05N-HCl and H2O, dried and evaporated. The residue was purified by column chromatography affording 133 mg of pale yellow powder (yield 61%), which was recrystallized from a mixture of methylene chloride, methanol and n-hexane to give 98 mg of pale yellow needles, m.p. 179°-180° C. (yield 45%).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:15](=[CH2:26])[CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:27].[Na+].OO>C1COCC1>[CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]([CH2:26][OH:27])[CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=C(CCNC(=O)OC(C)(C)C)c1cccc(OCC2CCCCC2)c1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC(CO)c1cccc(OCC2CCCCC2)c1
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 3-(3-(cyclohexylmethoxy)phenyl)but-3-enylcarbamate (90) (0.32 g, 0.89 mmol) in THF (10 ml) was added BH3 (1 M in THF, 2.4 ml, 2.4 mmol) at room temperature. After stirring for 4 hr, aqueous NaOH (1 M, 6.0 ml, 6.0 mmol) was added and the mixture was stirred at 60° C. for 2.5 hrs and room temperature for 18 hr. The mixture was added H2O2 (6 ml, 30%) and stirred at 50° C. for 2 hr. The reaction mixture was extracted with ethyle acetate (2×50 ml). Ethyle acetate part was washed with brine (50 ml), dried (Na2SO4) and concentrated under reduced pressure. Purification by flash chromatography (30 to 75% EtOAc-hexanes gradient) gave tert-butyl 3-(3-(cyclohexylmethoxy)phenyl)-4-hydroxybutylcarbamate (92) as a colorless oil. Yield (0.2 g, 60%): 1H NMR (400 MHz, MeOD) δ 7.17 (t, J=8.0 Hz, 1H), 6.73-6.78 (m, 3H), 3.74 (d, J=6.4 Hz, 2H), 3.58-3.68 (m, 2H), 2.91 (t, J=7.8 Hz, 2H), 2.66-2.76 (m, 1H), 1.85-2.00 (m, 3H), 1.67-1.78 (m, 5H), 1.39 (s, 9H), 1.20-1.35 (m, 3H), 1.01-1.14 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[C:5]([CH3:15])[CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.ClC1C=C([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)C2C(=C(Cl)C(OC)=CC=2)N=1>>[Cl:1][C:2]1[CH:11]=[C:10]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:9]2[C:4](=[C:5]([CH3:15])[CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1cc(C)c2nc(Cl)cc(Cl)c2c1
Reactant: COc1ccc(COc2cc(Cl)nc3c(Cl)c(OC)ccc23)cc1
Product: COc1ccc(COc2cc(Cl)nc3c(C)cc(OC)cc23)cc1
Yield: 58 %

Procedure:
2-Chloro-6-methoxy-4-(4-methoxybenzyloxy)-8-methyl-quinoline 221f was synthesized from compound 220f as a white solid in 58% yield, following the procedure as described for compound 221d. 1H NMR (CDCl3, 400 MHz) δ (ppm) 2.68 (s, 3H), 3.80 (s, 3H), 3.83 (s, 3H), 5.11 (s, 2H), 6.72 (s, 1H), 6.97 (d, J=9.03 Hz, 2H), 7.15 (dd, J=3.01 Hz and J=0.96 Hz, 1H), 7.20 (d, J=3.00 Hz, 1H), 7.40 (d, J=9.03 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:33])[CH:9]([N:20]2[CH2:25][CH2:24][CH:23]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:22][CH2:21]2)[CH2:10][NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:34]([S-:36])#[N:35].[K+].BrBr>C(O)(=O)C>[C:12]([NH:11][CH2:10][CH:9]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:22][CH2:21]1)[CH:8]([OH:33])[C:5]1[CH:4]=[CH:3][C:2]2[N:1]=[C:34]([NH2:35])[S:36][C:7]=2[CH:6]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(C(O)C(CNC(=O)c2ccccc2)N2CCC(Cc3ccccc3)CC2)cc1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(C(O)C(CNC(=O)c3ccccc3)N3CCC(Cc4ccccc4)CC3)cc2s1
Reaction time: 2 h

Procedure:
To a stirred solution of 5.3 g of (+) threo 1-(p-amino-phenyl)-2-(4-benzylpiperidin-1-yl)-3-benzoylaminopropan-1-ol and 4.6 g of KSCN in 100 ml of glacial acetic acid was added dropwise a solution of 1.95 g of Br2 in 25 ml of glacial acetic acid at room temperature. After stirring for 2 h., the yellow sospension was filtered and the solution was poured into 100 ml of concentrated ammonium solution. The cloudy basic solution was extracted with ethyl acetate dried and evaporated. The residue was chromatographed on silica gel elutin with ethylacetate/cyclohexane ½, providing providing 3.7 g of the title compound, m.p. 160-162° C., [α]20D=+20.3±0.5.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([O:8]C)=[O:7])#[N:2].[OH-].[Na+].Cl>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(CC(C)C)c(C#N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Cc1ccc(C(=O)O)cc1C#N
Reaction time: 1 h
Yield: 93.2 %

Procedure:
Methyl 3-cyano-4-(2-methylpropyl)benzoate (D24) (233 mg, 1.072 mmol) was dissolved in ethanol (4 ml) and 2M aqueous sodium hydroxide (1 ml, 2 mmol) was added. The reaction was stirred for 1 h. 2M aqueous HCl (10 mL) was added and the mixture extracted with dichloromethane (20 mL+10 mL). The organic phases were isolated and dried by phase separator and combined before the solvent was removed in vacuo to give the title compound as a white solid (203 mg, 0.999 mmol). MS (ES): C12H13NO2 requires 203; found 202 (M−H+).
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[N+:18]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]O)([O-:20])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][CH:4]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=2)=[CH:15][CH:16]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)CC(OCC)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1cccc(CO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CC(OCC)c1ccc(OCc2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Ethyl 3-ethoxy-3-(4-hydroxyphenyl)propionate (200 mg, 0.839 mmol) produced in Example 1 (1C) and 3-nitrobenzyl alcohol (200 mg, 0.926 mmol) were dissolved in acetone (4 mL), and potassium carbonate (136 mg, 0.984 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred at room temperature for 12 hours.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][P:11](=[O:25])([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([O:23][CH3:24])[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.Cl>[Fe].O>[CH2:1]([N:8]1[CH2:9][CH2:10][P:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([O:23][CH3:24])[CH:15]=2)(=[O:25])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(P2(=O)CCN(Cc3ccccc3)CC2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(P2(=O)CCN(Cc3ccccc3)CC2)ccc1N
Temperature: 95 °C
Yield: 41.9 %

Procedure:
To a solution of 1-benzyl-4-(3-methoxy-4-nitrophenyl)-1,4-azaphosphinane 4-oxide (0.224 g, 0.622 mmol) in 0.6 mL 4:1 ethanol:water was added iron powder (0.348 g, 6.22 mmol) and 0.30 mL ethanolic HCl (2.5 M). The reaction vessel was sealed and was heated to 95° C. for 1 h. The reaction mixture was cooled to rt, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-5% 7N ammonia in methanol:dichloromethane) to afford the desired product (86.1 mg, 42% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[F:20][C:21]([F:33])([F:32])[C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:20])([F:32])[F:33])[CH:23]=2)(=[O:30])=[O:29])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Product: O=S(=O)(Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1)c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 3-(trifluoromethyl)benzene-1-sulfonyl chloride.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:6]2[C:7]([O:9][C:10](=[O:11])[CH:3]1[CH2:4][CH2:5]2)=O.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:20][CH2:19]1.C1(C)C(C)=CC=CC=1>O>[N:25]1[CH:26]=[CH:27][CH:28]=[N:29][C:24]=1[N:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[C:7](=[O:9])[CH:6]3[C:2]([CH3:1])([CH3:12])[CH:3]([CH2:4][CH2:5]3)[C:10]2=[O:11])[CH2:19][CH2:20]1
Reactant: CC1(C)C2CCC1C(=O)OC2=O
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Solvent: Cc1ccccc1C
Solvent: O
Product: CC1(C)C2CCC1C(=O)N(CCCCN1CCN(c3ncccn3)CC1)C2=O

Procedure:
2,2-Dimethylcyclopentane-1,3-dicarboxylic anhydride (1.68 g., 10 mmole) and 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine (2.55 g., 11 mmole) were combined in 500 ml. of xylene and refluxed for 48 hours with water removal via a Dean-Stark trap. The solvent was removed in vacuo and the residue column chromatographed on 100 g. of silica gel using a gradient elution from straight chloroform to 5% ethanol/chloroform. Concentration of the product in vacuum and recrystallization from isopropanol with addition of 4N isopropanolic HCl and acetone gave 600 mg. of the title compound as the dihydrochloride, monohydrate; m.p. 227°-229° C. (d).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].C(NC(C)C)(C)C.[CH:33]#[C:34][CH2:35][CH2:36][CH3:37]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[C:33]#[C:34][CH2:35][CH2:36][CH3:37])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: C#CCCC
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccccc2C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CCCC#Cc1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Yield: 24 %

Procedure:
To a solution of 2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (693 mg, 1.54 mmol) in anhydrous DMF (5 mL) and DIPA (diisopropylamine, 10 mL) is added Pd(PPh3)4 (89 mg, 7.7% mmol), CuI (29 mg, 0.154 mmol) and pent-1-yne (1.5 mL, 15.4 mmol). The resulting solution is covered in argon and run in a microwave reaction: 110° C., 35 minutes. After the removal of DMF and DIPA in vacuo, the residue is dissolved in EtOAc (100 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 0%-40% EtOAc in heptane) to give a pure product (122) as a pale yellow solid (144 mg, 24%).