Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:14]([F:16])=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.[C:33](Cl)(=[O:38])[CH2:34][CH2:35][CH2:36][CH3:37]>ClCCl>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([N:17]4[CH2:22][CH2:21][N:20]([C:33](=[O:38])[CH2:34][CH2:35][CH2:36][CH3:37])[CH2:19][CH2:18]4)[C:14]([F:16])=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(Cl)cc3)c2cc1N1CCNCC1
Reactant: CCCCC(=O)Cl
Solvent: ClCCl
Product: CCCCC(=O)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
72 mg of 1-(4-chloro-benzyl)-5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1H-benzoimidazole (0.16 mmol) and 0.033 ml TEA (0.24 mmol) were dissolved in 1.5 ml dichloromethane and treated with 0.024 ml pentanoyl chloride (0.2 mmol). After 1.5 h stirring at rt, the reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 84 mg product as a light yellow solid (98%). MS (ISP) 535.3 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:31]1[N:36]([CH2:37][CH2:38][NH2:39])[CH2:35][CH2:34][O:33][CH2:32]1>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27]([NH:39][CH2:38][CH2:37][N:36]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)=[O:26])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Reactant: NCCN1CCOCC1
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(NC(=O)NCCN4CCOCC4)c3)C(C)(C)C2=O)cc1

Procedure:
A solution of 100 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9 in 2 mL of dioxane and 37 μl of 1-(2-aminoethyl)morpholine is heated by microwave at 130° C. for 15 minutes. The reaction mixture is concentrated under reduced pressure and the residue is purified by chromatography on a column of silica, eluting with a gradient (100/0 to 75/25 by volume) of dichloromethane and methanol/aqueous ammonia (6/1 by volume) to give 77 mg of 1-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)-3-(2-morpholin-4-ylethyl)urea, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][CH:2]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[S:4](=[O:11])(=[O:10])[NH:3]1.[H-].[Na+].Cl.Cl[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[Na+].[I-]>CN(C=O)C.O>[CH3:1][CH:2]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[S:4](=[O:11])(=[O:10])[N:3]1[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: ClCCN1CCOCC1
Reactant: CC1NS(=O)(=O)c2sccc21
Agent: Cl
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CC1c2ccsc2S(=O)(=O)N1CCN1CCOCC1
Reaction time: 0.33 h
Yield: 98.8 %

Procedure:
The product from Step B (1.06 g, 5.62 mmol) was added to a suspension of NaH (0.97 g, 22.5 mmol) in DMF (19 mL) followed by chloroethylmorpholine hydrochloride (2.11 g, 11.21 mmol), and the mixture was warmed to 80° C. at which point NaI (1.1 g) was added and the mixture stirred for 20 min. The reaction mixture was diluted with water (80 mL) and extracted with methylene chloride (3×25 mL). The combined extracts were evaporated to a residue which was dissolved in ethyl acetate (80 mL) and the solution was extracted with 2N HCl (3×20 mL); this aqueous solution was adjusted to pH 7.5 with 2N NaOH and extracted with ethyl acetate (3×15 mL). The combined extracts were dried (MgSO4) and evaporated to a residue which was purified by column chromatography [silica, CH2Cl2 /CH3OH(3:1)] to give 1.68 g (98%) of the desired product as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.COC(=O)CC1CC2C(=CC(OCCCCNC(N)=N)=CC=2)NC1=O.C[O:34][C:35](=[O:63])[CH2:36][C:37]1[C:38](=[O:62])[N:39]([CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:40]2[C:45]([CH:46]=1)=[CH:44][CH:43]=[C:42]([O:47][CH2:48][CH2:49][CH2:50][NH:51][C:52]([NH2:54])=[NH:53])[CH:41]=2>>[CH2:55]([N:39]1[C:40]2[C:45](=[CH:44][CH:43]=[C:42]([O:47][CH2:48][CH2:49][CH2:50][NH:51][C:52]([NH2:54])=[NH:53])[CH:41]=2)[CH:46]=[C:37]([CH2:36][C:35]([OH:63])=[O:34])[C:38]1=[O:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: COC(=O)Cc1cc2ccc(OCCCNC(=N)N)cc2n(Cc2ccccc2)c1=O
Agent: COC(=O)CC1Cc2ccc(OCCCCNC(=N)N)cc2NC1=O
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)NCCCOc1ccc2cc(CC(=O)O)c(=O)n(Cc3ccccc3)c2c1

Procedure:
The title compound was prepared according to the procedure of Example 84 except that [7-(4-guanidino-butoxy)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]acetic acid methyl ester trifluoroacetate was replaced with (1-benzyl-7-(3-guanidino-propoxy)-2-oxo-1,2-dihydro-quinolin-3-yl]acetic acid methyl ester.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([O:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:18][C:19]([F:20])([F:21])[F:22])[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:16])([F:15])[F:17])[CH:7]=2)=[CH:26][CH:25]=1
Reactant: N#Cc1ccc(N(CCCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: Oc1ccc(F)cc1
Product: N#Cc1ccc(N(CCCOc2ccc(F)cc2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1C from 4-[(3-hydroxypropyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-fluorophenol: MS (ES) m/z 421 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C@H:4]([CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1)[NH2:5].[OH:20][N:21]=[C:22]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:23](O)=[O:24].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1>[CH3:1][O:2][C:3](=[O:19])[C@H:4]([CH2:6][C:7]1[CH:8]=[C:9]([O:17][CH3:18])[C:10]([O:15][CH3:16])=[C:11]([O:13][CH3:14])[CH:12]=1)[NH:5][C:23](=[O:24])[C:22](=[N:21][OH:20])[CH2:26][CH:27]([CH3:29])[CH3:28]
Reactant: COC(=O)[C@@H](N)Cc1cc(OC)c(OC)c(OC)c1
Reactant: CC(C)CC(=NO)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cc1cc(OC)c(OC)c(OC)c1)NC(=O)C(CC(C)C)=NO
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.1 %

Procedure:
To a solution of 34.47 g of 3,4,5-trimethoxyphenylalanine methyl ester, 18.87 g of α-hydroxyiminoisocaproic acid, 14.96 g of N-hydroxysuccinimide in 1 liter of dioxane, was added 26.82 g of N,N'-dicyclohexylcarbodiimide, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was filtrated, and the filtrate was subjected to distillation to remove the solvent. The resulting residue was purified by means of a silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:2) to obtain 42.70 g of N-(2-hydroxyimino-4-methylpentanoyl)-(3,4,5-trimethoxy)phenylalanine methyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH:14](=O)[CH3:15].[BH3-]C#N.[Na+]>>[CH2:14]([N:8]1[C:7]2[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[O:11][CH2:10][CH2:9]1)[CH3:15]
Reactant: CC=O
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCN2
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN1CCOc2cc([N+](=O)[O-])ccc21
Yield: 74 %

Procedure:
This compound was prepared by General Method 3 (EXAMPLE 1) from 3,4-dihydro-7-nitro-2H-1,4-benzoxazine (EXAMPLE 1) (1.15 g, 6.39 mmol), acetaldehyde (3.59 mL, 64.2 mmol) and NaBH3CN (1.95 g, 31 mmol) to afford 984 mg (74%) of 4-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine, a yellow solid. Data for 4-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine: Rf 0.85 (11.5:1 CH2Cl2:MeOH); 1H NMR (400 MHz, CDCl3) δ 7.81 (dd, 1H, J=9.6, 2.6), 7.66 (d, 1H, J=2.7), 6.29 (d, 1H, J=9.2), 4.23 (t, 2H, J=4.7), 3.47 (t, 2H, J=4.7), 3.45 (q, 2H, J=7.2), 1.22 (t, 3H, J=7.0).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[CH2:8][CH2:7]1.[CH3:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C(N(CC)CC)C.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([CH3:23])=[CH:25][CH:26]=2)[CH2:10][CH2:11]1
Reactant: Nc1ccccc1N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2ccccc2N2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)cc1

Procedure:
2-[4-(3,4-dichlorobenzyl)-piperazin-1-yl]-phenylamine (45 mg) was dissolved in a solution of triethylamine in dichloromethane (3 mL, 0.29 M in triethylamine). This solution was added to a test tube containing 4-methylbenzoyl chloride (55 mg). After standing at ambient temperature for several days, the reaction was directly passed through a small pad of silica and eluted with 10% ethyl acetate in hexanes, then with 50% ethyl acetate in hexanes. Solvent removal left 10.7 mg of the product: MS m/z 453 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:5]1[CH:10]=[CH:9][C:8](Cl)=[CH:7][CH:6]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:58]([Si:62]([CH3:100])([CH3:99])[O:63][CH:64]([C:95]([CH3:98])([CH3:97])[CH3:96])[CH2:65][CH2:66][C:67]1[CH:72]=[CH:71][C:70]([C:73]([C:78]2[CH:83]=[CH:82][C:81](B3OC(C)(C)C(C)(C)O3)=[C:80]([CH3:93])[CH:79]=2)([CH2:76][CH3:77])[CH2:74][CH3:75])=[CH:69][C:68]=1[CH3:94])([CH3:61])([CH3:60])[CH3:59]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:20])[C@H:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([C:81]2[CH:82]=[CH:83][C:78]([C:73]([C:70]3[CH:71]=[CH:72][C:67]([CH2:66][CH2:65][CH:64]([O:63][Si:62]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:99])[CH3:100])[C:95]([CH3:98])([CH3:97])[CH3:96])=[C:68]([CH3:94])[CH:69]=3)([CH2:74][CH3:75])[CH2:76][CH3:77])=[CH:79][C:80]=2[CH3:93])=[CH:7][CH:6]=1
Reactant: COC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)OC)cc2)c(C)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 70.6 %

Procedure:
(R)-t-Butoxycarbonylamino-(4-chloro-phenyl)-acetic acid methyl ester (Example 167-(1); 37 mg, 0.124 mmol), palladium acetate (1.8 mg, 0.008 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (6.6 mg, 0.016 mmol), potassium phosphate (52 mg, 0.246 mmol) and water (0.2 mL) were added to a solution of 2-[4-(1-{4-[3-(t-butyldimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Example 23-(1); 50 mg, 0.082 mmol) in toluene (3 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for three hours. Then, the reaction mixture was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the target compound as a colorless oil (43.1 mg, 71%).
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:24])[N:12]([CH2:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=3)[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCO.O=[Pt]=O>[C:25]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]2[CH2:13][N:12]([CH2:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=3)[C:11](=[O:24])[CH2:10][CH2:9]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=c1ccc(C(c2ccccc2)c2ccccc2)cn1CCCc1cccc(O)c1
Agent: O=[Pt]=O
Solvent: CCO
Product: O=C1CCC(C(c2ccccc2)c2ccccc2)CN1CCCc1cccc(O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.4 %

Procedure:
5-(Diphenylmethyl)-1-[3-(3-hydroxyphenyl)propyl]pyridin-2(1H)-one (1 g) in EtOH (20 mL) was added dioxoplatinum (70 mg) at ambient temperature and the mixture was stirred at ambient temperature for 1 day under hydrogen atmosphere. The mixture was filtered through a bed of celite. The filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=1:3) to afford 5-(diphenylmethyl)-1-[3-(3-hydroxyphenyl)propyl]piperidin-2-one (550 mg) as a yellow oil.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].Br[CH2:19][CH:20]1[CH2:22][CH2:21]1>CN(C=O)C.CCOC(C)=O>[CH:20]1([CH2:19][O:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COCC2CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.2 %

Procedure:
A solution of N-boc-4-piperidinemethanol (0.500 g, 2.322 mmol) in DMF (10 mL) was added drop wise to a suspension of sodium hydride (60% in mineral oil) (0.186 g, 4.645 mmol) in dry DMF (15 mL) at 0 C. The mixture was stirred at 0 C for 15 minutes and room temperature for 10 minutes before being cooled down again and (bromomethyl)cyclopropane (0.227 mL, 2.322 mmol) was added drop wise. The reaction mixture was stirred at 0 C for 10 minutes, room temperature for 1 h and 80 C for 4 h. The reaction mixture was diluted with EtOAc (60 mL) and washed with water (3×20 mL). The aqueous washes were combined and re-extracted with EtOAc (3×20 mL). The organic extracts were combined, dried over sodium sulfate, filtered and evaporated to provide the title compound as a colorless oil (0.614 g, 98%). Method B HPLC-MS: MH+ requires m/z=270 Found: m/z=214 (MH+-tBu), Rt=2.33 min (83%).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:6])([CH3:5])[CH3:4].[C:19]([N:23]1[CH2:27][CH2:26][O:25][P:24]1Cl)([CH3:22])([CH3:21])[CH3:20]>O1CCCC1>[C:19]([N:23]1[CH2:27][CH2:26][O:25][P:24]1[O:18][C:8]1[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])=[CH:12][C:11]([CH3:13])=[CH:10][C:9]=1[C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(C)(C)N1CCOP1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C(C)(C)C)c(OP2OCCN2C(C)(C)C)c(C(C)(C)C)c1
Temperature: 40 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
A 500 ml, three neck flask equipped with a thermometer, an addition funnel and a condenser topped with a nitrogen sweep is charged with 4.4 g (0.11 mol) of sodium hydride. The sodium hydride is washed with two 20 ml portions of hexane and finally suspended in 45 ml of tetrahydrofuran (THF). To the resultant suspension is added dropwise a solution of 22.04 g (0.10 mol) of 2,6-di-tert-butyl-4-methylphenol in 150 ml of THF at such a rate to keep the reaction temperature between 20°-30° C. The resulting yellow solution is warmed to approximately 40° C. for 1 hour and then cooled in an ice bath. A solution of 18.16 g (0.10 mol) of 3-tert-butyl-2-chloro-1,3,2-oxazaphospholidine in 150 ml of THF is added and stirring continued for 16 hours at room temperature. The resulting cloudy mixture is filtered and the solvent evaporated under reduced pressure. The residue is treated with 200 ml of toluene and the resultat suspension filtered. The filtrate is concentrated in vacuo to yield a thick syrup. Triturating with methanol gives 24.5 g (67.0%) of colorless solid: mp 105°-107° C.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:16][N:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]=2[CH2:19][CH2:20][CH2:21][CH3:22])=[C:10]([C:34]([N:36]2[C@H:45]([CH2:46][O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:37]2)=[O:35])[CH:9]=1)=[O:7])(C)(C)C.N1C(C)=CC=CC=1C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C1COCC1>[CH2:19]([C:18]1[N:17]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:16]=[C:15]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:14]=1[C:11]1[CH:12]=[CH:13][C:8]([C:6]([OH:7])=[O:5])=[CH:9][C:10]=1[C:34]([N:36]1[C@H:45]([CH2:46][O:47][Si:48]([C:51]([CH3:53])([CH3:52])[CH3:54])([CH3:49])[CH3:50])[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37]1)=[O:35])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2Cc3ccccc3C[C@H]2CO[Si](C)(C)C(C)(C)C)c(C(=O)OCC)nn1-c1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: CCCCc1c(-c2ccc(C(=O)O)cc2C(=O)N2Cc3ccccc3C[C@H]2CO[Si](C)(C)C(C)(C)C)c(C(=O)OCC)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.1 %

Procedure:
To a solution of ethyl 4-(4-(tert-butoxycarbonyl)-2-((S)-3-((tert-butyldimethylsilyloxy)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5-butyl-1-phenyl-1H-pyrazole-3-carboxylate (335 mg, 0.445 mmol) in THF (5.0 mL) was added 2,6-lutidine (0.10 mL, 0.89 mmol) followed by TMS-OTf (0.121 mL, 0.668 mmol). After stirring at room temperature for 1 h, the reaction mixture was heated at 50° C. for 1 h. Additional equivalents of both 2,6-lutidine and TMS-OTf were added hourly until consumption of the starting material (6 additions). After cooling to room temperature, the reaction mixture was quenched with sat. aq. sodium bicarbonate solution. The mixture was extracted with EtOAc concentrated in vacuo. The residue was purified by flash chromatography (Isco 40 g column eluting with 0-80% EtOAc/hexanes) to give the title compound (115 mg, 37%). MS(ESI+) m/z 696.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][NH:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25]I>>[CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][N:14]([C:15]2[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=2)[CH3:25])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: N#Cc1ccc(NCc2ccc(OCc3ccccc3)cc2)cc1
Product: CN(Cc1ccc(OCc2ccccc2)cc1)c1ccc(C#N)cc1
Yield: 52.7 %

Procedure:
The procedure of Preparation Example 38 was repeated, except that 314 mg of 4-[N-(4-benzyloxybenzyl)amino]benzonitrile was used in place of 4-[N-(3-pyridyl)amino]benzonitrile, and 142 mg of methyl iodide was used in place of 4-benzyloxybenzyl chloride. The resulting crude product was purified by TLC (using a 2:1 mixture of hexane and ethyl acetate as the developing solvent) to obtain 173 mg of 4-[N-(4-benzyloxybenzyl)-N-methylamino]benzonitrile.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([CH:19]=[C:20]([O:22]CC2C=CC=CC=2)[CH:21]=1)[C:10]([NH:12][C:13]1[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=1)=[O:11])[CH3:5]>C1COCC1.CO.[Pd]>[OH:22][C:20]1[CH:19]=[C:9]([CH:8]=[C:7]([O:6][C@@H:4]([CH3:5])[CH2:3][O:2][CH3:1])[CH:21]=1)[C:10]([NH:12][C:13]1[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=1)=[O:11]
Reactant: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C)n2)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reaction time: 70 h
Yield: 94.7 %

Procedure:
To a solution of 3-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide (7.07 g) in THF (50 mL) and methanol (50 mL) was added 10% palladium on carbon (727 mg) as a slurry in THF (1 mL) and methanol (1 mL). The mixture was placed under vacuum and stirred under an atmosphere of hydrogen for 70 hours. The mixture was filtered through diatomaceous earth, and the diatomaceous earth washed with methanol (2×100 mL), followed by evaporation in vacuo. The residues were dissolved in ethyl acetate (10 mL), treated with isohexane (40 mL), the solid filtered off and washed with isohexane (50 mL) to afford the desired compound (5.17 g) which was used without further purification.
Reaction SMILES: S(Cl)([Cl:3])=O.[N+:5]([C:8]1[CH:28]=[CH:27][C:11]([CH2:12][O:13][C:14](=[O:26])[CH:15]([N:17]2[C@H:20]([S:21][C:22](=[O:24])[CH3:23])[CH2:19][C:18]2=[O:25])O)=[CH:10][CH:9]=1)([O-:7])=[O:6]>O1CCOCC1>[N+:5]([C:8]1[CH:28]=[CH:27][C:11]([CH2:12][O:13][C:14](=[O:26])[CH:15]([N:17]2[C@H:20]([S:21][C:22](=[O:24])[CH3:23])[CH2:19][C:18]2=[O:25])[Cl:3])=[CH:10][CH:9]=1)([O-:7])=[O:6]
Reactant: CC(=O)S[C@@H]1CC(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Product: CC(=O)S[C@@H]1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 2.86 g (~24 mmol) of thionyl chloride in 20 ml of dioxan is added dropwise to a suspension, stirred at room temperature, of 12 g of poly-Hunig base in a solution of 2.83 g (7.59 mmol) of 2-[(4R)-4-acetylthio-2-oxoazetidin-1-yl]-2-hydroxyacetic acid p-nitrobenzyl ester in 100 ml of dioxan. The mixture is stirred for 1.5 hours at room temperature and filtered off from the poly-Hunig base, which is subsequently washed with dioxan. The filtrate is concentrated in vacuo. The 2-[(4R)-4-acetylthio-2-oxoazetidin-1-yl]-2-chloroacetic acid p-nitrobenzyl ester obtained is used in the next stage in crude form.
Reaction SMILES: [N:1]1([CH:6]([CH2:16][CH2:17][CH2:18][CH3:19])[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[O:8])[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[N:1]1([CH:6]([CH2:16][CH2:17][CH2:18][CH3:19])[CH:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[OH:8])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CCCCC(C(=O)c1ccc(Cl)cc1)n1cncn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCCC(C(O)c1ccc(Cl)cc1)n1cncn1

Procedure:
The product (0.01 mol) of Stage 2 was added portionwise to a suspension of lithium aluminium hydride (0.005 mol) in diethyl ether (10 ml; dried over sodium) to maintain refluxing. The ethereal solution was refluxed for a further four hours; the excess lithium aluminium hydride was quenched with water (20.0 ml) and the mixture acidified with concentrated sulphuric acid. The ethereal layer was washed with water (4×25 ml) and dried over anhydrous sodium sulphate. Removal of the ether gave an oil which solidified on standing. Recrystallisation from methylene chloride/petroleum ether gave the title compound as a white solid, m.p. 93°-94°.