Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.[F-].[K+].[Br:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]=[C:37]=[O:38].O>C1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([C:37]([NH:36][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[Br:29])=[O:38])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([C:22]#[N:23])([CH3:24])[CH3:25])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C=Nc1ccccc1Br
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Agent: [F-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(C(=O)Nc3ccccc3Br)c3cnc4ccc(Br)cc4c32)cc1

Procedure:
To a suspension of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 0.050 g, 0.12 mmol) and potassium fluoride (0.010 g, 0.18 mmol) in dry benzene (6 ml) was added 1-bromo-2-isocyanatobenzene (0.036 g, 0.12 mmol) at RT. The reaction was stirred at reflux temperature for 6 hours. The reaction mixture was cooled and poured into cold water, extracted with ethyl acetate (2×20 ml). Organic layer was washed with water dried over sodium sulfate and concentrated. The crude product was crystallized in ethyl acetate\pet ether to obtain the title compound. Yield: 0.017 g (22%); 1H NMR (DMSO-d6, 300 MHz): δ 11.82 (s, 1H), 8.78 (s, 1H), 7.90 (d, 1H, J=9 Hz), 7.81 (d, 2H, J=8.1 Hz), 7.61-7.65 (m, 3H), 7.28 (d, 1H, J=8.1 Hz), 6.95-7.05 (m, 2H), 6.74 (d, 1H, 7.8 Hz), 6.41 (t, 1H, 7.2 Hz), 1.79 (s, 6H); MS: m/z 606 (M+).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.S(=O)(=O)(O)O.[OH:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1>C(O)(=O)C>[OH:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[I:1]
Reactant: O=C1CCC(=O)N1I
Reactant: N#Cc1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: N#Cc1ccc(O)c(I)c1

Procedure:
4-Hydroxy-3-iodobenzonitrile was prepared by the method analogous to Preparation 341 above using N-iodosuccinimide, acetic acid, sulfuric acid and 4-Hydroxybenzonitrile. Purified by ISCO™ (80 g SiO2) eluting with ethyl acetate:heptane (gradient 0:1 to 3:7, by volume) to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)=[CH:5][CH:4]=1.[C:20]([NH:23][NH2:24])(=O)[CH3:21].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:12]3[O:14][C:20]([CH3:21])=[N:23][N:24]=3)[CH:15]=[CH:16][CH:17]=2)=[CH:18][CH:19]=1
Reactant: CC(=O)NN
Reactant: COc1ccc(COc2cccc(C(=O)O)c2)cc1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(COc2cccc(-c3nnc(C)o3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[(4-Methoxybenzyl)oxy]benzoic acid (9.26 g, 35.9 mmol), acethydrazide (3.98 g, 53.8 mmol), HOBT (6.59 g, 43 mmol) and EDC (10.3 g, 53.8 mmol) were weighed into a 200 mL RB flask. DMF (60 mL) was added. The mixture was stirred vigorously at room temperature. The solid dissolved within 5 min. LC-MS showed complete consumption of the acid after 30 min. DMF was removed at 60° C. under vacuum. The residue was treated with 100 mL EtOAc/water (1/1) and was allowed to stand overnight. The solid was collected via filtration and washed with EtOAc. The crude N′-acetyl-3-[(4-methoxybenzyl)oxy]benzohydrazide (8 g) was suspended in 100 mL THF and was heated under reflux in the presence of Burgess' reagent (12.8 g, 53.8 mmol) for 1 hour. The solution was cooled and directly passed through a plug of silica gel (300 gram) which was washed thoroughly with 20% acetone/hexanes. The eluent was concentrated to give the crude product as white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.Cl.[C:19]1([C:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)C(C)C)C>C(O)C>[OH:17][CH2:16][CH2:15][NH:14][C:4]1[N:5]=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[C:7]([C:8]#[N:9])=[C:2]([N:28]2[CH2:27][CH:26]=[C:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:30][CH2:29]2)[N:3]=1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Reactant: C1=C(c2ccccc2)CCNC1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCCO)nc(NCCO)nc1N1CC=C(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 4-phenyl-1,2,3,6-tetrahydro-pyridine hydrochloride in ethanol in the presence of N-ethyl-diisopropylamine at 80° C. to yield 2,4-bis-(2-hydroxy-ethylamino)-6-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-pyrimidine-5-carbonitrile as an amorphous, brown solid; MS: [M+H]+=381.
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.C(#N)C.[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([NH2:28])=[S:27].O>C(OCC)(=O)C>[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]1[S:27][C:2]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=2)[N:28]=1
Reactant: NC(=S)c1ccccc1Cl
Reactant: CSc1ccc(C(Br)C(=O)c2ccc(C)cc2)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CSc1ccc(-c2sc(-c3ccccc3Cl)nc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
A 100 mL one-neck round-bottom flask equipped for magnetic stirring was charged with 2-bromo-2-(4-methylthiophenyl)-1(4-methylphenyl)ethanone from Step 3 (0.300 g, 0.895 mmol) and acetonitrile (20 mL). 2-Chlorothiobenzamide (0.154 g, 0.895 mmol) was added, and the suspension was heated and held at reflux for three hours. The reaction was cooled to room temperature, diluted with ethyl acetate (50 mL) and poured into water(50 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic solution was dried over MgSO4, filtered and evaporated in vacuo. The residue was purified via flash chromatography (silica gel; 5% ethyl acetate in hexane) to yield 2-(2-chlorophenyl)-4-(4-methylphenyl)-5-(4-methylthiophenyl)thiazole (0.284 g, 78%) as a white solid: mp 125°-126° C. 1H NMR (CDCl3) 300 MHz 8.40(m, 1H), 7.62-7.11(m, 11H), 2.50 (s, 3H), 3.36(s, 3H). Mass spectrum: MH+ =407.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([CH2:21][CH3:22])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:23])[C:4]=1[OH:24])[CH3:2].[CH2:25]([C@@H:27]1[O:29][CH2:28]1)Cl>[OH-].[Na+].C(O)(C)C.CC(=O)OCC>[CH2:21]([C:16]1[CH:15]=[C:14]([C:12]2[O:11][N:10]=[C:9]([C:7]3[CH:6]=[C:5]([CH3:23])[C:4]([O:24][CH2:25][C@@H:27]4[CH2:28][O:29]4)=[C:3]([CH2:1][CH3:2])[CH:8]=3)[N:13]=2)[CH:19]=[C:18]([CH3:20])[N:17]=1)[CH3:22]
Reactant: CCc1cc(-c2nc(-c3cc(C)c(O)c(CC)c3)no2)cc(C)n1
Reactant: ClC[C@H]1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCc1cc(-c2nc(-c3cc(C)c(OC[C@@H]4CO4)c(CC)c3)no2)cc(C)n1
Reaction time: 24 h

Procedure:
To a solution of 2-ethyl-4-[5-(2-ethyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenol (89 mg, 0.276 mmol) in 3 N aq. NaOH (1 mL) and isopropanol (4 mL), (R)-epichlorohydrine (142 mg, 1.53 mmol) is added. The mixture is stirred at rt for 24 h before another portion of (R)-epichlorohydrine (142 mg; 1.53 mmol) is added. Stirring is continued for another 24 h at rt. The mixture is diluted with EA (50 mL) and washed with 1M aq. NaOH (10 mL) and brine (10 mL). The org. phase is dried over MgSO4, filtered and evaporated to give crude (S)-2-ethyl-4-[3-(3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-pyridine; LC-MS*: tR=1.11* min; [M+1]+=380.24.
Reaction SMILES: O.[NH2:2][NH2:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:15][C:16]1[CH:33]=[CH:32][C:31]2[C@@H:30]3[C@H:21]([C@H:22]4[C@@:26]([CH2:28][C@@H:29]3[C:34]3[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][S:46]([CH2:49][CH2:50][CH2:51][C:52]([F:58])([F:57])[C:53]([F:56])([F:55])[F:54])(=[O:48])=[O:47])=[CH:36][CH:35]=3)([CH3:27])[C:25](=O)[CH2:24][CH2:23]4)[CH2:20][CH2:19][C:18]=2[CH:17]=1.C(=O)(O)[O-].[Na+]>CO>[OH:15][C:16]1[CH:33]=[CH:32][C:31]2[C@@H:30]3[C@H:21]([C@H:22]4[C@@:26]([CH2:28][C@@H:29]3[C:34]3[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][S:46]([CH2:49][CH2:50][CH2:51][C:52]([F:58])([F:57])[C:53]([F:56])([F:55])[F:54])(=[O:48])=[O:47])=[CH:36][CH:35]=3)([CH3:27])[C:25](=[N:2][NH2:3])[CH2:24][CH2:23]4)[CH2:20][CH2:19][C:18]=2[CH:17]=1
Reactant: NN
Reactant: C[C@]12C[C@H](c3ccc(OCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@]12C[C@H](c3ccc(OCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=NN
Reaction time: 16 h

Procedure:
100 μl of hydrazine hydrate and 3 mg of paratoluenesulphonic acid are added to 300 mg of the product obtained in Example 73 in 3 cm3 of methanol. Agitation is carried out for 16 hours at ambient temperature, 50 cm3 of an aqueous solution of sodium bicarbonate is added, extraction is carried out with methylene chloride, the solvent is evaporated off, the residue is chromatographed on silica (eluant: ethyl acetate) and 190 mg of expected product is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:31]([CH3:39])([CH3:38])[O:32][SiH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[C:4]([C:8]2[CH:9]=[C:10]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)[C:11](=[O:15])[N:12](C)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[Br:40][C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[C:43]([CH2:51][CH2:52]Br)[CH:42]=1.CCN(C(C)C)C(C)C>ClC(Cl)C>[Br:40][C:41]1[CH:46]=[CH:45][C:44]2[S:47](=[O:49])(=[O:48])[N:1]([C:2]3[C:3]([C:31]([CH3:39])([CH3:38])[O:32][SiH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[C:4]([C:8]4[CH:9]=[C:10]([NH:16][C:17]5[CH:22]=[CH:21][C:20]([C:23]([N:25]6[CH2:26][CH2:27][O:28][CH2:29][CH2:30]6)=[O:24])=[CH:19][N:18]=5)[C:11](=[O:15])[NH:12][CH:13]=4)[CH:5]=[CH:6][CH:7]=3)[CH2:52][CH2:51][C:43]=2[CH:42]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1CCBr
Reactant: Cn1cc(-c2cccc(N)c2C(C)(C)O[SiH2]C(C)(C)C)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: CC(C)(C)[SiH2]OC(C)(C)c1c(-c2c[nH]c(=O)c(Nc3ccc(C(=O)N4CCOCC4)cn3)c2)cccc1N1CCc2cc(Br)ccc2S1(=O)=O
Yield: 53.4 %

Procedure:
The mixture of 5-[3-Amino-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-1-methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-1H-pyridin-2-one (0.2 g, 0.36 mmol), 4-bromo-2-(2-bromo-ethyl)-benzenesulfonyl chloride (0.4 g, 1.08 mmol) and DIPEA (1 mL) in dichloroethane (10 mL) was microwaved at 120° C. for 30 min, then added 4-bromo-2-(2-bromo-ethyl)-benzenesulfonyl chloride (0.4 g, 1.08 mmol) and DIPEA (1 mL) and microwaved at 120° C. for 30 min. After repeating this process three times, the mixture was concentrated to afford a dark residue. Purification by silica gel chromatography (methylene chloride/acetone) afforded 0.15 g of 5-[3-(6-Bromo-1,1-dioxo-3,4-dihydro-1H-1lambda*6*-benzo[e][1,2]thiazin-2-yl)-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-1H-pyridin-2-one as a pale solid MS (ESI) 796.2 (M+H)+.
Reaction SMILES: C[C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7]Br)=[CH:4][CH:3]=1.O.O.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([O-:23])=[CH:19][CH:18]=1)([O-:16])=[O:15].[Na+].[OH-].[K+].[CH3:27]O>>[CH3:27][C:17]1([N+:14]([O-:16])=[O:15])[CH:22]=[CH:21][C:20]([O:23][CH2:7][C:6]([C:5]2[CH:4]=[CH:3][CH:2]=[CH:11][CH:10]=2)=[O:9])=[CH:19][CH2:18]1
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: O=[N+]([O-])c1ccc([O-])cc1
Reactant: CO
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1([N+](=O)[O-])C=CC(OCC(=O)c2ccccc2)=CC1
Yield: 62.3 %

Procedure:
4-Methylphenacyl bromide (XVI: X=Br) (63 g, 0.296 mole), 4-nitrophenol (XI) (42.4 g, 0.305 mole) and potassium hydroxide (22.5 g, 0.4 mole) were added to methanol (300 ml), and the mixture was heated under reflux for 4 hours. Thereafter, the reaction mixture was treated in the same manner as in Example 29 to obtain 50.0 g of 4-methyl-α-(4-nitrophenoxy)acetophenone (XII) (yield, 62.3%).
Reaction SMILES: [Si]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][CH:25]([CH2:43][CH3:44])[C:24]1=[O:45])[CH2:21][CH3:22])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:46]([N-]C(C)C)([CH3:48])[CH3:47].[Li+].C(Br)C=C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C1(C)C=CC=CC=1>[CH2:48]([C:25]1([CH2:43][CH3:44])[CH2:26][C@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[C@@H:28]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[N:23]([C@@H:20]([CH2:21][CH3:22])[CH2:19][OH:18])[C:24]1=[O:45])[CH:46]=[CH2:47]
Reactant: CC(C)[N-]C(C)C
Reactant: CCC1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: C=CCBr
Product: C=CCC1(CC)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
(5R,6S)-1-((S)-1-(Tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethylpiperidin-2-one (421 mg, 0.639 mmol; Example 202, Step A) was azeotroped with toluene (3×). THF (1.6 mL) was added. The mixture was sparged with argon for 5 minutes and then cooled to 0° C. 1.0 M lithium diisopropylamide solution in THF (1.246 mL, 1.246 mmol) was added dropwise. After 25 minutes, allyl bromide (0.166 mL, 1.917 mmol) was added dropwise. After 20 minutes, the mixture was quenched with sat. aq. NH4Cl solution. The mixture was extracted with ethyl acetate. The organic layer was washed with sat. aq. NaCl solution, dried over Na2SO4, and concentrated. The residue was dissolved in THF (3 mL) and 1.0M tetrabutylammonium fluoride solution in THF (2.335 mL, 2.335 mmol) was added. After stirring overnight, the mixture was partitioned between 5% aq. HCl and ethyl acetate. The organic layer was washed with sat. aq. NaCl solution, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel (eluent: 20 to 50% ethyl acetate/hexanes) to afford the title compound as the more polar major diastereomer.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[CH:4]([OH:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=1.[CH:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(OCC)(=O)C>[CH2:26]([NH:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[CH:4]([OH:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH:6]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2N)c1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 104.1 %

Procedure:
To a solution of 2-amino-5-chloro-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (0.7 g) in methanol (7 ml) were added benzaldehyde (229 mg) and acetic acid (130 mg). The mixture was stirred for 10 minutes at room temperature, to which was added sodium cyano-borohydride (135 mg). The mixture was stirred for 30 minutes at room temperature, to which was added ethyl acetate ester (50 ml). The mixture was washed with water and dried over anhydrous MgSO4, followed by distilling off the solvent. The residue was purified by means of a silica gel column chromatography to give the object 2-benzylamino-5-chloro-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (0.91 g) as a colorless oily compound.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:18](O)=[O:19].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:18]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)=[O:19]
Reactant: Cc1ccc(C(=O)O)cc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of tert-butyl piperazine-1-carboxylate (1.81 g, 9.7 mmol), 3-fluoro-4-methylbenzoic acid (1.50 g, 9.7 mmol), and triethylamine (6.8 mL, 49 mmol) in acetnitrile (30 mL), HBTU (4.06 g, 10.7 mmol) was added. After stirring at rt for 1 h, the mixture was poured onto water (150 mL), and the mixture was extracted with EtOAc (twice). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/EtOAc (4:1-2:1) to give 3.14 g (quant) of the title compound as a white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:14]=[CH:15][N:16](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(#N)C.[Br:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][C:48]=1[CH2:49]Br)[C:44]#[N:45]>C(OCC)(=O)C>[Br:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][C:48]=1[CH2:49][N:16]1[CH:17]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[N:14]=[CH:15]1)[C:44]#[N:45]
Reactant: CC(C)(C)[Si](C)(C)OCCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: N#Cc1ccc(CBr)c(Br)c1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCCCCc1cn(Cc2ccc(C#N)cc2Br)cn1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
To 4-[4-(tert-butyldimethylsilanyloxy)butyl]-1-trityl-1H-imidazole (3.95 g, 7.95 mmol) is added acetonitrile (300 mL). To this solution is added 3-bromo-4-bromomethylbenzonitrile (2.14 g, 7.78 mmol). The solution is stirred at 40° C. for 18 h. The solvent is then removed in vacuo and methanol (300 ml) is added. The solution is heated to 55° C. and stirred for 1.5 h. Saturated sodium bicarbonate is then added and stirred for 10 min. The organic solvent is removed in vacuo, and the crude product extracted into ethyl acetate and washed with water. The organic solvent is removed in vacuo to give the crude product. Chromatography (silica gel, 1:0 to 1:1 to 0:1 hexanes:ethyl acetate) gives the pure product. MS (ESI) m/z 448, 450 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:28][C:29]([N:37]1[N:41]=[N:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([CH2:48][N:49]([NH:62][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:50][C@H:51]([OH:61])[C@@H:52]([NH2:60])[CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:44][CH:43]=2)=[N:38]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30]>CN(C=O)C>[CH3:30][C:29]([N:37]1[N:41]=[N:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([CH2:48][N:49]([NH:62][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:50][C@H:51]([OH:61])[C@@H:52]([NH:60][C:11](=[O:13])[C@H:6]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:44][CH:43]=2)=[N:38]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:28]
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)NC(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
With the exclusion of air, 270 mg (1.43 mmol) of N-methoxycarbonyl-(L)-iso-leucine, 513 mg (2.67 mmol) of EDC and 241 mg (1.78 mmol) of HOBT are dissolved in 7.8 ml of DMF. After stirring for 15 min, 0.75 ml (5.4 mmol) of TEA and 510 mg (0.89 mmol) of 1-{4-[2-(1-methyl -1-phenyl-ethyl)-2H-tetrazol-5-yl]-phenyl}-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-amino-6-phenyl-2-azahexane (Example 25f) in 3.7 ml of DMF are added. After 20 hours, the mixture is worked up analogously to Example 25g to yield the title compound: HPLC20-100 : tRet =18.5; FAB MS (M+H)+ =743.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[CH:12]=[CH2:13].CN(C1CCCCC1)C1CCCCC1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>O1CCOCC1>[CH3:10][C:4]1[CH:3]=[C:2]([CH:13]=[CH:12][C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Cc1cc(Br)ccc1C#N
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: Cc1cc(C=CC(=O)OC(C)(C)C)ccc1C#N
Temperature: 70 °C
Yield: 80.6 %

Procedure:
A solution of 10.0 g (51.0 mmol) of 4-bromo-2-methylbenzonitrile in 80 mL of 1,4-dioxane was treated with 7.19 g (56.1 mmol) of tert-butyl acrylate, 10.96 g (56.1 mol) of N-methyldicyclohexylamine, 228 mg (0.76 mol) of 2-(di-tert-butylphosphino) biphenyl, and 396 mg (0.38 mol) of tris(dibenzylideneacetone)dipalladium(0)-chloroforin adduct. The resulting mixture was heated at 70° C. for 16 h and cooled to rt. The reaction mixture was filtered though a filter paper, and the filtrate was concentrated. The crude product was partitioned into four portions. Chromatography on four Biotage 40M cartridges using 19:1 v/v hexanes/EtOAc as the eluant followed by pooling of product fractions afforded 10.0 g of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.55 (s, 9H), 2.58 (s, 3H), 6.44 (d, J=16.0, 1H), 7.41 (d, J=8.0, 1H), 7.45 (s, 1H), 7.53 (d, J=16.0, 1H), 7.61 (d, J=8.0, 1H).
Reaction SMILES: C(OC([N:11]1[CH:16]=[CH:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:13](=[O:25])[CH2:12]1)=O)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:14]2[CH2:15][CH2:16][NH:11][CH2:12][C:13]2=[O:25])=[CH:19][CH:20]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)C=CN1Cc1ccc(F)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C1CNCCN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-benzyloxycarbonyl-1-(4-fluorobenzyl)-3,4-dihydro-pyrazin-2(1H)-one (0.5 g, 1.45 mmol) and Pearlman's catalyst (26 mg; 20% palladium hydroxide on carbon) in methanol (25 mL) was stirred under an atmosphere of hydrogen (1 atm) at room temperature overnight. The product mixture was filtered through a pad of Celite, and concentrated under vacuum to provide 1-(4-fluorobenzyl)piperazin-2-one. 1H NMR (400 MHz, d6 DMSO) δ 7.29 (dd, J=8.4, 5.7 Hz, 2H), 7.16 (t, J=9.0 Hz, 2H), 4.48 (s, 2H), 3.28 (s, 2H), 3.14 (t, J=5.3 Hz, 2H) 2.84 (t, J=5.3 Hz, 2H); ES MS (M+1)=209.