Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:33]C(=O)OC(C)(C)C)([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:22][CH:23]4[CH2:28][CH2:27][CH:26]([C:29]([F:32])([F:31])[F:30])[CH2:25][CH2:24]4)[C:14]=3[C:18]([F:21])([F:20])[F:19])[CH:9]=2)[CH2:4][O:3]1.CO.Cl.O>>[NH2:33][C:5]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:22][CH:23]3[CH2:28][CH2:27][CH:26]([C:29]([F:30])([F:31])[F:32])[CH2:25][CH2:24]3)[C:14]=2[C:18]([F:20])([F:21])[F:19])[CH:9]=1)([CH2:6][OH:7])[CH2:4][OH:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc3c(C(F)(F)F)c(OC4CCC(C(F)(F)F)CC4)ccc3c2)COC(C)(C)OC1
Agent: Cl
Solvent: CO
Solvent: O
Product: NC(CO)(CO)c1ccc2c(C(F)(F)F)c(OC3CCC(C(F)(F)F)CC3)ccc2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 106.8 %

Procedure:
Tert-butyl 2,2-dimethyl-5-(5-(trifluoromethyl)-6-(4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)-1,3-dioxan-5-ylcarbamate (1000.1 mg, 0.0016906 mol) (impure, assume 100% purity) was dissolved in methanol (30 mL, 0.73 mol), followed by 1 M of hydrogen chloride in water (30 mL, 0.030 mol). The reaction mixture was then heated at 80° C. for 2.5 hours. The solvent was removed under reduced pressure and the crude residue was treated with 4 N HCl in 1,4-dioxane. The solution was stirred for 1 hour and the solvent was then removed under reduced pressure. Ethyl ether was then added and the resulting solid was removed via filtration to give 815 mg of the desired product a white solid (64%). ESI-MS: 417 (M-16)+ 1H NMR (400 MHz, DMSO-d6) δ=8.21-7.97 (m, 3 H), 7.82-7.61 (m, 2 H), 5.57-5.41 (m, 4 H), 5.10 (br. s., 0.61 H), 4.98-4.88 (m, 0.32 H), 3.97-3.72 (m, 1 H), 2.15-1.91 (m, 2 H), 1.82-1.08 (m, 6 H)
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([CH2:7][C:8]([F:11])([F:10])[F:9])[C:4]([OH:6])=[O:5].Cl.[CH3:13]O>>[ClH:1].[NH2:2][CH:3]([CH2:7][C:8]([F:11])([F:10])[F:9])[C:4]([O:6][CH3:13])=[O:5]
Reactant: NC(CC(F)(F)F)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)C(N)CC(F)(F)F

Procedure:
1.186 g (6.127 mmol) of 2-amino-4,4,4-trifluorobutanoic acid hydrochloride (1:1) were initially charged in 11.6 ml of methanol which had been saturated with hydrogen chloride, and the mixture was stirred under reflux for 4 h. The reaction solution was concentrated and dried under high vacuum. This gave 1.275 g of the target compound (100% of theory).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C([O-])(O)=O.[Na+].[NH2:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1>CO>[CH2:1]([NH:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCBr
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCCCCCNc1cccc(O)c1

Procedure:
0.11 mol of n-heptyl bromide and 0.1 mol of NaHCO3 are added to 0.1 mol of m-aminophenol in 150 ml of methanol and the mixture is refluxed for 5 h. After cooling, the mixture is filtered and the solvent is removed in vacuo. The oil which remains is fractionated in vacuo, to give 3-(n-heptylamino)phenol; b.p. 130-140° C. (8·10−5 torr), m.p. 27-30° C., yld. 62%.
Reaction SMILES: [C:1](/[C:3](=[C:5]1/[C:6]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:7]=2[O:8][CH2:9][C:10]2[CH:15]=[C:14]([CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([OH:28])=O)[C:20]=4[N:19]=[C:18]3[CH2:29][CH2:30][CH3:31])[CH:13]=[CH:12][C:11]/1=2)/[CH3:4])#[N:2].C(N1C=CN=C1)([N:39]1C=CN=C1)=O.N.Cl>C1COCC1.O>[C:1](/[C:3](=[C:5]1/[C:6]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:7]=2[O:8][CH2:9][C:12]2[CH:13]=[C:14]([CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([NH2:39])=[O:28])[C:20]=4[N:19]=[C:18]3[CH2:29][CH2:30][CH3:31])[CH:15]=[CH:10][C:11]/1=2)/[CH3:4])#[N:2]
Reactant: CCCc1nc2c(C(=O)O)cccc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: CCCc1nc2c(C(N)=O)cccc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Temperature: 50 °C
Reaction time: 4 h
Yield: 100.9 %

Procedure:
[step 5] (E)-1-{[11-(1-cyanoethylidene)-3-fluoro-6,11-dihydrodibenzo[b,e]oxepin-8-yl]methyl}-2-propyl-1H-benzo[d]imidazole-4-carboxylic acid (97 mg, 0.20 mmol) obtained in step 4 was dissolved in THF (1.0 mL), 1,1′-carbonyldiimidazole (130 mg, 0.80 mmol) was added, and the mixture was stirred at 50° C. for 4 hr. After cooling to room temperature, 25% aqueous ammonia solution (55 μL, 0.80 mmol) was added, and the mixture was stirred at room temperature for 17 hr. To the mixture were added 1 mol/L hydrochloric acid and water, and the mixture was extracted 3 times with chloroform. The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0 v/v-93/7 v/v) to give the title compound (97 mg, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:18])[C:12]2[S:16][CH:15]=[N:14][C:13]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C@H:20]([C@H:22]1[CH2:26][N:25]([C@@H:27]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH3:28])[C:24](=[O:37])[CH2:23]1)[CH3:21].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:18][C@@H:20]([C@H:22]2[CH2:26][N:25]([C@@H:27]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[CH3:28])[C:24](=[O:37])[CH2:23]2)[CH3:21])[C:12]2[S:16][CH:15]=[N:14][C:13]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@H](C)O)CC2=O)cc1
Reactant: Oc1cc(OCc2ccccc2)cc2ncsc12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(OCc4ccccc4)cc4ncsc34)CC2=O)cc1
Temperature: 40 °C
Reaction time: 17 h

Procedure:
5-(benzyloxy)benzo[d]thiazol-7-ol (420 mg, 1.63 mmol), (R)-4-((S)-1-hydroxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one (607 mg, 2.31 mmol), and PPh3 (615 mg, 2.35 mmol) were dissolved in THF (15 ml). DEAD (0.36 mL, 2.30 mmol) was added and the resulting mixture was heated to 40° C. After 17 h, additional (R)-4-((S)-1-hydroxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one (105 mg, 0.40 mmol), PPh3 (110 mg, 0.42 mmol) and DEAD (0.060 mL, 0.38 mmol) were added. The reaction mixture was stirred an additional 1.5 h and was then concentrated directly onto silica gel. Purification by silica gel chromatography (70 to 100% EtOAc in hexanes) provided (R)-4-((R)-1-(5-(benzyloxy)benzo[d]thiazol-7-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 4.03C. LCMS-ESI+ (m/z): [M+H]+ calcd for C29H31N2O4S: 503.2; found 503.2.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]1[CH2:25][CH2:24][CH:23]=[CH:22][N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([Zn]CC)C.ICI.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Si:1]([O:18][CH2:19][C@@H:20]1[CH2:25][CH2:24][C@@H:23]2[C@@H:22]([CH2:33]2)[N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[Zn]CC
Reactant: CC(C)(C)OC(=O)N1C=CCC[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ICI
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC[C@H]2C[C@H]21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice cold solution of (S)-tert-butyl 2-((tert-butyldiphenylsilyloxy)methyl)-3,4-dihydropyridine-1(2H)-carboxylate (3.6 g, 8.0 mmol) in DCM (40 mL) was added a 1 M solution of diethylzinc (9.0 mL) followed by diiodomethane (3.2 g, 12.0 mmol) over 15 min. The reaction mixture was stirred for 30 min at 0° C., warmed to RT and stirred for 3 h. The pH of the reaction mixture was adjusted to pH 8 with saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, concentrated under reduced pressure, purified by silica gel chromatography (eluting with 0-15% EtOAc in petroleum ether) and combined with the product of a similar run to provide the title intermediate (4.5 g) as a colorless gummy liquid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][CH2:6][C:7]1([C:22](O)=[O:23])[CH2:11][CH2:10][N:9]([C:12](=[O:21])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:8]1.O>C(O)C>[CH2:1]([O:3][C:6]([C:7]1([CH2:22][OH:23])[CH2:11][CH2:10][N:9]([C:12](=[O:21])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:8]1)=[O:5])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COc1ccc(C(=O)N2CCC(CO)(C(=O)O)C2)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(CO)CCN(C(=O)c2ccc(OC)cc2)C1
Temperature: 80 °C
Yield: 60.9 %

Procedure:
Acetyl chloride (80.2 mL, 1130 mmol) was added to a suspension of 3-hydroxymethyl-1-(4-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid (210.0 g, 751.9 mmol) (see Preparation 9) in ethanol (2100 mL) and the reaction mixture was heated at 80° C. for 4 hours. Water (200 mL) was added then ethanol was removed by concentration under reduced pressure. The aqueous residue was partitioned between ethyl acetate (2 L) and saturated aqueous NaHCO3 (1500 mL). The organic layer was separated, washed with water (1500 mL) then concentrated under reduced pressure to afford the title compound as a colourless oil (140.7 g, 61%). (99.3:0.7 ratio of isomers)
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([C:30]3[CH:31]=[N:32][C:33]([N:36]([CH2:46][C:47]4[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=4)[CH2:37][C:38]4[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=4)=[N:34][CH:35]=3)[C:10]3[CH2:15][CH2:14][N:13]([C:16]4[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)=[CH:18][CH:17]=4)[C:11]=3[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:55][S:56](Cl)(=[O:58])=[O:57]>>[CH3:55][S:56]([N:27]1[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][C:19]2[CH:20]=[CH:21][C:16]([N:13]3[C:11]4[N:12]=[C:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)[N:8]=[C:9]([C:30]5[CH:31]=[N:32][C:33]([N:36]([CH2:46][C:47]6[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=6)[CH2:37][C:38]6[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=6)=[N:34][CH:35]=5)[C:10]=4[CH2:15][CH2:14]3)=[CH:17][CH:18]=2)[CH2:25][CH2:26]1)(=[O:58])=[O:57]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(CCN4CCNCC4)cc3)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(CCN4CCN(S(C)(=O)=O)CC4)cc3)cn2)cc1

Procedure:
In the same manner as Example 1-D-143, using a crude product (80 mg) of 5-{2-morpholin-4-yl-7-[4-(2-piperazin-1-yl-ethyl)-phenyl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl-bis-(4-methoxy-benzyl)-amine obtained in Example 1-D-143 and methanesulfonyl chloride (0.012 ml) instead of acetyl chloride, a crude product of 5-(7-{4-[2-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-phenyl}-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl-bis-(4-methoxy-benzyl)-amine was obtained as a colorless solid (88 mg, 100%). Using a crude product (88 mg) of 5-(7-{4-[2-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-phenyl}-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl-bis-(4-methoxy-benzyl)-amine, according to the above Deprotection method 2,5-(7-{4-[2-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-phenyl}-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-ylamine was obtained as a colorless powder (26 mg, 43%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH:9]([Cl:11])[Cl:10])[CH:5]=[C:4]([C:12]([Cl:15])([Cl:14])[Cl:13])[N:3]=1.[Cl:16]C1N=C(Cl)C=C(C(Cl)(Cl)Cl)N=1>>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]([Cl:16])([Cl:10])[Cl:11])[CH:5]=[C:4]([C:12]([Cl:15])([Cl:13])[Cl:14])[N:3]=1
Reactant: Clc1nc(OC(Cl)Cl)cc(C(Cl)(Cl)Cl)n1
Reactant: Clc1cc(C(Cl)(Cl)Cl)nc(Cl)n1
Product: Clc1nc(OC(Cl)(Cl)Cl)cc(C(Cl)(Cl)Cl)n1
Yield: 83 %

Procedure:
According to the gas chromatogram, the filtrate (113.8 g) consisted of 83% of the title compound, 4% of 2-chloro-4-dichloromethoxy-6-trichloromethylpyrimidine and 9% of 2,4-dichloro-6-trichloromethylpyrimidine. The total yield of the title compound was 87.6% of theory.
Reaction SMILES: [CH:1]1([C:7]2([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[O:12][C:11](=[O:13])[CH:10]=[C:9]([OH:14])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]([C:28]1[CH:33]=[C:32]([OH:34])[C:31]([CH3:35])=[CH:30][C:29]=1[S:36]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:24]([C:28]1[CH:33]=[C:32]([OH:34])[C:31]([CH3:35])=[CH:30][C:29]=1[S:36][C:10]1[C:11](=[O:13])[O:12][C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:8][C:9]=1[OH:14])([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(O)cc2C(C)(C)C)cc1
Reactant: O=C1C=C(O)CC(CCc2ccc(O)cc2)(C2CCCCC2)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccc(O)cc3)(C3CCCCC3)OC2=O)c(C(C)(C)C)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared as described in General Method 9 from 6-cyclohexyl-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one (prepared in Example NN; 210 mg, 0.664 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxy-5-methyl-phenyl) ester (prepared in Example RRR; 256 mg, 0.730 mmol), K2CO3 (367 mg, 2.655 mmol), and DMF (4 mL). The reaction was stirred at room temperature overnight and then worked up in the usual fashion. The crude product was flash chromatographed using CH2Cl2 :MeOH (98:2) to give the desired product as a solid, m.p. 100°-103° C. 1H NMR (DMSO-6) δ 1.0-2.1 (m, 13 H), 1.45 (s, 9 H), 1.80 (s, 3 H), 2.5-2.6 (2 H+DMSO), 2.7 (d, 1 H), 2.9 (d, 1 H), 6.6-6.7 (d, s, 3 H), 6.77 (s, 1 H), 6.9 (d, 2 H), 9.01 (s, 1 H), 9.13 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]3[C@@H:12]([NH:13][C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23](=[O:31])[C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)=[CH:19][N:18]=4)=[O:15])[C@H:7]3[C:6]=2[C:5]([F:32])=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO.O>[F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]3[C@@H:12]([NH:13][C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH:23]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[OH:31])=[CH:19][N:18]=4)=[O:15])[C@H:7]3[C:6]=2[C:5]([F:32])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(C(=O)c2ccc(F)cc2)cn1)N[C@@H]1[C@@H]2COc3c(F)ccc(F)c3[C@@H]21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(Nc1ccc(C(O)c2ccc(F)cc2)cn1)N[C@@H]1[C@@H]2COc3c(F)ccc(F)c3[C@@H]21
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.7 %

Procedure:
N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(4-fluorobenzoyl)-2-pyridinyl]urea (20 mg) was dissolved in methanol and sodium borohydride (appr. 20 mg) was added to the reaction mixture in small portions. The reaction mixture was stirred for about 3 h at ambient temperature. The reaction was monitored by TLC. The reaction mixture was diluted with water, acidified with 1N HCl and extracted into methylene chloride. Organic extract low as washed with water and bine, dried over magnesium sulfate and concentrated. Purification by column chromatography on silica (EtOAc/hexane) gave 12 mg of pure product.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][C:9]#[N:10])=[CH:6][CH:5]=1.Cl[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.[OH-].[Na+]>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([CH:8]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:9]#[N:10])=[CH:6][CH:5]=1
Reactant: ClCCN1CCOCC1
Reactant: N#CCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: N#CC(CCN1CCOCC1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a flask was added 1.4 g. (0.033 mole) of a 55% oil dispersion of sodium hydride. After washing the sodium hydride with hexane to remove the mineral oil, 20 ml. of a 2 to 1 mixture of toluene and DMF was added followed by the slow addition of 5.0 ml. (0.033 mole) of 4-chlorobenzyl cyanide. The resulting deep burgundy solution was stirred for one hour. The hydrochloride salt of 4-(2-chloroethyl)morpholine, 6.4 g. (0.033 mole), was neutralized with sodium hydroxide in a separate vessel and the resulting 4-(2-chloroethyl)morpholine free base was dissolved in 10 ml. of a 2 to 1 mixture of toluene and DMF. The free base solution was added slowly to the 4-chlorobenzyl cyanide solution at 0° C. and the reaction stirred at room temperature for two days. The reaction was poured into ice water and the organic layer extracted with ether. The ether extract was washed twice with 10% aqueous hydrochloric acid, the aqueous material made basic using concentrated ammonium hydroxide, and the desired free base material extracted into ethyl acetate. The ethyl acetate solution was dried, filtered, and concentrated. The crude product was purified by flash chromatography to give 3.7 g. (42% yield) of 2-(4-chlorophenyl)-4-(4-morpholinyl)butyronitrile as a yellow oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(OCC)C>O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCCCCCCCCBr
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCCCCCCCCCCCBr
Reaction time: 2 h
Yield: 200.2 %

Procedure:
175 g of 11-bromoundecanol (Fluka) is dissolved in 420 ml of tetrahydrofuran and combined at 25° with 101 g of imidazole as well as 130.1 g of tert-butyldimethylsilyl chloride in 140 ml of tetrahydrofuran, and agitated for 2 hours at 25°. For the working up step, 1.2 1 of diethyl ether is added, the thus-precipitated hydrochloride is filtered off, the mixture concentrated to dryness under vacuum and chromatographed on silica gel with hexane/ethyl acetate, yielding 509.6 g of 11-bromoundecyl-tert-butyldimethylsilyl ether as an oil.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:33])[NH:6][C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][N:22]=5)[S:20][C:13]=34)=[C:9]([F:32])[CH:8]=2)[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH3:48][N:49]1[CH2:54][CH2:53][N:52]([CH:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)[CH2:51][CH2:50]1>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([N:58]6[CH2:57][CH2:56][CH:55]([N:52]7[CH2:51][CH2:50][N:49]([CH3:48])[CH2:54][CH2:53]7)[CH2:60][CH2:59]6)=[O:27])=[CH:23][N:22]=5)[S:20][C:13]=34)=[C:9]([F:32])[CH:8]=2)=[O:33])[CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)O)cn4)sc23)c(F)c1)NC1CC1
Reactant: CN1CCN(C2CCNCC2)CC1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN1CCN(C2CCN(C(=O)c3ccc(-c4cc5nccc(Oc6ccc(NC(=O)NC7CC7)cc6F)c5s4)nc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.2 %

Procedure:
To a stirred solution of acid 225 (300 mg, 0.646 mmol) in DMF (10 mL) at 0° C. were added HOBT (198 mg, 1.292 mmol), EDC (248 mg, 1.292 mmol) and 1-methyl-4-(piperidin-4-yl)piperazine (118 mg, 0.646 mmol). The reaction mixture was stirred at room temperature overnight, diluted with NaHCO3 saturated solution, and extracted with EtOAc. The extract was dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified three times by Biotage (MeOH/EtOAc, 0-50%, 25 g column) followed by purification on Gilson [MeOH/H2O, 50-95%, HCOOH (0.05%)] to afford the title compound 234 (50 mg, 0.079 mmol, 12.29% yield) as a mono-formate salt. NMR (400 MHz, CD3OD) δ (ppm): 8.67 (dd, J1=0.8 Hz, J2=2.1 Hz, 1H,), 8.48 (s, 1H), 8.47 (s, 1H), 8.19 (dd, J1=0.8 Hz, J2=8.3 Hz, 1H), 8.16 (s, 1H), 7.97 (dd, J1=2.2 Hz, J2=8.2 Hz, 1H), 7.65 (dd, J1=2.4 Hz, J2=13.1 Hz, 1H), 7.29 (t, 1H, J=8.8 Hz, 1H), 7.20-7.18 (m, 1H), 6.65 (dd, J1=0.8 Hz, J2=5.5 Hz, 1H), 3.83 (br. s, 1H), 3.24 (br s, 1H), 3.01 (br. s, 6H), 2.85 (br. s, 3H), 2.76-2.70 (m, 2H), 2.67 (s, 3H), 2.61-2.57 (m, 1H), 2.02 (br. s, 1H), 1.91-1.85 (br. s, 1H), 1.56-1.49 (hr. s, 2H), 0.78-0.74 (m, 2H), 0.55-0.51 (m, 2H). MS: 630.4 (MH)+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]1([C:14](=[O:15])[NH:13][C:12](=[O:16])[N:11]1[CH3:17])[CH2:5]2.[Cl:18]N1C(=O)CCC1=O>CC(O)=O>[NH2:1][C:2]1[C:3]([Cl:18])=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]1([C:14](=[O:15])[NH:13][C:12](=[O:16])[N:11]1[CH3:17])[CH2:5]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN1C(=O)NC(=O)C12Cc1ccc(N)cc1C2
Solvent: CC(=O)O
Product: CN1C(=O)NC(=O)C12Cc1ccc(N)c(Cl)c1C2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(−)-5′-Amino-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione (265 mg, 1.15 mmol, described in Intermediate 47) was dissolved in AcOH (7 mL) and N-chlorosuccinimide (145 mg, 1.09 mmol) was added in one portion. The mixture was stirred at ambient temperature for 5 h, then the solvent was removed in vacuo. The residue was partitioned between saturated aqueous NaHCO3 (20 mL) and CH2Cl2 (70 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2::EtOAc—100:0 to 0:100, to give 5′-amino-4′-chloro-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione, which eluted first, and the title compound, which eluted second. MS: m/z=266 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.C1N2CN3CN(C2)CN1C3.C(O)(=[O:25])C.O>C(O)C>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)=[O:25]
Reactant: O=C(O)Cc1ccc(CBr)cc1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: CCO
Solvent: O
Product: O=Cc1ccc(CC(=O)O)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
The title compound was synthesized by referring to Org. Synth., 1963, IV, 690. A suspension of (4-bromomethylphenyl)acetic acid (6.0 g) and hexamethylenetetramine (11.1 g) in ethanol (80 ml) was stirred for 2 hours at 100° C., then acetic acid (20 ml) and water (20 ml) were sequentially added thereto followed by stirring for 1.5 hours at 100° C. The solvent was evaporated in vacuo, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. A solution of the residue in tetrahydrofuran was filtered through silica gel, then the solvent was evaporated in vacuo, and the resulting solid was washed with a hexane-diethyl ether system to provide the title compound (2.0 g).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[N:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:25]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:26])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCOCC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and morpholine-4-carbonyl chloride. The crude product was purified by preparative HPLC (37%, white crystals). HPLC-MS m/z=369.1 (M+1), Rt: 4.3 min.