Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:16]=[C:17]1[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH2:19][N:18]1[CH2:34][C:35](O)=[O:36].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[C:10]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][NH:9][C:35](=[O:36])[CH2:34][N:18]2[CH2:19][CH2:20][C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:17]2=[O:16])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)NCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,2-diphenylethanamine (0.20 g, 1.00 mmol) in dichloromethane (20 mL) under nitrogen was added 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.30 g, 1.00 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.38 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (0.61 mg, 0.005 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2, 400 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:1) gave the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.01 (t, J=5.6 Hz, 1H), 7.26-7.32 (m, 16H), 7.15-7.27 (m, 4H), 4.19 (t, J=7.9 Hz, 1H), 3.81 (s, 2H), 3.74 (dd, J=7.9, 5.6 Hz, 2H), 3.15 (t, J=6.4 Hz, 2H), 2.65 (t, J=6.4 Hz, 2H); MS (DCI+) m/z 475 (M+H)+, 492 (M+NH4)+.
Reaction SMILES: [OH-].[K+:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:22]1([CH2:28][C:29]([O:31]C)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH2:28][C:29]([O-:31])=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[K+:2]
Reactant: COC(=O)Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C([O-])Cc1ccccc1
Yield: 92 %

Procedure:
Under the reaction conditions described in Example 1, 64 ml KOH and 19.2 ml PPh3 were added over 43 min. After five more minutes, the reactor was cooled and vented. A 92% yield of potassium phenylacetate and 4% methyl phenylacetate was obtained on a nearly quantitative conversion. 98% of the stiochiometric amount of KOH was added.
Reaction SMILES: [OH-].[CH2:2]([N+:6]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][CH3:5].[C:19]([OH:24])(=[O:23])[CH:20]([CH3:22])[CH3:21]>O>[C:19]([O-:24])(=[O:23])[CH:20]([CH3:22])[CH3:21].[CH2:15]([N+:6]([CH2:2][CH2:3][CH2:4][CH3:5])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17][CH3:18]
Reactant: CC(C)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O
Product: CC(C)C(=O)[O-]

Procedure:
A 40 wt % solution of tetrabutylammonium hydroxide in water (250 mL, 99 g, 382 mmol), water (300 mL) and isobutyric acid (33.8 g, 382 mmol) was stirred at ambient temperature for 30 min. The solvent was removed in vacuo to afford the title compound (5) as a waxy solid, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([C:9]#[CH:10])[CH2:3][O:4][Si:5]([CH3:8])([CH3:7])[CH3:6].Cl[C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[CH2:16]([O:15][C:13](=[O:14])[C:10]#[C:9][C:2]([CH3:11])([CH3:1])[CH2:3][O:4][Si:5]([CH3:6])([CH3:8])[CH3:7])[CH3:17]
Reactant: C#CC(C)(C)CO[Si](C)(C)C
Reactant: CCOC(=O)Cl
Product: CCOC(=O)C#CC(C)(C)CO[Si](C)(C)C

Procedure:
The title compound was prepared from (2,2-dimethyl-but-3-ynyloxy)-trimethyl-silane and ethyl chloroformate in accordance with the procedures of G. Cai et al., Tetrahedron, 2006, (5697-5708).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:17]([O-:19])=[O:18])=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(O)Cc1cccc(F)c1
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 23.2 g. of 3-fluorophenylacetic acid and 100 ml. of conc. sulfuric acid is added dropwise 6.5 ml. of conc. nitric acid while maintaining the temperature below 40° C. The mixture is stirred at ambient temperature for 24 hours and then poured onto one kilogram of ice. The resulting precipitate is recovered by filtering, washed with water and dried in vacuo to obtain crude 5-fluoro-2-nitrophenylacetic acid, m.p. 137°-142° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[N:21]=[C:22]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[S:23][C:24]=1[CH2:25][CH2:26][CH2:27]O.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([O:17][CH2:27][CH2:26][CH2:25][C:24]3[S:23][C:22]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:31][CH:30]=4)=[N:21][C:20]=3[CH3:19])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1ccc2c(O)cccc21
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCCO
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCCOc1cccc2c1ccn2CC(=O)OC(C)(C)C

Procedure:
In analogy to the procedure described in example 3 c], (4-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 3 b]) was reacted with 3-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-1-ol in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield (4-{3-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-indol-1-yl)-acetic acid tert-butyl ester as colorless gum.
Reaction SMILES: [F:1][C:2](=[C:10]([F:12])[F:11])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[H-].[Na+].Br[CH2:16][C:17]1[CH:18]=[N:19][C:20]([Cl:23])=[CH:21][CH:22]=1>CN(C)C=O>[Cl:23][C:20]1[N:19]=[CH:18][C:17]([CH2:16][C:5]([CH2:4][CH2:3][C:2]([F:1])=[C:10]([F:11])[F:12])([C:6]#[N:7])[C:8]#[N:9])=[CH:22][CH:21]=1
Reactant: N#CC(C#N)CCC(F)=C(F)F
Reactant: Clc1ccc(CBr)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)=C(F)F)Cc1ccc(Cl)nc1
Yield: 60.9 %

Procedure:
By using (3,4,4-trifluoro-3-butenyl)malononitrile (0.21 g), N,N-dimethylformamide (5 ml), sodium hydride (60% in oil, 0.05 g) and 3-bromomethyl-6-chloropyridine (0.28 g) according to the similar method described in Production Example 1 was obtained 0.22 g of 2-((6-Chloro-3-pyridyl)methyl)-2-(3,4,4-trifluoro-3-butenyl)malononitrile represented by the following formula (the present invention compound (3)).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:19]=[CH:18][C:11]([O:12][CH2:13][CH:14]([OH:17])[CH2:15][NH2:16])=[CH:10][CH:9]=1.[CH3:20][C:21]1[CH:32]=[CH:31][C:24]([C:25]([CH2:27][C:28](=O)[CH3:29])=[O:26])=[CH:23][N:22]=1.C(O)C>C(O)=O>[CH3:20][C:21]1[CH:32]=[CH:31][C:24]([C:25]([CH:27]=[C:28]([NH:16][CH2:15][CH:14]([OH:17])[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:19][CH:18]=2)[CH3:29])=[O:26])=[CH:23][N:22]=1
Reactant: COCCCCOc1ccc(OCC(O)CN)cc1
Reactant: CC(=O)CC(=O)c1ccc(C)nc1
Solvent: O=CO
Solvent: CCO
Product: COCCCCOc1ccc(OCC(O)CNC(C)=CC(=O)c2ccc(C)nc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89 %

Procedure:
54.0 g of 1-(p-[4-methoxybutoxy]-phenoxy)-3-aminopropan-2-ol ##STR66## 37.3 g of 6-methylnicotinoyl-acetone ##STR67## 400 ml of ethanol and 0.1 ml of formic acid are heated to 50° for 1 hour and stirred at room temperature for a further 20 hours. Filtration gives 61.3 g of 1-(2-[6 -methylnicotinoyl]-1-methylvinylamino)-3-(p-[4-methoxy- butoxy]-phenoxy)-propan-2-ol ##STR68## Melting points: 143°-145°. A further 15.0 g of the same substance can be obtained from the filtrate. Yield: 89% of theory.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].ON1C2C=CC=CC=2N=N1.[C:44]([NH:51][CH2:52][CH2:53][C:54](O)=[O:55])([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45].Cl.CN(C)CCCN=C=NCC>CC#N>[C:47]([O:46][C:44]([NH:51][CH2:52][CH2:53][C:54]([NH:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24])=[O:55])=[O:45])([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)NCCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 67.2 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.7 g, 4.62 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, 1-hydroxybenzotriazole (0.3 g, 2.22 mmol), N—BOC-b-alanine (0.42 g, 2.22 mol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodimide hydrochloride 0.53 g, 2.78 mmol) were added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with 1N citric acid (30 ml), H2O (2×30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2: CH3OH 100:2) to give 3-[(tert-butoxy)carbonylamino]-N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}propanamide (0.57 g, 67%) as a white solid:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH2:7][O:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].[Cl:22][C:23]1[N:28]=[C:27](Cl)[C:26](=[O:30])[N:25]([CH2:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C:24]=1[CH3:42].C(N(CC)CC)C>C(OCC)(=O)C>[C:14]([O:13][C:12]([NH:11][CH2:10][CH2:9][O:8][CH2:7][C:6]1[CH:5]=[C:4]([CH:21]=[CH:20][CH:19]=1)[CH2:3][CH2:2][NH:1][C:27]1[C:26](=[O:30])[N:25]([CH2:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C:24]([CH3:42])=[C:23]([Cl:22])[N:28]=1)=[O:18])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCOCc1cccc(CCN)c1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1c(Cl)nc(NCCc2cccc(COCCNC(=O)OC(C)(C)C)c2)c(=O)n1CC(=O)OCc1ccccc1
Yield: 45.1 %

Procedure:
A mixture of tert-butyl 2-{[3-(2-aminoethyl)benzyl]oxy}ethylcarbamate (preparation 105) (270 mg, 0.92 mmol), benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17) (300 mg, 0.92 mmol), and triethylamine (140 ml, 1.01 mmol) in ethyl acetate was heated under reflux overnight. The cooled suspension was diluted with ethyl acetate, then washed with hydrochloric acid (2N), NaHCO3 solution, brine, then dried over MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using ethyl acetate:pentane (40:60) as eluant, and triturated with ether, to give the title compound as a white solid, (243 mg, 45%). Re-purifiing the ether filtrate by column chromatography on silica gel provided an additional (176 mg, 33%) of the desired product.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][CH:9]([OH:13])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1B(O)O.CC(C)([O-])C.[K+]>COCCOC.C(O)(C)(C)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>[C:15]1([CH3:14])[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[C:2]1[N:7]=[C:6]([CH2:8][CH:9]([OH:13])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1
Reactant: CCCC(O)Cc1cccc(Br)n1
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: COCCOC
Product: CCCC(O)Cc1cccc(-c2c(C)cc(C)cc2C)n1
Temperature: 50 °C
Yield: 77.8 %

Procedure:
1-(6-Bromopyridin-2-yl)pentan-2-ol (3.23 g, 13.2 mmol) was dissolved in 30 mL of 1,2-dimethoxyethane. Tetrakis(triphenylphosphine)palladium(0) (0.76 g, 0.66 mmol) was added and the solution was heated to 50° C. for 15 min. After cooling the solution, 2,4,6-trimethylbenzeneboronic acid (2.60 g, 15.9 mmol) in 15 mL 1,2-dimethoxyethane was added to parent solution. Potassium t-butoxide (2.96 g, 26.5 mmol) in 15 mL t-butanol was added last. The reaction was heated at 90° C. for 0.5 h. After cooling, the solution was filtered and concentrated. Flash chromatography (20% ethyl acetate/hexanes) gave the title compound (2.91 g, 77% yield).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3([CH2:20][C:21]([NH:23][OH:24])=[O:22])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[OH:27]OS([O-])=O.[K+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([S:13]([C:14]3([CH2:20][C:21]([NH:23][OH:24])=[O:22])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:27])=[CH:11][CH:12]=2)=[CH:25][CH:26]=1
Reactant: O=C(CC1(Sc2ccc(Oc3ccc(F)cc3)cc2)CCOCC1)NO
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(CC1(S(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCOCC1)NO
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
2-{4-[4-(4-Fluorophenoxy)phenylthio]-tetrahydropyran-4-yl}-N-hydroxyacetamide (500 mg) was dissolved in methanol (25 ml). OXONE (400 mg) in water (5 ml) was added. After stirring for 30 minutes, the mixture was partitioned between methylene chloride and water. Preparative TLC on silica gel and elution with 10% methanol/methylene chloride gave 2-{4-[4-(4-fluorophenoxy)phenylsulfinyl]-tetrahydropyran-4-yl}-N-hydroxyacetamide (402 mg, m.p. 120° C.).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[O:17]1[CH2:19][C@H:18]1[CH2:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>CO.CS(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:19][C@H:18]([OH:17])[CH2:20][O:21][C:22]4[CH:30]=[CH:29][CH:28]=[C:27]5[C:23]=4[CH:24]=[CH:25][NH:26]5)[CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CS(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2c[nH]c3cc(F)ccc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 6-fluoro-3-(piperidin-4-yl)-1H-indole (1.00 g, 4.6 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.91 g, 4.8 mmol). The product was isolated as a white foam. Yield 0.75 g (40%). mp 94°-97° C. FDMS m/e=407 (M+ of free base). α[D]589 =+7.97 (c=1.00, methanol/dimethylsulfoxide).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C:9]([F:23])=[CH:8][C:7]=1[Br:24])C.O[Li].O>CO>[Br:24][C:7]1[CH:8]=[C:9]([F:23])[C:10]([O:12][CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:20])([CH3:22])[CH3:21])([CH3:17])[CH3:18])=[CH:11][C:6]=1[CH2:5][C:4]([OH:25])=[O:3]
Reactant: CCOC(=O)Cc1cc(OCCO[Si](C)(C)C(C)(C)C)c(F)cc1Br
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCOc1cc(CC(=O)O)c(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a solution of {2-bromo-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-fluoro-phenyl}-acetic acid ethyl ester (0.508 g, 1.16 mmol) in MeOH was added LiOH.H2O (0.036 g, 1.51 mmol). The mixture was stirred at room temperature for two hours, and then solvent was removed under reduced pressure. 2N NaOH was added to the residue, and the mixture was washed with diethyl ether. The aqueous phase was taken to pH 1 with 2N HCl and was extracted with EtOAc. The combined EtOAc extracts were washed with water, brine dried over MgSO4, filtered and concentrated to dryness under reduced pressure to yield {2-bromo-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-fluoro-phenyl}-acetic acid (0.352 g, 74%) as a white solid.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[CH:29]=[CH:28][C:17]([O:18][C:19]2[N:27]=[CH:26][CH:25]=[CH:24]C=2C(O)=O)=[CH:16][CH:15]=1.CN(C=O)C>C(Cl)Cl>[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[CH:29]=[CH:28][C:17]([O:18][C:19]2[N:27]=[CH:26][CH:25]=[CH:24][C:1]=2[C:2]([Cl:4])=[O:3])=[CH:16][CH:15]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccnc1Oc1ccc(Nc2ccccn2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccnc1Oc1ccc(Nc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 2M solution of oxaloyl chloride (3.86 mL, 7.71 mmol) was added slowly to a suspension of 2-(4-(pyridin-2-ylamino)phenoxy)nicotinic acid (1580 mg, 5.14 mmol) in CH2Cl2 (20 mL). DMF (0.040 mL, 0.514 mmol) was added drop wise and the mixture was stirred at RT for 2 h. The mixture was concentrated under reduced pressure to deliver a yellow solid. The solid was suspended in CH2Cl2 (5 ml) and filtered to deliver 2-(4-(pyridin-2-ylamino)phenoxy)nicotinoyl chloride as a yellow solid that was taken on without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[O:16]([NH2:18])[CH3:17]>CO>[CH3:17][O:16][N:18]=[C:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: CON
Agent: Cl
Solvent: CO
Product: CON=C1CCN(c2ccc(N)cc2)CC1
Yield: 63.5 %

Procedure:
A solution of 1-(4-aminophenyl)-4-piperidone (300 mg, 1.58 mmol) and methoxylamine hydrochloride (250 mg, 3.0 mmol) in methanol (5 mL) was heated at reflux for 30 min. The solvent was evaporated, water added and extracted with ethyl acetate. The combined organic layers were washed with water and brine then dried over sodium sulfate. Concentration to dryness afforded 1-(4-amino-phenyl)-piperidin-4-one O-methyl-oxime (220 mg, 64%) as a semisolid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[N+:7]([C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[CH:15][NH:16]2)=[CH:12][CH:11]=1)([O-])=O.Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CC#N>[N:23]1([CH2:22][CH2:21][N:16]2[C:17]3[C:13](=[CH:12][CH:11]=[C:10]([NH2:7])[CH:18]=3)[CH:14]=[CH:15]2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1ccc2ccn(CCN3CCOCC3)c2c1
Temperature: 25 °C

Procedure:
K2CO3 (5.08 g, 36.726 mmol) was added to a slurry of 6-nitroindole (1.985 g, 12.242 mmol), 4-(2-chloroethyl)morpholine hydrochloride (2.278 g, 12.242 mmol), and CH3CN (100 ml). The mix was heated to reflux for 18 h, then cooled to RT, filtered, and concentrated in vacuo. The crude was eluted through a silica gel column with a gradient of 3:97 to 5:95 and finally 8:92 MeOH/CH2Cl2, to yield upon drying the desired intermediate which was hydrogenated under conditions previously described.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([N:65]1[CH2:71][CH2:70][CH2:69][CH:68]([NH2:72])[CH2:67][CH2:66]1)(OC(C)(C)C)=O>>[NH:65]1[CH2:71][CH2:70][CH2:69][CH:68]([NH:72][C:27](=[O:29])[C:26]2[CH:30]=[CH:31][C:23]([NH:22][C:20]3[N:19]=[CH:18][C:9]4[N:10]([CH3:17])[C:11](=[O:16])[C:12]([F:15])([F:14])[CH2:13][N:7]([CH:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[C:8]=4[N:21]=3)=[C:24]([O:32][CH3:33])[CH:25]=2)[CH2:67][CH2:66]1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-N—Boc-hexahydro azepine 4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. Further, after washing with water (10 ml), t-butoxycarbonyl (Boc) protection group was removed using 40% TFA in dichloromethane (6 ml) and purified the product using preparative HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10-2.05 (m, 16H) 2.88 (d, J=3.28 Hz, 1H) 3.01 (br. s., 2H) 3.31 (s, 3H) 3.34 (br. s., 1H) 3.94 (s, 3H) 4.06 (t, J=13.26 Hz, 3H) 4.46 (m, 1H) 7.47 (d, J=8.1 Hz, 1H) 7.50 (s, 1H) 7.91 (s, 1H) 8.21 (s, 1H) 8.23-8.30 (m, 2H). [M+H] calculated for C28H37F2N7O3, 558. found 558.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([O:16][CH2:17][CH3:18])[CH:13]=[C:12]([O:19][CH2:20][CH3:21])[N:11]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+].O>C(O)C>[CH2:17]([O:16][C:14]1[CH:13]=[C:12]([O:19][CH2:20][CH3:21])[N:11]=[C:10]([N:7]2[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]2)[N:15]=1)[CH3:18]
Reactant: CCOc1cc(OCC)nc(N2CCN(C(C)=O)CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1cc(OCC)nc(N2CCNCC2)n1
Yield: 103.7 %

Procedure:
A solution of 1-acetyl-4-(4,6-diethoxypyrimidin-2-yl)piperazine (1.8 g) and sodium hydroxide (1.0 g) in ethanol (10 ml)—water (10 ml) was refluxed under heating for 11 hr. The reaction mixture was poured into water and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated to give the title compound (1.6 g) as a pale-brown oil.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:20]=[C:21]([C:22]([O:24]C)=[O:23])[C:4]=2[N:3]=1.[Li+].[OH-].Cl>C1COCC1.O>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:4]=2[N:3]=1
Reactant: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C)n2Cc1cccc2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2c(C(=O)O)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
A mixture of methyl 2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole-4-carboxylate (170 mg, 0.41 mmol) and LiOH (172 mg, 4.1 mmol) in THF (15 mL) and water (10 mL), was stirred at 50° C. for 1 h. Then the pH of the reaction mixture was neutralized with 1N aq. HCl. Then the mixture was stirred at rt for 1 h, filtered to give the desired product (150 mg, 91%), as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.51 (s, 3H), 3.07 (t, 4H, J=4.8 Hz), 3.70 (t, 4H, J=4.8 Hz), 6.09 (s, 2H), 6.38 (d, 1H, J=7.8 Hz), 7.32-7.46 (m. 3H), 7.60-7.73 (m, 2H), 7.87 (d, 1H, J=7.8 Hz), 8.02 (d, 1H, J=8.4 Hz), 8.23 (d, 1H, J=8.1 Hz); LC-MS: m/e=402 [M+1]+