Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4](=[O:15])[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:6].C([Mg]Cl)(C)C.[CH2:22]([Mg]Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[O:15]=[C:4]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])[CH3:6]
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (1.16 g, 5 mmol) in THF (10 mL) was cooled to −15° C. and slowly charged with isopropylmagnesium chloride (2.0M, 2.37 mL, 0.95 eq). After a clear solution was obtained, benzylmagnesium chloride (1.0M, 4.99 mL, 1.0 eq) was added dropwise with stirring at rt overnight. The reaction mixture was quenched with NH4Cl solution and extracted with EtOAc (10 mL×2). The combined organic layers were washed with water, brine, dried over sodium sulfate before being filtered, concentrated to give a white solid as (S)-tert-butyl 3-oxo-4-phenylbutan-2-ylcarbamate. Mass Spectrum (ESI) m/e=264 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([F:23])[CH:22]=1)[O:5][C:6]1[C:11]2[CH2:12][C:13]([CH3:16])([CH3:15])[O:14][C:10]=2[CH:9]=[C:8]([C:17]([OH:19])=O)[CH:7]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH3:52][N:53]1[CH:57]=[CH:56][C:55]([NH2:58])=[N:54]1>C(Cl)Cl>[CH3:52][N:53]1[CH:57]=[CH:56][C:55]([NH:58][C:17]([C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:20]=[C:21]([F:23])[CH:22]=[C:2]([F:1])[CH:3]=3)[C:11]3[CH2:12][C:13]([CH3:15])([CH3:16])[O:14][C:10]=3[CH:9]=2)=[O:19])=[N:54]1
Reactant: CC1(C)Cc2c(Oc3cc(F)cc(F)c3)cc(C(=O)O)cc2O1
Reactant: Cn1ccc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cn1ccc(NC(=O)c2cc(Oc3cc(F)cc(F)c3)c3c(c2)OC(C)(C)C3)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
To a mixture of 4-(3,5-difluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (113b) (0.308 g, 0.00096 mol), EDCI (0.28 g, 0.0015 mol), HOBt (0.21 g, 0.0015 mol) and NMM (0.49 g, 0.0048 mol) in CH2Cl2 (15 mL) was added 1-methyl-1H-pyrazol-3-amine (0.11 g, 0.001 mol) in one portion. The mixture was stirred at room temperature overnight. The reaction mixture was washed with water, aq. citric acid and then sat. NaHCO3. The organic phase was dried over Na2SO4 and concentrated to give a brown oil. The crude oil was purified by prep. HPLC to give the title compound (95 mg, 51% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.82 (s, 1 H), 7.20 (m, 2 H), 7.03 (d, 2 H), 6.73 (s, 1 H), 6.42 (m, 3 H), 3.72 (s, 3 H), 2.84 (s, 2 H), 1.42 (s, 6 H); LCMS for C21H19F2N3O3 m/z 400.4 (M+H)+.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[NH:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]=[O:14].[CH3:15][Si:16]([CH3:23])([CH3:22])[CH2:17][CH2:18][O:19][CH2:20]Cl>CCCCCC>[CH3:15][Si:16]([CH3:23])([CH3:22])[CH2:17][CH2:18][O:19][CH2:20][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]=[O:14]
Reactant: O=Cc1ncc[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccnc1C=O
Reaction time: 1.5 h
Yield: 98 %

Procedure:
Sodium hydride (463 mg, 60% dispersion in mineral oil, 11.4 mmol) was washed with hexane under an atmosphere of dry nitrogen. N,N-Dimethylformamide (15 ml) was added, the resultant mixture was stirred at room temperature and imidazole-2-carboxaldehyde (1 g, 10.4 mmol) was added portionwise. The reaction was then stirred for 1.5 hours, 2-(trimethylsilyl)ethoxy methyl chloride (2.03 ml, 11.4 mmol) was added, and the resultant mixture was then stirred at room temperature for 18 hours. The reaction was quenched by the addition of aqueous ammonium chloride solution and the resultant mixture then extracted with ethyl acetate (2×). The combined organic extracts were dried (Na2SO4), filtered, concentrated under reduced pressure and then azeotroped with xylene to give the title compound, 2.3 g, 98% yield.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9](Cl)=[CH:8][CH:7]=1)=[O:5].[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN1CCCC1=O>[C:18]1([S:24][C:9]2[CH:10]=[CH:11][C:6]([C:4](=[O:5])[C:3]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:2]=3[OH:1])=[CH:7][CH:8]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(O)cc1O
Reactant: Sc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(Sc2ccccc2)cc1)c1ccc(O)cc1O
Yield: 42.8 %

Procedure:
A mixture of 39 g (156 mmol) of 2,4-dihydroxy-4′-chlorobenzophenone, 22.4 g (204 mmol) of thiophenol and 26 g (188 mmol) of potassium carbonate is stirred in 300 ml of N-methyl-2-pyrrolidone for 24 hours at a temperature of 210° C. After cooling the reaction mixture is neutralized with hydrochloric acid (10%) and extracted with 4×250 ml of ethyl acetate. The solution so obtained is washed with water and afterwards with a saturated solution of sodium chloride. The residue which is obtained, after drying over anhydrous magnesium sulfate, filtration and evaporation of the solvent is subjected to chromatography on silica gel (ethyl acetate/hexane 1:5). The product is recrystallized from ethyl acetate/hexane. 21.5 g of the compound are obtained as yellow crystals with a melting point of 117-118° C.
Reaction SMILES: [C:1]1([C@@H:7]([N:9]2[C:13]3[CH2:14][O:15][C:16](=[O:17])[C:12]=3[NH:11][C:10]2=[O:18])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.[Pd]>[C:1]1([C@@H:7]([N:9]2[C@H:13]3[CH2:14][O:15][C:16](=[O:17])[C@H:12]3[NH:11][C:10]2=[O:18])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](c1ccccc1)n1c2c([nH]c1=O)C(=O)OC2
Agent: [Pd]
Solvent: CC(=O)O
Product: C[C@@H](c1ccccc1)N1C(=O)N[C@@H]2C(=O)OC[C@@H]21
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.6 %

Procedure:
A solution of 3.7 g (15.16 mmol) of 1-[(S)-(1-phenylethyl)]-1H-furo-[3,4-d]-imidazol-2,4(3H,6H)-dione in 100 ml of acetic acid is placed in a 250-ml autoclave and 0.4 g of palladium on activated carbon (5 percent) was added. Then the autoclave was flushed twice successively with hydrogen and filled to 50 bars. This mixture was stirred for 15 hours at room temperature. The catalyst was then filtered off. The solvent was evaporated at 20 mbars and the residue was chromatographed over silica gel with ethyl acetate. 2.0 g (54 percent yield) of the title product was eluted. Recrystallization in methanol yields white needles. Concerning the product:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])[CH:13]=1)[C:8](O)=[O:9])=[O:4].B.C1COCC1.C(O)(=O)C.O>C1COCC1>[OH:9][CH2:8][C:7]1[CH:6]=[C:5]([CH:13]=[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1cc(C(=O)O)cc(N(C)S(C)(=O)=O)c1
Agent: B
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1cc(CO)cc(N(C)S(C)(=O)=O)c1
Temperature: 75 °C
Reaction time: 3 h
Yield: 85.8 %

Procedure:
To a stirring solution of 234 mg of 3-(methoxycarbonyl)-5-(N-methylmethylsulfonamido)benzoic acid in 10 mL of THF at r.t. was added 1.2 mL of BH3.THF (1.0 M in THF). After the solution was stirred at 75° C. for 3 h, 3 mL of acetic acid:H2O (1:1) was added and stirring was continued until bubbling ceased. Saturated NaHCO3 solution was added to a pH=7, and the solution was concentrated. Water was added, and the aqueous layer was extracted with EtOAc (2×). The combined extracts were washed with water and brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (1.5% MeOH/CHCl3) provided 191 mg of methyl 3-(hydroxymethyl)-5-(N-methylmethylsulfonamido)benzoate as a pale yellow oil in 86% yield.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:12]Br.S([O-])([O-])(=O)=S.[Na+].[Na+].CO>C(Cl)Cl>[Br:12][C:11]1[CH:10]=[C:5]([CH:4]=[CH:3][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: BrBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 106.1 %

Procedure:
To a stirred suspension of methyl 4-hydroxybenzoate (180 g, 1183 mmol) in DCM (3 L) was added dropwise bromine (64 mL, 1242 mmol) under nitrogen and at 0° C. and the reaction mixture was left to stir at room temperature for 36 hrs. A solution of sodium thiosulfate (500 mL of a 10% solution) was then added while keeping the temperature around 15° C. followed by addition of MeOH (250 mL). The organic layer was washed with water, then brine, dried over magnesium sulfate, filtered and concentrated to dryness afford methyl 3-bromo-4-hydroxybenzoate (290 g) as a white solid. Mass Spectrum: [M−H]− 229.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH2:11][NH2:12].C(OCC)(=O)C>C(O)C>[NH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:9]=2)[NH:12][N:11]=1
Reactant: NN
Reactant: N#Cc1cc(Br)ccc1F
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1n[nH]c2ccc(Br)cc12
Temperature: 140 °C
Yield: 96.5 %

Procedure:
To a solution of 5-bromo-2-fluorobenzonitrile (0.40 g, 2.0 mmol.) in ethanol (3 mL) was added hydrazine (0.64 g, 20 mmol.). The reaction mixture was heated in a microwave reactor at 140° C. for 20 minutes. Ethyl acetate (100 mL) was added. The organic layer was washed with water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure to yield 3-amino-5-bromoindazole 165 (0.41 g, 1.93 mmol.). The crude product was used in the next step without further purification.
Reaction SMILES: N1C(=O)NC(=O)NC1=O.[CH3:10][C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH2:15])=O>CN(C=O)C>[CH3:10][C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]#[N:15]
Reactant: Cc1ncccc1C(N)=O
Agent: O=c1[nH]c(=O)[nH]c(=O)[nH]1
Solvent: CN(C)C=O
Product: Cc1ncccc1C#N
Reaction time: 2.5 h

Procedure:
Cyanuric acid (418 mg, 2.2 mmol) was added in one portion to a suspension of 2-methyl-nicotinamide (intermediate 29) (613 mg, 4.5 mmol) in 2.5 ml of DMF cooled in ice. The reaction was stirred for 2.5 hours then poured into ice. The reaction was extracted with ethyl acetate until the organic layer no longer contained product. The combined organic layers, were dried over Na2SO4, filtered and concentrated. Purified on normal phase chromatography with ethyl acetate/heptane 0 to 50 gradient then 50/50 EA/heptane. Yield (216 mg, 41%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.78 (s, 3 H), 7.25 (dd, J=7.71, 4.98 Hz, 1 H), 7.89 (dd, J=7.81, 1.56 Hz, 1 H), 8.68 (s, 1 H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1F)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([Cl:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].Cl.Cl.[NH2:25][C@H:26]1[CH2:30][NH:29][CH2:28][C@@H:27]1[OH:31]>>[NH2:25][C@@H:26]1[C@@H:27]([OH:31])[CH2:28][N:29]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([Cl:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:3][C:2]=2[Br:1])[CH2:30]1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(F)c(Br)c1
Reactant: N[C@H]1CNC[C@@H]1O
Agent: Cl
Product: N[C@H]1CN(c2ccc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2Br)C[C@@H]1O

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 1 using 3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-fluorobenzamide (Stage 76.2) and (3S,4S)-4-aminopyrrolidin-3-ol dihydrochloride (Stage 76.3) to give the title product as a beige solid. HPLC (Condition 7) tR=6.08 min, UPLC-MS (Condition 3) tR=0.82 min, m/z=476.1/478.1 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH2:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O1CCOCC1>C(Cl)Cl.O>[NH:15]1[CH2:16][CH2:17][CH2:18][C@@H:13]([CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CNC(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: O=C(NC[C@@H]1CCCNC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
1,1-Dimethylethyl (3S)-3-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-piperidinecarboxylate (·9.3 mmol) was dissolved in DCM (25 mL) and treated with a 4M HCl solution in 1,4-dioxane (24 mL, 96 mmol). The reaction was stirred at room temperature for 3 h, at which time LC/MS indicated that all starting material was consumed. The reaction was concentrated in vacuo to give a thick gum. This material was dissolved in water and extracted with ethyl acetate. The aqueous phase was separated and treated with solid Na2CO3 to bring the pH to ˜10. The product was then extracted into CHCl3 (3×) and the combined organic phases were dried (Na2SO4) and concentrated to yield the desired product as an orange oil (2.3 g, 100% for two steps).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)=[O:4].ON1C2C=CC=CC=2N=N1.[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][NH:28][CH3:29].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][N:28]([CH3:29])[C:11]([C@H:8]1[CH2:7][CH2:6][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]1)=[O:13]
Reactant: CNCCN(C)C
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H](C(=O)N(C)CCN(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
trans-4-(Methoxycarbonyl)cyclohexanecarboxylic acid (8.84 g) obtained in Reference Example 1(2) is dissolved in chloroform (100 ml), and thereto are added 1-hydroxybenzotriazole (7.14 g), 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (10.00 g) and N,N,N′-trimethylethylenediamine (5.33 g) under ice-cooling. The mixture is then stirred at room temperature for 4 hours. Saturated aqueous sodium hydrogen carbonate solution is poured to the reaction solution and the mixture is extracted with chloroform. The organic layer is washed with saturated brine and dried over sodium sulfate. The solvent is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: chloroform/methanol/28% ammonia water=200/10/1) to give methyl trans-4-{[[2-(dimethylamino)ethyl](methyl)amino]carbonyl}-cyclohexanecarboxylate-(11.98 g). APCI-MS M/Z:271[M+H]+
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].C(=O)C1C=CC=CC=1.NC1C=CC=CC=1N>>[N+:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Agent: Nc1ccccc1N
Solvent: O=Cc1ccccc1
Product: O=[N+]([O-])CCc1ccccc1
Yield: 94.5 %

Procedure:
Example 219 A) trans-b-Nitrostyrene (63.0 g, 0.42 mole) was reacted with benzaldehyde (53.4 g, 0.5 mole) and 1,2-diaminobenzene (54.4 g, 0.5 mole) according to the procedure of Chikashita et. al. (Synth. Commun. 1985, 15 (6), 527) to yield (2-nitroethyl)benzene (60.0 g, 95%) as a yellow oil.
Reaction SMILES: Cl.C[C@H]1[C@H](CC2C=CC=CC=2)NC(=N)C1.[N+:16](/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O-:18])=[O:17].C(=O)C1C=CC=CC=1.NC1C=CC=CC=1N>>[N+:16]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Agent: C[C@@H]1CC(=N)N[C@H]1Cc1ccccc1
Agent: Cl
Agent: Nc1ccccc1N
Solvent: O=Cc1ccccc1
Product: O=[N+]([O-])CCc1ccccc1
Yield: 94.5 %

Procedure:
Isomer B: (±) (trans) 4-methyl-5-(phenylmethyl)pyrrolidin-2-imine, monohydrochloride ##STR224## 219 A) trans-b-Nitrostyrene (63.0 g, 0.42 mole) was reacted with benzaldehyde (53.4 g, 0.5 mole) and 1,2-diaminobenzene (54.4 g, 0.5 mole) according to the procedure of Chikashita et. al. (Synth. Commun. 1985, 15 (6), 527) to yield (2-nitroethyl)benzene (60.0 g, 95%) as a yellow oil.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].[I-:11].[Na+].C(=O)([O-])O.[Na+]>CC(C)=O>[I:11][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10]
Reactant: OCCOCCOCCCl
Reactant: [I-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: OCCOCCOCCI
Yield: 80.8 %

Procedure:
A 25 ml reaction flask, equipped with a reflux condenser, an oil bath and a magnetic stirrer was charged with 2 g (11.9 mmol) of 2-[2-(2-chloroethoxy)-ethoxy]-ethanol (Fluka), 4 g of sodium iodide and 3 g of sodium hydrogencarbonate in 20 ml of Acetone. The reaction mixture is refluxed over night and when cold, filtered. The filtrate is concentrated at the rotavap, dissolved in 5 ml of CH2Cl2 and filtered again. Then the filtrate is concentrated again at the rotavap to yield 2.5 g of a yellow oil. The NMR shows a pure substance (CDCl3) 2.58 s broad (1H/OH); 3.22 t (2H/CH2-J); 3.53-3.77 m (10H/CH2—O).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([O:21]C)=[O:20])=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.C[C@H]1NCCN(C(=O)C2C=CC=CC=2)C1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[C@@H]1CN(C(=O)c2ccccc2)CCN1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 7H-indolo[2,1-a][2]benzazepine-10-carboxylate, 13-cyclohexyl, 6-carboxylic acid (200 mg, 0.48 mmol), 3(R)-methyl-1-benzoylpiperazine hydrochloride (130 mg, 0.58 mmol) and triethylamine (0.20 mL) in DMF (3 mL) was added HATU (220 mg, 0.58 mmol). The reaction mixture was stirred at rt for 1 h, diluted with H2O (˜5 mL) stirred for 30 min, and the solids (290 mg) collected by filtration and flushed with H2O. The crude solids were dissolved into MeOH/THF (1:1, 4 mL) and treated with 1M aqueous NaOH (0.75 mL). The reaction mixture was stirred and heated at 80° C. with microwave irradiation for 15 min in a sealed tube. The clear solution was diluted with H2O (5 mL), neutralized with 1M aqueous HCl (0.75 mL) and concentrated to remove organic solvents. The resultant solids were collected by filtration, washed with H2O and dried under vacuum to yield 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 6-[[(2R)-4-benzoyl-2-methyl-1-piperazinyl]carbonyl]-13-cyclohexyl (257 mg, 0.44 mol, 90%). LCMS: m/e 586 (M−H)−, ret time 1.48 min, column A, 2 minute gradient.
Reaction SMILES: Br[C:2]1[C:3](=[O:35])[N:4]([CH2:19][C@H:20]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5](=[O:18])[N:6]([CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:7]=1[CH3:8].[F:36][C:37]1[C:42]([O:43][CH3:44])=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O>C1C=CC=CC=1.CCO.COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:31]([O:30][C:28]([NH:27][C@H:20]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:19][N:4]1[C:3](=[O:35])[C:2]([C:38]2[CH:39]=[CH:40][CH:41]=[C:42]([O:43][CH3:44])[C:37]=2[F:36])=[C:7]([CH3:8])[N:6]([CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:5]1=[O:18])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: COc1cccc(B(O)O)c1F
Reactant: Cc1c(Br)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)C2CCCCC2)c(=O)n1Cc1c(F)cccc1F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: COCCOC
Solvent: CCO
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3F)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)C3CCCCC3)c2=O)c1F
Temperature: 80 °C
Yield: 32.3 %

Procedure:
5-Bromo-3-[2(R)-tert-butoxycarbonylamino-2-cyclohexylethyl]-1-[2,6-difluorobenzyl]-6-methyl-pyrimidine-2,4(1H,3H)-dione 4b (1.0 g, 1.79 mmol) in benzene/EtOH/ethylene glycol dimethyl ether (20/2/22 mL) was added 2-fluoro-3-methoxyphenylboronic acid (382 mg, 2.24 mmol) and saturated Ba(OH)2/water (˜0.5 M, 15 mL). The reaction mixture was deoxygenated with N2 for 10 minutes, tetrakis(triphenylphosphine) palladium (0) (208 mg, 0.18 mmol) was added and the reaction mixture was heated at 80° C. overnight under N2. The reaction mixture was partitioned between brine and EtOAc. The organic layer was dried (sodium sulfate), evaporated, and purified by flash chromatography (silica, 30% EtOAc/hexanes) to give compound 4c (348 mg, 32.3%). MS (CI) m/z 502.2 (MH+-Boc).
Reaction SMILES: Br[C:2]1[C:3](=[O:35])[N:4]([CH2:19][C@H:20]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5](=[O:18])[N:6]([CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:7]=1[CH3:8].[F:36][C:37]1[C:42]([O:43][CH3:44])=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCO.COCCOC>[C:31]([O:30][C:28]([NH:27][C@H:20]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:19][N:4]1[C:3](=[O:35])[C:2]([C:38]2[CH:39]=[CH:40][CH:41]=[C:42]([O:43][CH3:44])[C:37]=2[F:36])=[C:7]([CH3:8])[N:6]([CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:5]1=[O:18])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: COc1cccc(B(O)O)c1F
Reactant: Cc1c(Br)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)C2CCCCC2)c(=O)n1Cc1c(F)cccc1F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCO
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3F)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)C3CCCCC3)c2=O)c1F
Temperature: 80 °C
Yield: 32.3 %

Procedure:
5-Bromo-3-[2(R)-tert-butoxycarbonylamino-2-cyclohexylethyl]-1-[2,6-difluorobenzyl]-6-methyl-pyrimidine-2,4(1H,3H)-dione 11b (1.0 g, 1.79 mmol) in bezene/EtOH/ethylene glycol dimethyl ether (20/2/22 mL) was added 2-fluoro-3-methoxyphenylboronic acid (382 mg, 2.24 mmol) and saturated Ba(OH)2/water (˜0.5 M, 15 mL). The reaction mixture was deoxygenated with N2 for 10 minutes, tetrakis(triphenylphosphine) palladium (0) (208 mg, 0.18 mmol) was added and the reaction mixture was heated at 80° C. overnight under N2. The reaction mixture was partitioned between brine and EtOAc. The organic layer was dried (sodium sulfate), evaporated, and purified by flash chromatography (silica, 30% EtOAc/hexanes) to give compound 11c (348 mg, 32.3%). MS (CI) m/z 502.2 (MH+−Boc).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH:8]1[CH2:13][CH2:12][N:11](C(OCC)=O)[CH2:10][CH2:9]1.[OH-].[K+]>CC(O)C>[NH:11]1[CH2:12][CH2:13][CH:8]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:9][CH2:10]1
Reactant: CCOC(=O)N1CCC(Nc2ccccn2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: c1ccc(NC2CCNCC2)nc1

Procedure:
A mixture of 90 parts of ethyl 4-(2-pyridinylamino)-1-piperidinecarboxylate, 90 parts of potassium hydroxide and 720 parts of 2-propanol is stirred and refluxed for 2 days. The reaction mixture is evaporated. 1000 Parts of water are added to the residue and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane, yielding 13 parts of N-(4-piperidinyl)-2-pyridinamine.