Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=O)[O:5][N:4]=1)[CH3:2].[CH2:13]([N:16]=C=O)[CH2:14][CH3:15].COC1C=C[N+]([O-])=CC=1.O>C1(C)C=CC=CC=1.C(N1C=CN=C1)=C>[CH2:13]([NH:16][C:9](=[O:11])[CH:8]([C:6]1[O:5][N:4]=[C:3]([CH2:1][CH3:2])[N:7]=1)[CH3:12])[CH2:14][CH3:15]
Reactant: CCc1noc(C(C)C(=O)O)n1
Reactant: CCCN=C=O
Agent: C=Cn1ccnc1
Agent: COc1cc[n+]([O-])cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCNC(=O)C(C)c1nc(CC)no1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 47.3 %

Procedure:
Employing anhydrous conditions, 17 mmol of about 90% pure α-(3-ethyl-1,2,4-oxadiazol-5-yl)-propionic acid (=3 ethyl-α-methyl-1,2,4-oxadiazol-5-yl-acetic acid) were dissolved in 40 ml of toluene and about 20.5 mmol of n-propyl-isocyanate and about 60 mg of the catalyst (a saturated solution of 4-methoxy-pyridine-1-oxide.1 H2O in N-vinyl-imidazole) were added to the solution. While a slow stream of nitrogen was continuously passed over the surface, the reaction mixture was stirred for 5.5 hours at room temperature and the reaction mixture was evaporated in vacuo. The residue was dissolved in 100 ml of a 1:1 mixture of ethyl acetate and diethyl ether and this solution was extracted 4 times at pH 2.0 with 10 ml of water. The combined acid washings were extracted once with 10 ml of ethyl acetate and discarded. The two organic layers were combined and extracted 3 times at pH 7.0 with 10 ml of water. The combined washings were extracted once with 10 ml of ethyl acetate and discarded. The combined organic layers were treated with activated carbon, dried over anhydrous magnesium sulfate, filtered and completely evaporated in vacuo. The residue was stirred in 20 ml of n-hexane, whereupon diethyl ether was added slowly till the solid was almost completely dissolved. After filtration, the solution was gradually cooled to -18° C. and the crystalline precipitate was collected by filtration, washed repeatedly with n-hexane and with very cold diethyl ether to obtain 1.7 g (about 50% yield) of N-propyl-α-(3-ethyl-1,2,4-oxadiazol-5-yl)-propionamide with a purity of about 95% (according to TLC and PMR spectrum) and a m.p. of 52°-53° C.
Reaction SMILES: O[CH:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[NH:13][C:14](=[O:29])[C:15]2[C:20]([S:21][CH3:22])=[CH:19][C:18]([C:23]([F:26])([F:25])[F:24])=[CH:17][C:16]=2[O:27][CH3:28])[CH2:3]1.COCCN(S(F)(F)[F:40])CCOC>>[F:40][CH:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[NH:13][C:14](=[O:29])[C:15]2[C:20]([S:21][CH3:22])=[CH:19][C:18]([C:23]([F:26])([F:25])[F:24])=[CH:17][C:16]=2[O:27][CH3:28])[CH2:3]1
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)N[C@@H]1CCCC[C@@H]1N1CCC(O)C1
Reactant: COCCN(CCOC)S(F)(F)F
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)N[C@@H]1CCCC[C@@H]1N1CCC(F)C1

Procedure:
The title compound, light yellow solid, MS: m/e=435.3 [(M+H)+], was prepared in accordance with the general method of example 17 from cis-N-[2-(3-Hydroxy-pyrrolidin-1-yl)-cyclohexyl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (example 24) and bis(2-methoxyethyl)aminosulfur trifluoride. The two diastereomers were not separated.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([N:8]2[CH2:12][CH2:11][CH:10]([C:13]#[N:14])[C:9]2=[O:15])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].I[CH:21]([CH3:23])[CH3:22].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C:10]([CH:21]([CH3:23])[CH3:22])([C:13]#[N:14])[C:9]2=[O:15])=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)I
Reactant: N#CC1CCN(C(=O)c2ccc(F)cc2)C1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C1(C#N)CCN(C(=O)c2ccc(F)cc2)C1=O
Reaction time: 0.08 h

Procedure:
To a solution of 1-(4-fluorobenzoyl)-2-oxopyrrolidine-3-carbonitrile (500 mg) obtained in Step F of Example 1 in N,N-dimethylformamide (5 mL) was added sodium hydride (60% in mineral oil, 130 mg) in an ice bath, and the mixture was stirred at the same temperature for 5 min. To the reaction mixture was added 2-iodopropane (1.1 mL) in an ice bath, and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture was added 10% aqueous citric acid solution in an ice bath, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (310 mg).
Reaction SMILES: [C:1]([C:5]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[C:7]([Cl:15])[C:6]=1[NH:16][C:17]([O:19]C)=O)(OC)=[O:2].C([O-])(=O)C.[NH4+:25]>>[Cl:15][C:7]1[CH:8]=[C:9]([O:13][CH3:14])[C:10]([O:11][CH3:12])=[C:5]2[C:6]=1[NH:16][C:17](=[O:19])[NH:25][C:1]2=[O:2]
Reactant: [NH4+]
Reactant: COC(=O)Nc1c(Cl)cc(OC)c(OC)c1C(=O)OC
Agent: CC(=O)[O-]
Product: COc1cc(Cl)c2[nH]c(=O)[nH]c(=O)c2c1OC
Temperature: 128 °C
Yield: 48.7 %

Procedure:
A mixture of 1.21 g (4.0 mmol) of methyl 2-carbomethoxy-6-chloro-3,4-dimethoxybenzenecarbamate and 3.17 g (20 mmol) of ammonium acetate was prepared and heated to 128° C. A solution was obtained and after one hour a white solid precipitated. The reaction mixture was cooled to room temperature, 25 mL of water was added, and the reaction mixture was cooled to 5° C. The product was filtered and washed with 2×5 mL of distilled water and 1×10 mL of methanol. Drying under vacuum gave 500 mg (49%) of white product, mp 286°-289° C. NMR (TFA) δ 4.02 (s, 3H, OCH3), 4.12 (s, 3H, OCH3), 7.60 (s, 1H, ArH), 9.68 (br s, 1H, NH).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].Cl.[CH3:14][NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>>[CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[C:10]([N:15]([CH3:14])[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[NH:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CNc1cccc2ccccc12
Reactant: CCc1cccc(N(C)C#N)c1
Agent: Cl
Product: CCc1cccc(N(C)C(=N)N(C)c2cccc3ccccc23)c1
Reaction time: 14 h

Procedure:
In a 5 ml round bottom flask was placed N-(3-ethylphenyl)-N-methylcyanamide (340 mg, 2.18 mmol), N-methyl-1-naphthylamine hydrochloride (440 mg, 2.28 mmol) and a stir bar. The flask was evacuated via aspirator and flushed with N2. This was immediately placed in a preheated 160° C. oil bath and allowed to stir under N2 for 14 h. The resultant brown glass was dissolved in methanol (5 ml) and diluted with hot distilled water (20 ml). This solution was basified with 0.1N NaOH (25 ml) and extracted with CHCl3 (5×20 ml) to yield a brown oil upon drying (540 mg). A TLC of this brown oil showed a mixture of reactants and product. Reactants were eluted by column chromatography with benzene. The product was eluted with benzene/EtOH 2:1 (TLC Rf =0.09, CHCl3 :EtOH, 1:1) to afford a pale yellow oil, 380 mg (56%). IR (neat) 3323 (--NH), 1690-1570 (broad, --C=NH). 1H-NMR (CDCl3) δ 1.02 (t, 3H, J=7.5), 2.35 (q, 2H, J=7.5), 2.96 (s, 3H), 3.27 (s, 3H), 5.70 (broad s, 1H), 6.45-7.73 (m, 11H, H-aromat). 13C-NMR (CDCl3) CN3, 163.4; Ar, 145.9, 144.4, 142.5, 134.0, 129.7, 128.2, 127.8, 125.9, 125.5, 125.3, 125.1, 123.6, 123.1, 123.0, 122.5, 120.8; NCH3, 40.1; N'CH3, 39.4; CH2, 28.2; CH3, 15.0. Mass Spec. m/e calcd for C21H23N3, 317.1892, Found, 317.1881.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][C:11]=1[C:18]1(OC)[CH2:22][CH2:21][CH2:20][CH2:19]1.[Cl:25]CC1C=CC(C2C(F)=CN=C(OC)C=2)=C(C2C(C)(C)CCC=2)C=1.CC1(C)C(C2C=C(CO)C=CC=2C2C(F)=CN=C(OC)C=2)=CCC1>>[Cl:25][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])=[C:11]([C:18]2[CH2:22][CH2:21][CH2:20][CH:19]=2)[CH:12]=1
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C2(OC)CCCC2)c1
Reactant: COc1cc(-c2ccc(CCl)cc2C2=CCCC2(C)C)c(F)cn1
Agent: COc1cc(-c2ccc(CO)cc2C2=CCCC2(C)C)c(F)cn1
Product: COc1ccc(F)c(-c2ccc(CCl)cc2C2=CCCC2)c1

Procedure:
Compound 66.68G was synthesized from 66.68F using a method analogous to the method used to prepare compound 66.12D from 66.12C. MS ESI m/e: 317.1 (M+1)+.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][C@H:9]([CH3:22])[C:8]1=[CH:7][C:6](=[O:23])[CH2:5][CH2:4]2.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.S([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[CH3:22][C@@H:9]1[C:8]2[C@:3]([CH:2]=[O:1])([CH2:4][CH2:5][C:6](=[O:23])[CH:7]=2)[C@@H:20]2[C@H:11]([C@H:12]3[C@@:16]([CH2:18][CH2:19]2)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]3)[CH2:10]1
Reactant: C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(CO)CCC(=O)C=C12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C=O)CCC(=O)C=C12
Temperature: 40 °C
Reaction time: 5 h

Procedure:
To a solution of 19-hydroxy-6α-methyl-4-androstene-3,17-dione in dimethylformamide at 40° C. is rapidly added one equivalent of Jones Reagent. The solution is stirred for about 5 hours at 40° C., cooled and a 1% aqueous sodium sulfite solution is added. The precipitate which forms is collected, washed well with water and crystallized from ether-hexane to yield 6α-methyl-4-androstene-3,17,19-trione.
Reaction SMILES: S(O[CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.BrCC1CCCCO1.[NH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]2([C:54]3[C:45](=[CH:46][C:47]4[O:52][CH2:51][CH2:50][O:49][C:48]=4[CH:53]=3)[O:44][CH2:43]2)[C:35]1=[O:55].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[O:55]=[C:35]1[C:36]2([C:54]3[C:45](=[CH:46][C:47]4[O:52][CH2:51][CH2:50][O:49][C:48]=4[CH:53]=3)[O:44][CH2:43]2)[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:34]1[CH2:12][CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:17][CH2:18]1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: CC(C)(C)OC(=O)N1CCC(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)CC1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using tert-butyl 4-(tosyloxymethyl)piperidine-1-carboxylate to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, tert-butyl 4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]piperidine-1-carboxylate was obtained (99%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.34-7.26 (m, 1H), 7.14-7.19 (m, 1H), 7.08-7.01 (m, 1H), 6.88 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.19 (s, 1H), 4.87 (d, J=9.0 Hz, 1H), 4.62 (d, J=9.0 Hz, 1H), 4.23-4.06 (m, 6H), 3.80-3.44 (m, 2H), 2.76-2.59 (m, 2H), 2.11-1.93 (m, 1H), 1.74-1.60 (m, 2H), 1.45 (s, 9H), 1.37-1.20 (m, 2H).
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH2:10]1)(C)(C)C.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31].O>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[CH2:22]([O:21][C:18]1[CH:17]=[CH:16][C:15]([CH:11]2[O:12][CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:6]([OH:29])=[O:5])[CH2:10]2)=[CH:20][CH:19]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(OCc3ccccc3)cc2)C1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCN1CCOC(c2ccc(OCc3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude 3-{2-[4-(benzyloxy)-phenyl]morpholin-4-yl}-propionic acid tert-butyl ester (see §3) was treated with a mixture of TFA, water, and CH2Cl2 (30:3:67; 3 mL) and stirred at RT for 2 h. Subsequently, the volatiles were removed in vacuo, and the crude product was purified by preparative HPLC to afford 3-{2-[4-(benzyloxy)-phenyl]-morpholin-4-yl}-propionic acid trifluoroacetic acid salt; Rt=1.86 min. (System A), [M+H]+ Found: 342.19; Calc: 342.17. Conditions for the preparative LC-MS: Injection of the crude product dissolved in 600 L DMSO/CH3CN 1:2; column Waters Sunfire 19×100 mm 5 μm 45° C., mobile phase water/CH3CN/TFA 0.1% 25 mL/min, run 20 min 10%-90% CH3CN, detection with UV 210-260 nm.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:11]=[CH:12][C:13]([N:16]([CH3:18])[CH3:17])=[N:14][CH:15]=3)[O:9][C:5]=2[CH:4]=1.Br.C(=O)(O)[O-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:17][N:16]([CH3:18])[C:13]1[N:14]=[CH:15][C:10]([C:8]2[O:9][C:5]3[CH:4]=[C:3]([OH:2])[CH:20]=[CH:19][C:6]=3[N:7]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc2nc(-c3ccc(N(C)C)nc3)oc2c1
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Product: CN(C)c1ccc(-c2nc3ccc(O)cc3o2)cn1
Reaction time: 0.08 h
Yield: 19.6 %

Procedure:
5-(6-Methoxy-1,3-benzoxazol-2-yl)-N,N-dimethylpyridin-2-amine (31 mg, 0.12 mmol) was mixed with hydrogen bromide (48% aq., 2 mL) and a crystal of tetrabutylammonium bromide was added. The reaction was run at 120° C. for 5 minutes in a microwave reactor. The reaction mixture was added to sodium bicarbonate (sat. aq.) and the solid was collected. The solid was then dissolved in CH2Cl2/ethyl acetate, dried (MgSO4), filtered and evaporated in vacuo, giving the title compound (6 mg) as a purple solid. 1H NMR (400 MHz, CD3OD) δ ppm 8.83 (d, 1H) 8.17 (dd, 1H) 7.44 (d, 1H) 7.02 (d, 1H) 6.75-6.88 (m, 2H) 3.19 (s, 6H); MS m/z (M+H) 256; (M−H) 254.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][NH2:34]>>[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][NH:34][C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1nccc(-c2cnc3c(NCCN4CCOCC4)nccn23)n1
Reactant: NCc1cccc(Cl)c1
Product: Clc1cccc(CNc2nccc(-c3cnc4c(NCCN5CCOCC5)nccn34)n2)c1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
The mixture of [3-(2-methanesulfonyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 50 supra) (200 mg, 0.50 mmol) and 3-chlorobenzylamine (281 mg, 1.99 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1˜20:1) to afford the crude product (125 mg). Then the crude product was purified by prep-HPLC. Several drops of concentrated HCl were added to the fractions with product. After sonicating for several minutes, solution was concentrated under reduced pressure to afford {3-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-(2-morpholin-4-yl-ethyl)-amine; hydrochloride. (Yield 60 mg, 26.0%). 1H NMR (300 MHz, CD3OD): δ 8.71 (s, 1H), 8.42 (s, 1H), 8.38 (s, 1H), 7.59 (d, 1H, J=6.6 Hz), 7.49-7.28 (m, 5H), 4.87 (brs, 2H), 4.16 (brs, 2H), 3.93 (brs, 4H), 3.58-3.28 (m, 5H). LC-MS: [M+H]+ 466.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[Li].BrC1C(F)=CC=CC=1F>>[NH2:15][C:7]1[C:6]([C:4]([C:19]2[C:18]([F:17])=[CH:23][CH:22]=[CH:21][C:20]=2[F:24])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: [Li]c1c(F)cccc1F
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Agent: Fc1cccc(F)c1Br
Product: CCSc1ncc(C(=O)c2c(F)cccc2F)c(N)n1
Yield: 70 %

Procedure:
The same procedure was used as described in Example 2, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methylamide (200 mg, 0.830 mmol, Example 1) and a solution of 2,6-difluorophenyl lithium (˜3 equiv, freshly prepared from 1-bromo-2,6-difluorobenzene (Aldrich), as in Example 2A), to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2,6-difluoro-phenyl)-methanone as a white solid (170 mg, 70% yield). HRMS, observed:296.0667; Calcd for (M+H)+: 296.0664.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:10]2[C:11]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18][C:12]=3[NH:13][C:14]=2[CH:15]=[CH:16][CH:17]=1.C(Cl)Cl>C(C(O)=O)(F)(F)F>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:10]2[C:11]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18][C:12]=3[NH:13][C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cccc(-c4c(F)cccc4F)c3c2CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cccc(F)c1-c1cccc2[nH]c3c(c12)CCNCC3
Yield: 87.2 %

Procedure:
tert-Butyl 10-(2,6-difluorophenyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.700 g, 1.76 mmol) was dissolved in CF3CO2H (4 mL) and CH2Cl2 (14 mL) and the reaction mixture was stirred at rt for 3 h. The reaction mixture was cooled in an ice bath and quenched with cold 1N NaOH (100 mL). The resulting mixture was extracted with 3% CH3OH in CH2Cl2 (3×50 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude product (0.51 g) was chromatographed (SiO2 30 g, eluted with 90:10:1 CH2Cl2:CH3OH:conc. NH4OH) to yield 10-(2,6-difluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.458 g) in 87% yield. 1H NMR (400 MHz, Acetone-d6) δ 2.35-2.38, 2.74-2.77, 2.95-2.98, 6.84, 7.08, 7.12, 7.36, 7.50; MS (ESI+) for C18H16F2N2 m/z 299.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](N(OC)C)=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([Mg]Br)[CH2:23][CH3:24]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16](=[O:17])[CH2:22][CH2:23][CH3:24])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CCC[Mg]Br
Solvent: C1CCOC1
Product: CCCC(=O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-(4-benzyloxy-phenyl)-N-methoxy-N-methyl-acetamide (10.51 mmol, 3.0 g) in anhydrous THF at 0° C. was added n-propyl magnesium bromide (2.0 M solution in THF, 20 mL) drop-wise over 30 min. After completion of addition, the reaction mixture was warmed to room temperature and stirred for 30 min. The reaction mixture was cooled to 0° C. and quenched by adding saturated aqueous NH4Cl drop-wise followed by addition of ethyl acetate. The organic layer was separated, dried, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography by eluting with 5% ethyl acetate in hexanes to provide 1-(4-benzyloxy-phenyl)-pentan-2-one.
Reaction SMILES: [C:1]([C:8]([O:10]CC)=O)#[C:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:25]=[C:24]([NH2:26])[NH:23][N:22]=2)=[CH:17][CH:16]=1.C(OCC)(=O)C>C(O)(=O)C>[OH:10][C:8]1[N:23]2[N:22]=[C:21]([C:18]3[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)[CH:25]=[C:24]2[N:26]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:1]=1
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: COc1ccc(-c2cc(N)[nH]n2)cc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(O)n2nc(-c3ccc(OC)cc3)cc2n1
Reaction time: 3 h

Procedure:
Diethyl acetylenedicarboxylate (883 μL, 5.6 mmol) was added to a solution of 3-(4-methoxyphenyl)-1H-pyrazol-5-amine (1.1 g, 5.6 mmol) in acetic acid (5 mL). The very thick mixture was allowed to stand at room temperature with occasional stirring for 3 h. Ethyl acetate (5 mL) and hexanes (15 mL) were added and the precipitate was filtered, and dried under high vacuum. Yield: 1.26 g (76%); LCMS m/z 314.1 (M+H)+, ret. time=2.25 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:33])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[O:26])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[O:34]1[CH2:39][CH2:38][CH:37]([C:40](Cl)=[O:41])[CH2:36][CH2:35]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:33])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:40]([CH:37]4[CH2:38][CH2:39][O:34][CH2:35][CH2:36]4)=[O:41])[CH2:29][CH2:28]3)=[O:26])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CCOCC1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCNCC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCN(C(=O)C3CCOCC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 73, the title compound rac-{(3R,4S)-4-(3,4-dichloro-phenyl)-1-[1-(tetrahydro-pyran-4-carbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using tetrahydro-2H-pyran-4-carbonyl chloride instead of propionyl chloride and was obtained as a white foam. MS m/e: 606.3 [M]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][N:13]=1)[C:7]([O:9]C)=O)([O-:3])=[O:2].[CH2:14]([NH2:16])[CH3:15]>>[CH2:14]([NH:16][C:7](=[O:9])[C:6]1[CH:11]=[CH:12][N:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:15]
Reactant: CCN
Reactant: COC(=O)c1ccnc([N+](=O)[O-])c1
Product: CCNC(=O)c1ccnc([N+](=O)[O-])c1

Procedure:
A mixture of 500 mg. of methyl 2-nitroisonicotinate and 2 ml. of 70% ethylamine was stirred at room temperature for 5 hours. The reaction mixture was extracted with ethyl acetate. The extract was washed with water, dried and then the solvent was distilled off. The crystalline residue was recrystallized from ethyl acetate-n-hexane to give 328 mg. of the desired product.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[CH3:13].[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CS(C)=O.O>[CH3:9][O:8][C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]([CH3:13])=[C:2]([N:24]2[CH2:23][CH2:22][CH:21]([N:18]3[CH2:17][CH2:16][N:15]([CH3:14])[CH2:20][CH2:19]3)[CH2:26][CH2:25]2)[CH:7]=1
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: COc1cc(F)c(C)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)c(C)cc1[N+](=O)[O-]

Procedure:
1-Fluoro-5-methoxy-2-methyl-4-nitrobenzene (INTERMEDIATE 7, 0.370 g, 2.00 mmol), 1-methyl-4-(piperidin-4-yl)piperazine (0.367 g, 2.00 mmol), and potassium carbonate (0.415 g, 3.00 mmol) in DMSO (2.0 mL) were stirred at 80° C. for 15 h. DCM (20 mL) and water (20 mL) were added to the reaction mixture. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the title product. (0.640 g, 92%).