Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]=O.[C:14]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:15]>C(#N)C>[NH2:15][C:14]1[CH:16]=[CH:12][C:3]2[C:4](=[O:11])[N:5]([CH3:10])[C:6](=[O:9])[N:7]([CH3:8])[C:2]=2[N:1]=1
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1c(N)c(C=O)c(=O)n(C)c1=O
Solvent: CC#N
Product: Cn1c(=O)c2ccc(N)nc2n(C)c1=O
Yield: 39.5 %

Procedure:
0.18 g of 6-amino-5-formyl-1,3-dimethyluracil and 0.45 g of cyanomethylenetriphenylphosphorane were added to 20 ml of dried acetonitrile. The solution was heated under reflux for 12 hr in a stream of argon. After cooling, the precipitated crystal was separated by filtration to give 0.08 g of 7-amino-1,3-dimethylpyrido[2,3-d]pyrimidine-2,4-dione (Compound 15).
Reaction SMILES: CI.[Mg].[CH3:4][C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.Cl.Cl[CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[Cl-].[NH4+]>CCOCC.O>[CH3:4][C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: Cc1cc2ccccc2[nH]1
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: CI
Solvent: O
Product: Cc1[nH]c2ccccc2c1Cc1ccncc1

Procedure:
Methyl iodide (32.0 g) in dry ether (100 ml) was added dropwise to a stirred mixture of magnesium and dry ether (50 ml) at such a rate that the reaction was not too vigorous. After completion of the addition the mixture was heated under reflux for 30 minutes and then cooled to 0°. A solution of 2-methylindole (16.9 g) in dry ether (100 ml) was added dropwise with stirring and the resulting mixture was then heated under reflux for 1.5 hours. It was then cooled to 0° and 4-chloromethyl pyridine hydrochloride (10.5 g) was added portionwise with stirring. The mixture was heated under reflux with stirring for 3 hours and then cooled. A solution of ammonium chloride (30 g) in water (200 ml) was added dropwise with stirring and then the layers were separated. The ether layer was dried (Na2SO4) and evaporated to give an oil which was chromatographed on silica gel. Elution with chloroform initially gave some impurity together with the starting indole. Further elution gave 2-methyl-3-(4-pyridylmethyl)indole (8.0 g), m.p. 126°-127° C. (from ether).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:7][N:6]([CH3:8])[C:5]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH2:4]1.[H-].[Na+].[CH3:24]I.O>O1CCCC1>[CH3:24][O:1][CH2:2][CH:3]1[O:7][N:6]([CH3:8])[C:5]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)([CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH2:4]1
Reactant: CN1OC(CO)CC1(Cn1ccnc1)c1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCC1CC(Cn2ccnc2)(c2ccc(Cl)cc2)N(C)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-(Hydroxymethyl)-3-(4-chlorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine (3: R1 =4-Cl, R2 =H) 2.50 g, 8 mmol) is added to a suspension of 1.32 g (24 mmol) of 50% by weight sodium hydride in 50 ml anhydrous tetrahydrofuran, at 0° C. under a nitrogen atmosphere. After stirring for 1 hour at 0° C., 1.28 g (9 mmol) of methyl iodide is added and the resulting suspension is heated to reflux and stirred for 20 hours. Upon cooling to room temperature, the reaction mixture is poured into 100 ml of water and then extracted with chloroform (3×75 ml). The combined organic extracts are dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure. The crude residue is flash-chromatographed on neutral silica gel using chloroform-methanol (98:2 by volume) as eluent. Following crystallization from ethyl acetate, 1.67 g (64%) of compound 3 (R1 =4-Cl, R2 =CH3) are obtained, mp 123°-126° C.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[C:53]([O:54][CH2:55][CH2:56][CH2:57][O:58][C:59]2[C:60]([O:96][CH3:97])=[CH:61][C:62]3[C:68](=[O:69])[N:67]4[CH:70]=[C:71]([C:73]5[CH:78]=[CH:77][C:76]([N:79]6[CH2:84][CH2:83][N:82]([CH3:85])[CH2:81][CH2:80]6)=[CH:75][CH:74]=5)[CH2:72][C@H:66]4[C:65](=[O:86])[N:64]([CH2:87][O:88][CH2:89][CH2:90][Si:91]([CH3:94])([CH3:93])[CH3:92])[C:63]=3[CH:95]=2)=[CH:52][C:12]2[N:13]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[C:14](=[O:43])[C@@H:15]3[CH2:21][C:20](/[CH:22]=[CH:23]/[CH2:24][NH:25]C(=O)OCC4C5C=CC=CC=5C5C4=CC=CC=5)=[CH:19][N:16]3[C:17](=[O:18])[C:11]=2[CH:10]=1>CN(C=O)C.C(Cl)Cl>[NH2:25][CH2:24]/[CH:23]=[CH:22]/[C:20]1[CH2:21][C@H:15]2[C:14](=[O:43])[N:13]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:50])([CH3:51])[CH3:49])[C:12]3[CH:52]=[C:53]([O:54][CH2:55][CH2:56][CH2:57][O:58][C:59]4[C:60]([O:96][CH3:97])=[CH:61][C:62]5[C:68](=[O:69])[N:67]6[CH:70]=[C:71]([C:73]7[CH:74]=[CH:75][C:76]([N:79]8[CH2:84][CH2:83][N:82]([CH3:85])[CH2:81][CH2:80]8)=[CH:77][CH:78]=7)[CH2:72][C@H:66]6[C:65](=[O:86])[N:64]([CH2:87][O:88][CH2:89][CH2:90][Si:91]([CH3:92])([CH3:94])[CH3:93])[C:63]=5[CH:95]=4)[C:9]([O:8][CH3:7])=[CH:10][C:11]=3[C:17](=[O:18])[N:16]2[CH:19]=1
Reactant: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(N5CCN(C)CC5)cc4)C[C@H]1C(=O)N3COCC[Si](C)(C)C)N(COCC[Si](C)(C)C)C(=O)[C@@H]1CC(/C=C/CNC(=O)OCC3c4ccccc4-c4ccccc43)=CN1C2=O
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(N5CCN(C)CC5)cc4)C[C@H]1C(=O)N3COCC[Si](C)(C)C)N(COCC[Si](C)(C)C)C(=O)[C@@H]1CC(/C=C/CN)=CN1C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Piperidine (0.40 mL, 4.0 mmol, 14.2 eq.) was added to a stirred solution of Fmoc amine 14e (0.358 g, 0.282 mmol, 1.0 eq.) in DMF (5.0 mL). The clear solution was stirred at room temperature for 30 minutes. The reaction mixture was diluted with DCM (300 mL) and washed with water (3×300 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to afford the crude product which did not undergo further purification (0.296 g, assumed 100% yield). LC/MS (2.049 min (ES+)), m/z: 1051.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:5]2[CH:6]=[C:7]([C@@:11]3([CH3:16])[CH2:15][CH2:14][CH2:13][NH:12]3)[NH:8][C:9]=2[CH:10]=1.CC#N.[CH3:24][O:25][C:26](=[O:29])[CH2:27]Br.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:5]2[CH:6]=[C:7]([C@@:11]3([CH3:16])[CH2:15][CH2:14][CH2:13][N:12]3[CH2:27][C:26]([O:25][CH3:24])=[O:29])[NH:8][C:9]=2[CH:10]=1
Reactant: COC(=O)CBr
Reactant: COC(=O)c1cc(F)cc2[nH]c([C@@]3(C)CCCN3)cc12
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN1CCC[C@]1(C)c1cc2c(C(=O)OC)cc(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 63.9 %

Procedure:
To a stirred mixture of (R)-methyl 6-fluoro-2-(2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate (1.0, 1.27 mol), CH3CN (50 ml) and methylbromoacetate (0.58 g, 3.82 mmol) was added DIPEA (0.82 g, 6.35 mmol). The reaction mixture was stirred at room temperature for about 20 hours. The reaction mixture was then diluted with CH2Cl2 (15 ml) and washed with water three times. The organic layer was dried with MgSO4 and concentrated to give 0.85 g of (R)-methyl 6-fluoro-2-(1-(2-methoxy-2-oxoethyl)-2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate. 1H NMR (CD3OD-d4) δ 7.47 (dd, 1H, J=2.4, 12.0 Hz), 7.27 (dd, 1H, J=2.4, 9.0 Hz), 6.89 (s, 1H), 3.95 (s, 3H), 3.66-3.68 (m, 1H), 3.64 (s, 3H), 3.16-3.17 (m, 2H), 2.72-2.75 (m, 1H), 1.88-2.02 (m, 4H), and 1.44 (s, 3H). MS (ESI) m/e [M+1]+ 349.0.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][NH2:22].[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:22][CH2:21][CH2:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[F:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1ccccc1F
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
0.38 ml of 4-tert-butylbenzaldehyde (2.25 mmol) and 0.200 ml 2-(2-fluoro-phenyl)-ethyl-amine (1.5 mmol) were dissolved in 4.5 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2.5 h. After cooling down to rt, 85 mg (2.25 mmol) sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was then refluxed for 3 h. After cooling down to rt, the reaction mixture was treated with 4 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:2) to give 280 mg light yellow oil (65%). MS (ISP) 286.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:20](F)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.CS(O)(=O)=O.CS(O)(=O)=O.[NH2:32][CH:33]1[CH2:36][NH:35][C:34]1([CH3:38])[CH3:37]>>[NH2:32][CH:33]1[CH2:36][N:35]([C:20]2[C:2]([F:1])=[CH:3][C:4]3[C:5]([CH:19]=2)=[N:6][C:7]2[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=2[CH:13]=3)[C:34]1([CH3:38])[CH3:37]
Reactant: CC1(C)NCC1N
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Agent: CS(=O)(=O)O
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CC(N)C4(C)C)cc3nc21
Temperature: 100 °C
Reaction time: 5 h
Yield: 32.4 %

Procedure:
(RS)-8-(3-Amino-2,2-dimethyl-1-azetidinyl)-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid was prepared under the conditions described in Example 15, but starting with 1.45 g of 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo-[b][1,8]naphthyridine-3-carboxylic acid and 2.33 g of 3-amino-2,2-dimethylazetidine dimethanesulphonate. The reaction mixture is heated with stirring to approximately 100° C. for 5 hours. 0.6 g of (RS)-8-(3-amino-2,2-dimethyl-1-azetidinyl)-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a yellow solid, which decomposes at 285° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[CH2:29]([N:31]([CH2:35][CH3:36])[CH2:32][CH2:33][NH2:34])[CH3:30]>>[CH2:29]([N:31]([CH2:35][CH3:36])[CH2:32][CH2:33][NH:34][C:3]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])=[CH:8][CH:9]=1)=[O:2])[CH3:30]
Reactant: CCN(CC)CCN
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1
Product: CCN(CC)CCNC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1
Yield: 76 %

Procedure:
By the same procedure as described in the example 45, synthesis was carried out starting with 4-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid methyl ester and using N,N-diethylethylenediamine. Then, the product was recrystallized using isopropanol and hexane to give the desired compound.
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[C:34]([C:40]([F:43])([F:42])[F:41])[CH:33]=1.Cl>CC(N(C)C)=O>[CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10](=[O:23])[N:9]([CH2:36][C:35]3[CH:38]=[CH:39][C:32]([F:31])=[CH:33][C:34]=3[C:40]([F:42])([F:41])[F:43])[C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Fc1ccc(CBr)c(C(F)(F)F)c1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)n(Cc2ccc(F)cc2C(F)(F)F)c1=O
Reaction time: 8 h
Yield: 37.8 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles) and 4-fluoro-2-trifluoromethylbenzyl bromide (455 mg, 1.77 mmoles) in dimethylacetamide (6 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The combined organic solutions were washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (3.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Recrystallization from hexane gave the title compound (184 mg, 38%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.10 (br. s., 1 H), 10.11 (br. s., 1 H), 7.67 (dd, J=9.09, 2.78 Hz, 1 H), 7.45 (ddd, J=8.40, 2.65 Hz, 1 H), 7.29 (dd, J=8.59, 5.31 Hz, 1 H), 5.13 (s, 2 H), 4.64 (t, J=12.00 Hz, 1 H), 4.13 (d, J=5.81 Hz, 2 H), 2.24 (q, 2 H), 1.78 (d, J=12.63 Hz, 2 H), 1.53-1.73 (m, 3 H), 1.28 (q, J=12.72 Hz, 2 H), 1.10 (q, J=12.63 Hz, 1 H)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[C:10]([Cl:17])[N:9]=1.C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:17][C:10]1[N:9]=[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: C1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Cl)nc1N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
piperazine (1.38 g) was added to a stirred solution of 2,6-dichloro-3-nitropyridine (3.0 g, prepared according to J. Heterocyclic Chem. 1994, 31, 73) and diisopropylethylamine (3.0 ml) in dichloromethane (100 ml) at 0° C. under N2. The resulting solution was stirred at room temperature for 2 hours then poured into saturated aqueous sodium bicarbonate, extracted with dichloromethane, dried over sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography (ethyl acetate:methanol 8:2) to afford 1-(6-Chloro-3-nitro-pyridin-2-yl)-piperazine (2.99 g) as a red solid. M.p. 50-53° C.; MS (ES+) 243/245 (M+H+).
Reaction SMILES: [CH3:1][CH2:2][CH:3]([C:15]([OH:17])=[O:16])[CH2:4][C:5]1[C:6]([I:14])=[CH:7][C:8]([I:13])=[C:9]([NH2:12])[C:10]=1[I:11].S(Cl)(Cl)=O.O1CC[CH2:24][CH2:23]1.C(O)(=O)C(C)(C)C>C(O)C.C(Cl)Cl>[CH3:1][CH2:2][CH:3]([C:15]([O:17][CH2:23][CH3:24])=[O:16])[CH2:4][C:5]1[C:6]([I:14])=[CH:7][C:8]([I:13])=[C:9]([NH2:12])[C:10]=1[I:11]
Reactant: C1CCOC1
Reactant: CCC(Cc1c(I)cc(I)c(N)c1I)C(=O)O
Agent: CC(C)(C)C(=O)O
Solvent: ClCCl
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(CC)Cc1c(I)cc(I)c(N)c1I
Temperature: 150 °C

Procedure:
2 g (3.5 mmol) of iopanoic acid was dissolved in 50 ml absolute ethanol, and 0.4 ml (5,25 mmol) thionyl chloride was added. The reaction was refluxed for 3 hours. After cooling, the reaction mixture was evaporated and reconstituted in 100 ml methylene chloride. The organic mixture was washed twice with 25 ml 5% NaOH and twice with 25 ml water. The methylene chloride layer was dried over MgSO4 and evaporated to dryness, yielding 1.73 g of ethyliopanoate (82.4%). The structure was provided by 1H nuclear magnetic resonance and mass spectrometry (M+ 599). The radioisotope exchange reaction was carried out using a known procedure with some modification (Zupon, et al., 1983; Kroschwitz, 1989). Briefly, 10 mg of the ester and 0.3 ml of tetrahydrofuran were placed in a vial and treated with 1.6 mCi of [131I]sodium iodide (in 100 μl of 0.1M sodium borate buffer). Pivalic acid (25 mg) was then added. The reaction vial was sealed and heated at 150° C. for 1.5 hours. The vial was cooled and the ethyliopanoate reconstituted in methylene chloride (0.1 ml) and chromatographed on a silica gel column with methylene chloride/methanol (9:1) as the eluent. This yielded 0.54 mCi ethyliopanoate (34%). Radiochemical purity was determined by co-chromatography on a silica gel plate eluted with methylene chloride methanol (9:1); unlabeled ester served as the standard, with a retardation factor of 0.80.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([F:10])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.Br[CH2:12][C:13]([N:15]1[CH2:19][C@@H:18]([F:20])[CH2:17][C@H:16]1[C:21]#[N:22])=[O:14]>>[F:10][C:5]12[CH2:8][CH2:9][C:2]([NH:1][CH2:12][C:13]([N:15]3[CH2:19][C@@H:18]([F:20])[CH2:17][C@H:16]3[C:21]#[N:22])=[O:14])([CH2:7][CH2:6]1)[CH2:3][CH2:4]2
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CBr
Reactant: NC12CCC(F)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(F)(CC1)CC2
Yield: 89.7 %

Procedure:
Using 4-amino-1-fluorobicyclo[2,2,2]octane (50.0 mg) and (2S,4S)-1-(2-bromoacetyl)-4-fluoropyrrolidine-2-carbonitrile (82.1 mg), the same procedure was followed as in Example 10 to obtain (2S,4S)-1-[[N-(4-fluorobicyclo[2,2,2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (93.1 mg).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:19])C(=O)C1.O>C(Cl)(Cl)Cl.CC(O)=O>[Br:19][C:8]1[S:9][CH:10]=[CH:11][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(-c2ccsc2)cc1
Solvent: O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Brc1sccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
3-Phenylthiophene (0.58 g, 3.62 mmol) was dissolved in 15 mL of a 1:1 solution of CHCl3 and AcOH followed by the portion-wise addition of 0.77 g (4.3 mmol) of NBS. The mixture was stirred at room temperature for 1 h, poured into 25 mL of H2O, and diluted with 30 mL of hexanes. The organic layer was washed successively with 2×10 mL of 10% aqueous KOH solution, 2×10 mL of H2O, and 2×10 mL of brine, and concentrated in vacuo to provide 0.68 g (78% yield) of 2-bromo-3-phenylthiophene as an oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3([CH3:17])OCC[O:13]3)=[CH:8][C:7]=2[C:18]2[C:19]3[NH:26][C:25]([CH3:27])=[C:24]([C:28]([NH:30][CH:31]4[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]4)=[O:29])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:3][CH2:2]1.[ClH:44]>CC(C)=O.O1CCOCC1>[ClH:44].[C:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)=[C:7]([C:18]2[C:19]3[NH:26][C:25]([CH3:27])=[C:24]([C:28]([NH:30][CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[O:29])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH:8]=1)(=[O:13])[CH3:17]
Reactant: Cc1[nH]c2c(-c3cc(C4(C)OCCO4)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1

Procedure:
tert-Butyl 4-[({4-[2-(cyclopropylmethoxy)-5-(2-methyl-1,3-dioxolan-2-yl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl}carbonyl)amino]piperidine-1-carboxylate from example D.e55 (1.77 g; 2.99 mmol) is dissolved in dry acetone (30 mL). After addition of 4M HCl in dioxane (3 mL) the stirred mixture is gently refluxed until the starting material is consumed according to LC-MS. At ambient temperature the product is precipitated by addition of tert.-butyl methyl ether, isolated by suction filtration, washed with several portions of tert.-butyl methyl ether and dried in high vacuo at 40° C. to yield 1.40 g of the title compound as pale yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]#[N:12])[N:8]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:7]=1.[C:18]([O:22][C:23]([N:25]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]2[CH:33]=[N:34][C:35]([NH2:38])=[CH:36][CH:37]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]2[CH:33]=[N:34][C:35]([NH:38][C:2]3[N:3]=[CH:4][C:5]4[CH:10]=[C:9]([C:11]#[N:12])[N:8]([CH:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)[C:6]=4[N:7]=3)=[CH:36][CH:37]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: N#Cc1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)nc2)CC1
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(Nc3ncc4cc(C#N)n(C5CCCC5)c4n3)nc2)CC1
Yield: 49.6 %

Procedure:
Following Buchwald Procedure A, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile (95 mg, 0.385 mmol) and 4-(6-amino-pyridin-3-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (124 mg, 0.424 mmol) gave 4-[6-(6-cyano-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (96 mg) [following SiO2 chromatography, eluting with a 1-3% MeOH/dichloromethane and subsequent trituration with a diethyl ether]. The material is used directly in the next step.
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:14]3[CH:25]=[C:24]([CH2:26][CH3:27])[O:23][C:15]=3[C:16]([O:19][CH:20]([F:22])[F:21])=[N:17][CH:18]=2)=[O:12])=CC=1)([O-])=O.[NH2:28][C:29]1[C:36]([Cl:37])=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=1[Cl:38]>>[Cl:37][C:36]1[CH:35]=[C:32]([C:33]#[N:34])[CH:31]=[C:30]([Cl:38])[C:29]=1[NH:28][C:11]([C:13]1[C:14]2[CH:25]=[C:24]([CH2:26][CH3:27])[O:23][C:15]=2[C:16]([O:19][CH:20]([F:21])[F:22])=[N:17][CH:18]=1)=[O:12]
Reactant: CCc1cc2c(C(=O)Oc3ccc([N+](=O)[O-])cc3)cnc(OC(F)F)c2o1
Reactant: N#Cc1cc(Cl)c(N)c(Cl)c1
Product: CCc1cc2c(C(=O)Nc3c(Cl)cc(C#N)cc3Cl)cnc(OC(F)F)c2o1
Yield: 10.7 %

Procedure:
Starting from 7-difluromethoxy-2-ethylfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (100 mg) and 4-amino-3,5-dichlorobenzonitrile (99 mg). Purification by column chromatography on silica eluting with 1% methanol in dichloromethane afforded the title compound as a white solid (12 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:29]([N:31]1[CH2:35][CH2:34][C@H:33]([F:36])[CH2:32]1)=[O:30])[C@H:10]([CH:12]1[CH2:17][CH2:16][CH:15]([NH:18]C(=O)OCC2C=CC=CC=2)[CH2:14][CH2:13]1)[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:29]([N:31]1[CH2:35][CH2:34][C@H:33]([F:36])[CH2:32]1)=[O:30])[C@H:10]([CH:12]1[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]1)[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: C[C@@H](C1CCC(NC(=O)OCc2ccccc2)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Agent: [Pd]
Solvent: CO
Product: C[C@@H](C1CCC(N)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1

Procedure:
To a solution of the slower eluting diastereomer of the material prepared in Step A (0.60 g, 1.2 mmol) in methanol (100 mL) was added 10% palladium on carbon (0.20 g). The mixture was placed under 3 atm of hydrogen gas for 3 h, then filtered through Celite. The solution was then concentrated in vacuo, affording the title compound as a clear oil. LC/MS 372.3 (M+H).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[Cl:11])[N:4]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:3]=1.O.[CH3:22][N:23]1CCN(C)C1=O>[C-]#N.[C-]#N.[Zn+2].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>[Cl:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[N:4]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:3]=[C:2]([C:22]#[N:23])[C:10]=12
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2c(Cl)ccnc21
Reactant: CN1CCN(C)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1cn(S(=O)(=O)c2ccccc2)c2nccc(Cl)c12
Temperature: 140 °C
Reaction time: 1.5 h

Procedure:
To the solution of 3-bromo-4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine in 1,3-dimethyl-2-imidazolidinone was added Zn(CN)2 and tetrakis(triphenylphosphine)palladium(0) at ambient temperature. This was stirred at 140° C. for 1.5 hours. The reaction was cooled and was added water, extracted with EtOAc. The organic layer was washed with brine and was dried over MgSO4 and evaporated. Resultings were purified by silica gel column chromatography to afford 4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile as white powder.