Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](C(C)(C)C)=[N:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C([C:20]1[C:25](Br)=[C:24](I)[CH:23]=[CH:22][N:21]=1)(C)(C)C.FC(F)(F)C1C=C(I)C(Cl)=CN=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC1C=CC=CC=1C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:10]1[C:11]2[C:2]3[N:3]([CH:4]=[CH:5][C:6]=2[CH:7]=[CH:8][N:9]=1)[C:23]1[C:24](=[CH:25][CH:20]=[N:21][CH:22]=1)[N:1]=3
Reactant: CC(C)(C)c1cc2ccnc(N)c2cn1
Reactant: CC(C)(C)c1nccc(I)c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: FC(F)(F)c1cc(I)c(Cl)cn1
Solvent: Cc1ccccc1C
Product: c1cc2ccn3c4cnccc4nc3c2cn1

Procedure:
A vigorously stirred mixture of 20.1 g (100 mmol) of 1-amino-6-tert-butyl-2,7-naphthyridine S41, 37.4 g (110 mmol) of 2-tert-butyl-3-bromo-4-iodopyridine (S27) or 27.9 g (110 mmol) of 2-trifluoromethyl-4-iodo-5-chloropyridine, 35.0 g (250 mmol) of potassium carbonate, 200 g of glass beads (diameter 3 mm), 2.6 g (10 mmol) of triphenylphosphine and 450 mg (2 mmol) of palladium(II) acetate in 500 ml of o-xylene is heated under reflux until the 1-amino-6-tert-butyl-2,7-naphthyridine has been consumed (typically 3-30 h). After cooling, the solid is filtered off via a silica-gel bed, rinsed with 1000 ml of THF, and the filtrate is evaporated to dryness. The residue is dissolved in 75 ml of ethyl acetate at the boiling temperature, and 250 ml of n-heptane are slowly added. After cooling, the solid which has crystallised out is filtered off with suction, washed twice with 50 ml of n-heptane each time and dried in vacuo. The solids obtained in this way are freed from low-boiling components and non-volatile secondary components by sublimation (p about 1×10−5 mbar, T about 170-200° C.). Purity according to 1H-NMR typically >99.5%.
Reaction SMILES: N#N.[C:3]1([CH:9]=[CH:10][C:11]([NH2:13])=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].[CH2:19]([O:21][C:22](=[O:27])[C:23](=O)[CH2:24]Br)[CH3:20].FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH2:19]([O:21][C:22]([C:23]1[N:13]=[C:11]([CH:10]=[CH:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[O:12][CH:24]=1)=[O:27])[CH3:20]
Reactant: NC(=O)C=Cc1ccccc1
Reactant: CCOC(=O)C(=O)CBr
Agent: N#N
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCOC(=O)c1coc(C=Cc2ccccc2)n1

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 3-phenyl-acrylamide (10.31 g, 67.95 mmol) and NaHCO3 (28.47 g, 339.73 mmol) in THF (260 mL) was treated with 3-bromo-2-oxo-propionic acid ethyl ester (13.04 mL, 88.33 mmol) and the reaction mixture was heated at reflux for 15 h. 3-Bromo-2-oxo-propionic acid ethyl ester (13.04 mL, 88.33 mmol) was added again and the reaction mixture was stirred at reflux for 15 h. The reaction mixture was then filtered over celite and the solvents were evaporated under reduced pressure. The residue was dissolved in THF (30 mL) and treated at 0° C., dropwise, with trifluoroacetic anhydride (30.0 mL, 215.83 mmol). The reaction mixture was then stirred at rt overnight. Sat. aq. Na2CO3 was added and the mixture was extracted with EA (3×150 mL), dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (1:9 EA-Hept) gave the title compound as a yellow solid. TLC: rf (1:9 EA-Hept)=0.1. LC-MS-conditions 02: tR=1.01 min; [M+H]+=244.48.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[OH:16])[N:12]=[CH:11][CH:10]=[C:9]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][CH2:28][CH3:29])=[O:26])=[C:20]([Cl:30])[CH:19]=1)=[O:5])[CH3:2].Br[CH2:32][CH:33]1[CH2:38][CH2:37][N:36]([C:39](OC(C)(C)C)=O)[CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+].C=O.C([BH3-])#N.[Na+]>CN(C)C=O.C(OCC)(=O)C.CCCCCC.C(O)(=O)C.O>[CH2:1]([NH:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:32][CH:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1)[N:12]=[CH:11][CH:10]=[C:9]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][CH2:28][CH3:29])=[O:26])=[C:20]([Cl:30])[CH:19]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: CCNC(=O)Nc1ccc(Oc2ccnc3cc(O)c(C(=O)NCC)cc23)cc1Cl
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OCC4CCN(C)CC4)c(C(=O)NCC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
N6-Ethyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide (78.0 mg, 0.182 mmol), tert-butyl 4-(bromomethyl)-1-piperidinecarboxylate (75.9 mg, 0.273 mmol) and potassium carbonate (31.4 mg, 0.228 mmol) were heated and stirred in dimethylformamide (1 ml) at 60° C. for 15 hours. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained product was stirred in trifluoroacetic acid (1 ml) at room temperature for 1 hour, and then the reaction solution was concentrated under reduced pressure, the residue was dissolved in methanol and triethylamine was added dropwise for neutralization. After distilling off the solvent, the residue was dissolved in a tetrahydrofuran (2 ml)-methanol (2 ml) mixed solvent, and then a 37% formaldehyde aqueous solution (0.340 ml), acetic acid (0.070 ml) and sodium cyanoborohydride (34.3 mg, 0.546 mmol) were added in that order at room temperature and the mixture was stirred for 15 minutes. After adding basic silica gel to the reaction solution and concentrating it, it was subjected to silica gel column chromatography, the target fraction was concentrated under reduced pressure, the obtained crude product was suspended in ethyl acetate, the suspension was diluted with hexane, and the crystals were filtered out, washed with hexane and blow-dried to obtain the title compound (58.1 mg, 0.108 mmol, 59%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[C:16]([NH2:18])=[O:17])[N:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[N:11]=[CH:10]3)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:37]([O:41][C:42]([N:44]1[CH2:48][CH2:47][CH:46](N)[CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38]>C1COCC1>[C:37]([O:41][C:42]([N:44]1[CH2:48][CH2:47][CH:46]([NH:18][C:16]([C:15]2[CH:14]=[C:13]3[C:9]([CH:10]=[N:11][N:12]3[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:8][C:7]=2[O:6][C:5]2[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=2)=[O:17])[CH2:45]1)=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(N)=O)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(=O)NC3CCN(C(=O)OC(C)(C)C)C3)cc21
Reaction time: 18 h
Yield: 94 %

Procedure:
A solution of 5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (compound 10g, prepared as described in Example 46) in THF was treated with carbonyldiimidazole (1.2 equivalents) at room temperature under nitrogen atmosphere. After stirring for 18 hours, the reaction was treated with 3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (1 equivalent). After 18 additional hours, the solvent was allowed to slowly evaporate and the residue was purified in a Sep Pak cartridge eluting with a gradient of 100% CH2Cl2 to 5% MeOH/CH2Cl2 to provide compound 11g-13 as an oil in 94% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:14]N)[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[C:7]2[Cl:13].[F:16][C:17]([F:22])([F:21])[C:18](O)=O>>[Cl:13][C:7]1[C:6]2[C:11](=[C:2]([F:1])[CH:3]=[C:4]3[N:14]([CH2:18][C:17]([F:22])([F:21])[F:16])[CH:11]([CH3:6])[CH:2]([CH3:3])[C:5]3=2)[NH:10][C:9](=[O:12])[CH:8]=1
Reactant: O=C(O)C(F)(F)F
Reactant: NNc1cc(F)c2[nH]c(=O)cc(Cl)c2c1
Product: CC1c2c(cc(F)c3[nH]c(=O)cc(Cl)c23)N(CC(F)(F)F)C1C

Procedure:
This compound was prepared using the method described in Example 23 from 8-fluoro-6-hydrazino-4-chloroquinolin-2(1H)-one and trifluoroacetic acid. Spectral data for compound 151: 1H NMR (500 MHz, acetone-d6) δ 10.36 (s, 1H), 7.06 (d, J=11.5 Hz, 1H), 6.78 (s, 1H), 4.11 (qn, J=6.8 Hz, 1H), 4.08 (dq, J=16.4, 9.9 Hz, 1H), 3.93 (dq, J=16.4, 9.2 Hz, 1H), 3.86 (qn, J=6.6 Hz, 1H), 1.45 (d, J=6.6 Hz, 3H), 1.17 (d, J=6.8 Hz, 3H).
Reaction SMILES: N.C([S:5][CH2:6][CH:7]([CH3:22])[C:8]([N:10]([CH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:11][C:12]([OH:14])=[O:13])=[O:9])(=O)C>>[SH:5][CH2:6][CH:7]([CH3:22])[C:8]([N:10]([CH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:11][C:12]([OH:14])=[O:13])=[O:9]
Reactant: CC(=O)SCC(C)C(=O)N(CC(=O)O)C1CCCCCC1
Agent: N
Product: CC(CS)C(=O)N(CC(=O)O)C1CCCCCC1
Yield: 87.5 %

Procedure:
Ammonia gas was bubbled slowly through a stirred methanolic solution of N-(3-acetylthio-2-methylpropanoyl)-N-cycloheptyl glycine (7.2 g, 0.023 mol) for two hours. The reaction mixture was then concentrated and the residue redissolved in methylene chloride (300 ml). This solution was washed with 5% aqueous sodium bisulfate (5×200 ml), dried over MgSO4, filtered and concentrated to yield 5.5 g (88%) crude product. This material was purified further by HPLC, with ethyl acetate/toluene/hexane/acetic acid (50:25:50:2) as the eluent. Rf 0.5 (Toluene/Acetic Acid, 7:3), Rf 0.3 (Ethyl acetate/hexane, acetic acid 50;50;2).
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[S:14][CH:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[N:17]=2)=O)=[C:8]([Cl:21])[C:7]([O:22][CH3:23])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1N=C(C2C=C(O)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[Cl:21][C:8]1[C:7]([O:22][CH3:23])=[CH:6][CH:5]=[C:4]2[C:9]=1[N:10]=[C:11]([C:13]1[S:14][CH:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[N:17]=1)[CH:2]=[C:1]2[OH:3]
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2nc(C3CC3)cs2)c1Cl
Agent: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1ccc2c(O)cc(-c3nc(C4CC4)cs3)nc2c1Cl
Yield: 84 %

Procedure:
Compound 269a was synthesized from compound 268a (3.50 g, 1 eq) as an orange solid in 84% yield, following the procedure as described for compound 218a (80° C. overnight). 1H NMR (CDCl3, 400 MHz): δ (ppm) 1.04-1.07 (m, 4H), 2.13-2.18 (m, 1H), 4.06 (s, 3H), 6.75 (s, 1H), 7.06 (d, J=9.10 Hz, 1H), 7.09 (s, 1H), 8.27 (d, J=9.10 Hz, 1H), 9.92 (br s, 1H); MS (ESI, EI+): m/z=333.13 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([F:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:21])=[O:14])=[C:11]([F:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1F
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(OCc2ccccc2)cc1F

Procedure:
4-Benzyloxy-2-fluoro-benzoic acid (2 g, 8.12 mmol) was suspended in thionyl chloride (5.9 mL) and heated to reflux for 30 minutes. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was dissolved in toluene and re-concentrated twice to remove residual thionyl chloride. This procedure provided the title compound in crude form, which was used in the next reaction without further purification.
Reaction SMILES: O=[C:2]1[N:8]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=O)[C:7]2[CH:30]=[CH:31][CH:32]=[N:33][C:6]=2[NH:5][C:4]2[CH:34]=[CH:35][CH:36]=[CH:37][C:3]1=2.C([O-])(=O)C.[NH4+:42].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[N:42]1[C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:28])[CH3:26])[CH2:19][CH2:20][CH2:21]3)=[CH:16][CH:17]=2)=[CH:9][N:8]2[C:2]=1[C:3]1[CH:37]=[CH:36][CH:35]=[CH:34][C:4]=1[NH:5][C:6]1[N:33]=[CH:32][CH:31]=[CH:30][C:7]2=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)CN3C(=O)c4ccccc4Nc4ncccc43)cc2)CCC1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3cn4c(n3)-c3ccccc3Nc3ncccc3-4)cc2)CCC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
To a solution of tert-butyl (1-(4-(2-(6-oxo-6,11-dihydro-5H-benzo[e]pyrido[3,2-b][1,4]diazepin-5-yl)acetyl)phenyl)cyclobutyl)carbamate (0.3 g, 1 eq.) in acetic acid (5 mL) was added ammonium acetate (1.5 g, 20 eq.). The reaction was stirred at 120° C. for 2 hours. The reaction was carefully poured onto a saturated sodium bicarbonate solution (10 mL). The mixture was extracted with dichloromethane (3×25 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by column chromatography (25-100% ethyl acetate in hexanes), giving tert-butyl (1-(4-(9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-2-yl)phenyl)cyclobutyl)carbamate (0.21 g, 73%). LCMS: 480 [M+H].
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:71]1[CH2:75][CH2:74][CH2:73][C:72]1=[O:76].[Cl-].[NH4+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:76]=[C:72]1[CH2:73][CH2:74][CH2:75][N:71]1[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(I)cc12
Reactant: O=C1CCCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: O=C1CCCN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Temperature: 25 °C
Yield: 82 %

Procedure:
The 7-iodo-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (20.8 mg, 0.05 mmol) prepared in step D of Example 1-1, tris(dibenzylideneacetone)dipalladium (2.2 mg, 0.0025 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (4.2 mg, 0.0075 mmol), cesium carbonate (22.8 mg, 0.07 mmol), and 2-pyrrolidone (4.6 μl) were suspended in 1,4-dixane (0.5 ml), and the suspension was then stirred under heating to reflux overnight. Thereafter, the reaction solution was cooled to a room temperature, and a saturated ammonium chloride aqueous solution was then added thereto, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate hexane=2:1 to 5:1), so as to obtain 7-(2-oxopyrrolidin-1-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (15.3 mg; yield: 82%) in the form of a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([C:24]([F:35])([F:34])[F:23])[CH:30]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cccc(C(F)(F)F)c4)c3O2)cc1
Yield: 90.2 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.0 g, 13.05 mmol) with 3-(trifluoromethyl)phenylboronic acid (3.72 g, 19.57 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.512 g, 0.652 mmol), and potassium carbonate (4.5 g, 32.62 mmol) generally according to the procedure described for Intermediate 37 provided 5.28 g (90%) of (±)-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a white solid. mp 90-93° C.; Anal. calcd. for C23H19F3O4S: C, 61.6; H, 4.27. Found: C, 61.52; H, 4.21.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.C[Al](C)C.[C:22](OCC)(=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>C1(C)C=CC=CC=1>[C:23]1([C:22]2[N:4]([CH:5]3[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]3)[CH2:3][CH2:2][N:1]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(NCCN)CC1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2CCN=C2c2ccccc2)CC1
Temperature: -10 °C

Procedure:
To tert-butyl 4-[(2-aminoethyl)amino]piperidine-1-carboxylate (6 g) taken in dry toluene (50 ml) cooled to −10° C., trimethylaluminium was added slowly in dry toluene under nitrogen atmosphere. Reaction mixture was allowed to warm to r.t. and a second lot of solution of tert-butyl 4-[(2-aminoethyl)amino]piperidine-1-carboxylate (6 g in 50 ml of toluene) was added very slowly to it. The combined mixture was heated up to 55° C. for 30 minutes. A solution of ethyl benzoate (7.4 g in 50 ml of dry toluene) was added very-very slowly to the reaction mixture at 55° C. over a period of 40 minutes. After the completion of addition, the reaction mixture was refluxed for over night. Reaction mixture was cooled to 0° C. and water (3×50 ml) was added. The combined mixture was filtered through celite pad. The filtrate was concentrated under reduced pressure and the resulting oil was purified by column chromatography to afford tert-butyl 4-(2-phenyl-4,5-dihydro-1H-imidazol-1-yl)piperidine-1-carboxylate as a pure product.
Reaction SMILES: [F:1][CH:2]([F:34])[N:3]1[CH:7]=[C:6]([S:8]([N:11]2[C:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([F:23])[C:13]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:12]2)(=[O:10])=[O:9])[CH:5]=[N:4]1.C(OCC)(=O)C.[ClH:41]>C(O)C>[ClH:41].[F:34][CH:2]([F:1])[N:3]1[CH:7]=[C:6]([S:8]([N:11]2[C:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([F:23])[C:13]([CH2:24][NH:25][CH3:26])=[CH:12]2)(=[O:9])=[O:10])[CH:5]=[N:4]1
Reactant: CN(Cc1cn(S(=O)(=O)c2cnn(C(F)F)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2cnn(C(F)F)c2)c(-c2cccnc2F)c1F
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
tert-Butyl {[1-{[1-(difluoromethyl)-1H-pyrazol-4-yl]sulfonyl}-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (380 mg) was dissolved in ethanol (10 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (10 mL) was added, and the mixture was stirred at 40° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 240 mg, 72%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+].O>O1CCOCC1>[N:30]([CH2:12][CH2:13][C@@H:14]1[CH2:16][C@@H:15]1[CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=2)[CH2:19][CH2:18]1)=[N+:31]=[N-:32]
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: [N-]=[N+]=NCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Temperature: 100 °C

Procedure:
2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl 4-methylbenzenesulfonate (65 mg, 0.15 mmol) from step 1 of this example was dissolved in dioxane (1.2mL). Sodium azide (22.3 mg, 0.34 mmol) was added, then water (0.3 mL). The reaction was heated to 100° C. to reflux for 2 hours. The reaction was cooled to room temperature, water (10 mL) was added and extracted with EtOAc (10 mL×2). The combined organic phase was dried by magnesium sulfate, filter, concentrated and purified by column chromatography through a 12 gram RediSep Rf™ silica gel cartridge eluting with 5% ethyl acetate/hexanes to give the title compound as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([N:15]([C:22]2[N:23]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[N:24]=[C:25]3[C:30]=2[CH:29]=[CH:28][CH:27]=[CH:26]3)[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:14])=[C:8]([Cl:38])[CH:7]=1)C.[OH-].[Li+]>C(OC(C)=O)(C)C.[Cl-].[Na+].O>[Cl:38][C:8]1[CH:7]=[C:6]([CH2:5][C:4]([OH:39])=[O:3])[CH:11]=[CH:10][C:9]=1[NH:12][C:13]([N:15]([C:22]1[N:23]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[N:24]=[C:25]2[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]2)[CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)=[O:14]
Reactant: CCOC(=O)Cc1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(Cl)c1
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)C
Product: O=C(O)Cc1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 2.2, (3-chloro-4-{3-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-3-cyclohexyl-ureido}-phenyl)-acetic acid ethyl ester was treated with 1 N aqueous lithium hydroxide solution in THF/MeOH 1/1 for 14 h at ambient temperature to give the title compound as off-white solid. MS: m/e=536.8 [M+H+].
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:8]=2[NH:7][C:6]1=[O:16].C(=O)([O-])[O-].[Ca+2].[Br-:23].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>CO.ClCCl>[Br:23][C:11]1[C:12]([O:14][CH3:15])=[CH:13][C:8]2[NH:7][C:6](=[O:16])[N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:17])[C:9]=2[CH:10]=1
Reactant: COc1ccc2c(c1)[nH]c(=O)n2CCN(C)C
Reactant: [Br-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CO
Product: COc1cc2[nH]c(=O)n(CCN(C)C)c2cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 157 %

Procedure:
To a solution of 1,3-dihydro-1-(2-dimethylaminoethyl)-5-methoxy-2H-benzimidazol-2-one (0.28 g) in methanol (10 ml) and dichloromethane (15 ml) were added calcium carbonate (0.25 g) and benzyltrimethylammonium tribromide (0.49 g). The reaction mixture was stirred at room temperature for 16 hours and the insoluble matter was filtered off. The solvent was then distilled off under reduced pressure and the residue was diluted with 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: chloroform:methanol=10:1) to give 0.35 g of 6-bromo-1,3-dihydro-1-(2-dimethylaminoethyl)-5-methoxy-2H-benzimidazol-2-one.
Reaction SMILES: C[N:2]1C(C)=CC(=O)N(C)C1=O.C[N:13]1[CH:20]=[C:19]([CH3:21])[C:17](=[O:18])[N:16](C)[C:14]1=O.CN1C=C(CC2C=CC=CC=2)C(=O)N(C)C1=O>>[CH3:21][C:19]1[C:17](=[O:18])[NH:16][C:14]([NH2:2])=[N:13][CH:20]=1
Reactant: Cc1cn(C)c(=O)n(C)c1=O
Reactant: Cc1cc(=O)n(C)c(=O)n1C
Agent: Cn1cc(Cc2ccccc2)c(=O)n(C)c1=O
Product: Cc1cnc(N)[nH]c1=O

Procedure:
In accordance with the above procedure, but where in place of 1,3,6-trimethyluracil there is employed 1,3,5-trimethyluracil or 1,3-dimethyl-5-benzyluracil, there is obtained the corresponding 5-methylisocytosine or 5-benzylisocytosine.