Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=O)[C:18](=[N:20][OH:21])[CH3:19])=[CH:13][CH:12]=2)[CH3:9])=[CH:4][CH:3]=1.Cl.[CH2:24]([O:26][NH2:27])[CH3:25]>N1C=CC=CC=1>[CH2:24]([O:26][N:27]=[C:17]([C:14]1[CH:15]=[CH:16][C:11]([O:10][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH3:9])=[CH:12][CH:13]=1)[C:18](=[N:20][OH:21])[CH3:19])[CH3:25]
Reactant: CC(=NO)C(=O)c1ccc(OC(C)c2ccc(Cl)cc2)cc1
Reactant: CCON
Agent: Cl
Solvent: c1ccncc1
Product: CCON=C(C(C)=NO)c1ccc(OC(C)c2ccc(Cl)cc2)cc1

Procedure:
A mixture of 29.0 g of 1-(4-(1-{4-chlorophenyl}-ethoxy)-phenyl)-1,2-propanedione-2-oxime and 9.4 g of O-ethylhydroxylamine hydrochloride in 150 ml of pyridine is boiled at reflux for 1 hour. After cooling, the reaction mixture is concentrated by evaporation in vacuo. The residue is dissolved in ethyl acetate; the organic phase is washed twice with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation. The crude product is stirred together with hexane; filtration is carried out and the filter residue is dried, yielding the title product having a melting point of 132-134° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C@@H:3]2[CH2:7][N:8]([C:10]3[N:15]=[C:14]([NH:16][C:17]4[CH:21]=[CH:20][NH:19][N:18]=4)[CH:13]=[C:12]([CH3:22])[N:11]=3)[CH2:9][C@@H:2]12.[C:23](=O)([O:34][C@@H:35]([CH3:40])[C:36]([F:39])([F:38])[F:37])[O:24]C1C=CC([N+]([O-])=O)=CC=1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH3:22][C:12]1[CH:13]=[C:14]([NH:16][C:17]2[CH:21]=[CH:20][NH:19][N:18]=2)[N:15]=[C:10]([N:8]2[CH2:7][C@@H:3]3[C@H:2]([O:1][CH2:6][CH2:5][N:4]3[C:23]([O:34][C@@H:35]([CH3:40])[C:36]([F:39])([F:38])[F:37])=[O:24])[CH2:9]2)[N:11]=1
Reactant: Cc1cc(Nc2cc[nH]n2)nc(N2C[C@H]3NCCO[C@@H]3C2)n1
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1cc(Nc2cc[nH]n2)nc(N2C[C@@H]3[C@@H](C2)OCCN3C(=O)O[C@@H](C)C(F)(F)F)n1
Temperature: 100 °C

Procedure:
To a mixture of 2-[(4aR,7aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl]-6-methyl-N-(1H-pyrazol-3-yl)pyrimidin-4-amine (20 mg) in CHCl3 (3 mL) were added 4-nitrophenyl (2S)-1,1,1-trifluoropropan-2-yl carbonate (37 mg) prepared in Referential Example 2 and DIEA (30 mg) at room temperature. After 4-hour stirring at 100° C. in a sealed tube, the resulting mixture was cooled to room temperature and concentrated. The residue was diluted with MeOH (5 mL). To the resulting mixture was added potassium carbonate (100 mg) at 0° C. and stirred at 0° C. for 30 min. The mixture was poured into saturated aqueous solution of NH4Cl and extracted with CHCl3. The extract was washed with brine, dried over MgSO4 and concentrated. The residue was purified with silica gel column chromatography (eluent: CHCl3/MeOH=99/1˜80/20) to give (2S)-1,1,1-trifluoropropan-2-yl (4aR,7aR)-6-[4-methyl-6-(1H-pyrazol-3-ylamino)pyrimidin-2-yl]hexahydropyrrolo[3,4-b][1,4]oxazine-4(4aH)-carboxylate as a pale yellow foam.
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.C(=O)([O-])[O-].[Na+].[Na+].C(N(CC)CC)C.[ClH:23].[Cl:24][C:25]1[CH:26]=[C:27]([N:31]2[CH2:36][CH2:35][N:34]([CH:37](Cl)[CH2:38][CH3:39])[CH2:33][CH2:32]2)[CH:28]=[CH:29][CH:30]=1>CN(C)C=O>[ClH:24].[ClH:23].[Cl:24][C:25]1[CH:26]=[C:27]([N:31]2[CH2:32][CH2:33][N:34]([CH2:37][CH2:38][CH2:39][N:3]3[CH2:4][CH:5]4[CH2:8][CH2:9][CH:1]([CH2:7][CH2:6]4)[CH2:2]3)[CH2:35][CH2:36]2)[CH:28]=[CH:29][CH:30]=1
Reactant: C1CC2CCC1CNC2
Reactant: CCC(Cl)N1CCN(c2cccc(Cl)c2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Clc1cccc(N2CCN(CCCN3CC4CCC(CC4)C3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-azabicyclo[3.2.2]nonane, (4 g, 0.032 mol), sodium carbonate (4 g, 0.045 mol) and triethylamine 3 mL in 50 mL of dimethylformamide is added 4-(3-chlorophenyl)-1-piperazinylpropylchloride hydrochloride (4 g, 0.0115 mol). The reaction mixture is stirred at room temperature overnight, the solvent is removed under vacuum and the remaining solid is extracted in 3×100 mL methylene chloride. The methylene chloride extracts are collected, dried over anhydrous sodium sulfate and evaporated under reduced pressure.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(CN)CCCCC1.[O:15]=[C:16]1[C:24]2([CH2:28][O:27][C:26]3[CH:29]=[C:30]4[C:34](=[CH:35][C:25]2=3)[CH2:33][CH2:32][O:31]4)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]1[CH2:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39](O)=[O:40].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[N:1]1([C:39]([C:38]2[CH:42]=[CH:43][CH:44]=[CH:45][C:37]=2[CH2:36][N:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]3([CH2:28][O:27][C:26]4[CH:29]=[C:30]5[C:34](=[CH:35][C:25]3=4)[CH2:33][CH2:32][O:31]5)[C:16]2=[O:15])=[O:40])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Reactant: C1CCNCC1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21)N1CCCCC1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using piperidine to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, 1′-[2-(piperidin-1-ylcarbonyl)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (88%) as a colorless solid: mp 168-170° C.; 1H NMR (300 MHz, DMSO-d6) δ7.42-7.10 (m, 6H), 6.99 (dd, J=7.5, 7.5 Hz, 1H), 6.65-6.44 (br, 1H), 6.39 (s, 1H), 4.90-4.64 (m, 4H), 4.54-4.39 (m, 2H), 3.77-3.42 (br, 2H), 3.21-3.07 (m, 2H), 2.94 (t, J=8.2, 1.5 Hz, 1H), 1.66-1.33 (m, 6H); 13C NMR (75 MHz, DMSO-d6) δ177.7, 167.9, 161.6, 161.2, 142.7, 136.4, 132.6, 129.6, 129.1, 128.1, 126.6, 124.1, 123.5, 120.9, 120.3, 109.8, 92.9, 80.5, 72.6, 65.4, 57.4, 47.9, 42.3, 41.4, 28.8, 26.4, 25.7, 24.4, 15.6; MS (ES+) m/z 481.2 (M+1).
Reaction SMILES: Cl[CH2:2][N:3]1[C:7](=[O:8])[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:4]1=[O:21].[P:22]([O-:40])([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].[K+].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[O:21]=[C:4]1[NH:5][C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7](=[O:8])[N:3]1[CH2:2][O:40][P:22](=[O:23])([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1COP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 70 °C
Yield: 70 %

Procedure:
A mixture of 250 kg 3-(chloromethyl)-5,5-diphenyl-2,4-imidazolidinedione from Step (A), 270 kg of potassium dibenzyl phosphate, 6 kg of potassium carbonate, 0.75 kg of potassium iodide, and 500 kg of acetonitrile is heated at 70° C. to reflux for 2 to 5 hours or until the reaction is essentially complete. The reaction mixture is cooled to 40° C. to 65° C. and filtered. The solution is stirred with at least 11 kg of activated carbon and filtered using a filter-aid. The reaction solvent is replaced by adding toluene in portions and vacuum distilling. The resulting slurry is cooled to less than 5° C. The title compound is collected by filtration and washed with cold toluene. The wet cake is dried at 50° C. under vacuum to give phosphoric acid dibenzyl ester 2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl ester, 315 kg (70% yield); mp 118.6-119.7° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)=[CH:5][CH:4]=1.FC(F)(F)S(OC1CCC2C(=CC(OC)=CC=2)C=1)(=O)=O.C([Sn](CCCC)(CCCC)[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:40]=1[N+:47]([O-:49])=[O:48])CCC>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](=[CH:5][CH:4]=1)[CH2:7][CH2:8][C:9]([C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:40]=1[N+:47]([O-:49])=[O:48])=[CH:10]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(OC)cc1[N+](=O)[O-]
Reactant: COc1ccc2c(c1)CC(=O)CC2
Agent: COc1ccc2c(c1)C=C(OS(=O)(=O)C(F)(F)F)CC2
Product: COc1ccc2c(c1)C=C(c1ccc(OC)cc1[N+](=O)[O-])CC2

Procedure:
Synthesized from 7-methoxy-2-tetralone according to an analogous synthetic method to Preparation Example 82 described above, 7-methoxy-3,4-dihydronaphthalen-2-yl trifluoromethanesulfonate (3.5 g) and tributyl(4-methoxy-2-nitrophenyl)tin (18 g) were used according to an analogous synthetic method to Preparation Example 77 to provide the title compound (1.9 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[CH3:9][C@@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][NH:11]1>CC(O)C.CCN(C(C)C)C(C)C>[F:8][C:5]1[CH:4]=[N:3][C:2]([N:14]2[CH2:13][CH2:12][NH:11][C@H:10]([CH3:9])[CH2:15]2)=[N:7][CH:6]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: C[C@@H]1CNCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@@H]1CN(c2ncc(F)cn2)CCN1
Yield: 117.8 %

Procedure:
A solution of 2-chloro-5-fluoropyrimidine (239 mg, 1.80 mmol) and (R)-2-methylpiperazine (271 mg, 2.71 mmol) in iPrOH (1 mL) and DIEA (617 μL) was heated in MW at 130° C. for 30 min. Solvent was removed under reduced pressure and the crude (600 mg) was purified by chromatography on silica using DCM/methanol (9/1) as eluent to afford The title compound as a white solid (416 mg, quantitative). TLC-DCM/MeOH (8/2); Rf: 0.3. 1H NMR (DMSO-d6) δ 8.14 (s, 2H), 4.48 (d, J=13.2 Hz, 2H), 4.33 (brs, 1H), 2.98-3.13 (m, 2H), 2.83 (m, 2H), 2.67 (t, J=12.7 Hz, 1H), 1.20 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26](O)=[O:27])[CH:19]=3)[O:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:43][O:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][O:46]1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26]([NH:43][O:44][CH:45]4[CH2:50][CH2:49][CH2:48][CH2:47][O:46]4)=[O:27])[CH:19]=3)[O:14]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(/C=C/C(=O)O)ccc1O2
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(/C=C/C(=O)NOC3CCCCO3)ccc1O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (E)-3-{1′-tert-butoxycarbonyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (387 mg, 1 mmol) in DCM (15 ml) was cooled down to 0° C. EDC (383 mg, 2 mmol) and HOBT (135 mg, 1 mmol) were added, and the mixture was stirred at RT for 1 h. NH2OTHP (146 mg, 1.25 mmol) in DCM (1 ml) was added dropwise and the mixture was stirred at RT. After 4 h, the reaction mixture was washed with a saturated NaHCO3 solution and brine, dried over Na2SO4 and concentrated. The crude residue was purified by column chromatography (eluent: DCM/MeOH 98:2) to give (E)-3-{1′-tert-butoxycarbonyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)([CH3:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[CH3:27][S:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:38]=1[NH:37][CH:36]=[CH:35]2>ClCCl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:35]3[C:34]4[C:38](=[C:30]([CH2:29][S:28][CH3:27])[CH:31]=[CH:32][CH:33]=4)[NH:37][CH:36]=3)([CH3:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(C)(O)c1ccc2c(c1)OCCO2
Reactant: CSCc1cccc2cc[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CC(C)(c1ccc2c(c1)OCCO2)c1c[nH]c2c(CSC)cccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
600 mg (2.25 mmol) of the compound from Example 91A and 0.21 ml (2.70 mmol) of trifluoroacetic acid were added to 399 mg (2.25 mmol) of the compound from Example 8A in 4 ml of dichloromethane. The reaction mixture was stirred at RT for 30 min. Purification of the crude product by preparative HPLC (mobile phase: acetonitrile/water gradient) resulted in 576 mg (60% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:21])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14](F)=[C:13]([N+:18]([O-])=O)[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[N:22]1([CH2:28][CH2:29][NH2:30])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[C:3]([CH3:21])=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[C:13]([NH2:18])[C:14]([NH:30][CH2:29][CH2:28][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1c(Cl)cnc2[nH]c(-c3ccc(F)c([N+](=O)[O-])c3)nc12
Reactant: NCCN1CCOCC1
Product: Cc1c(Cl)cnc2[nH]c(-c3ccc(NCCN4CCOCC4)c(N)c3)nc12
Temperature: 180 °C

Procedure:
5-Chloro-4-methylpyridine-2,3-diamine (Example 249b) (1.47 g, 9 mmol) and 4-fluoro-3-nitrobenzoic acid (1.73 g, 9 mmol) were mixed in phosphorous oxychloride (50 ml) and heated to 110° C. for 64 h. When cool, the excess phosphorous oxychloride was removed in vacuo to afford a brown semi-solid (about 4 g) consisting of 6-chloro-2-(4-fluoro-3-nitrophenyl)-7-methyl-3H-imidazo[4,5-b]pyridine and various inorganic material. To 1.0 g of this crude material, (2-morpholin-4-ylethyl)amine (2 ml) was added and the mixture heated in the microwave oven (180° C., 20 min).
Reaction SMILES: [Na].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11].[C:12](OCC)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1>C(O)C.O>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[NH:2][C:3]2=[O:11])=[O:19])[CH:14]=1
Reactant: CCOC(=O)c1cccnc1
Reactant: O=C1Cc2ccccc2N1
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=C1Nc2ccccc2C1C(=O)c1cccnc1
Yield: 18.5 %

Procedure:
To a solution of 2.1 g (0.090 mole) of sodium metal in 100 ml of ethanol, was added 10.0 g (0.075 mole) of 2-oxindole, followed by 13.6 g (0.090 mole) of ethyl nicotinate. The resulting slurry was heated under reflux for 3 hours and then the mixture was cooled and filtered. The residue was discarded, and the filtrate was evaporated in vacuo. The residue thus obtained was dissolved in ca. 150 ml of water, and the aqueous solution was washed with chloroform. To the aqueous solution was then added 5.8 ml of glacial acetic acid and the resulting mixture was cooled in an ice-bath. The solid was recovered by filtration and recrystallized from ethanol to give 3.3 g of the title compound as yellow needles, m.p. 169°-170° C. Analysis: Calcd. for C14H10N2O2 : C, 70.58; H, 4.23; N, 11.76%. Found: C, 70.66; H, 4.41; N, 11.73%.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][C:13]23[CH2:22][CH:17]4[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]4)[CH2:14]2)[CH2:20]3)(=O)=O)=CC=1.[I-:24].[Na+]>CC(=O)CC>[C:13]12([CH2:12][CH2:11][I:24])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2
Reactant: Cc1ccc(S(=O)(=O)OCCC23CC4CC(CC(C4)C2)C3)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: ICCC12CC3CC(CC(C3)C1)C2
Yield: 57.6 %

Procedure:
A solution of 2-(1-adamantyl)ethyl p-toluene-sulfonate (4.0 g) and sodium iodide (2.5 g) in 2-butanone (20 ml) is heated for 2 hours under reflux. The cooled solution is filtered and concentrated to a residue which is partitioned between dichloromethane and water. The organic layer is washed with aqueous sodium thiosulfate and water. The dried solution is evaporated to a crystalline mass which is recrystallized from ethanol to give 2-(1-adamantyl)ethyl iodide (2.0 g), m.p. 93°-94°. An analytical sample is obtained by recrystallization from the same solvent, m.p. 97°-98°.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[C:5](=[C:10]([NH:14][CH2:15][CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].COCCNC1C=CC=C(C(O)=O)C=1C(O)=O>>[CH2:18]([O:17][CH2:16][CH2:15][NH:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:25])=[O:2])[C:5]=1[C:6]([OH:8])=[O:7])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1cccc(NCCOCc2ccccc2)c1C(=O)OC
Agent: COCCNc1cccc(C(=O)O)c1C(=O)O
Product: O=C(O)c1cccc(NCCOCc2ccccc2)c1C(=O)O

Procedure:
3-(2-Benzyloxy-ethylamino)-phthalic acid dimethyl ester (2.50 g, 7.28 mmol) was treated in the same manner as described above for the synthesis of 3-(2-methoxy-ethylamino)-phthalic acid. The product of the reaction, which contained a mixture of diacid and monomethyl esters, was used without further purification.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[O:8][C:7]([CH2:9][OH:10])=[CH:6][CH:5]=1.[CH2:11](I)[CH3:12]>CN(C=O)C>[Br:3][C:4]1[O:8][C:7]([CH2:9][O:10][CH2:11][CH3:12])=[CH:6][CH:5]=1
Reactant: OCc1ccc(Br)o1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCc1ccc(Br)o1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (95%, 19 mg, 0.75 mmol) was diluted in dry DMF (0.5 mL) and cooled to 0° C. A solution of (5-bromo-2-furanyl)methanol (120 mg, 0.68 mmol) was added, and the mixture was stirred for 5 minutes. Ethyl iodide (117 mg, 0.75 mmol) was added, and the mixture was stirred at it overnight. The reaction mixtures were quenched by the careful addition of water, then extracted with diethyl ether. The combined organics were dried and concentrated. The residue was purified by flash chromatography, eluting with 10% EtOAc/hexanes. The desired fractions were combined and concentrated to afford the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]([C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N-:20]=[N+:21]=[N-:22].CN(C)C(=[NH2+])N(C)C.C1OCCOCCOCCOCCOCCOC1>CC(C)=O>[N:20]([CH2:2][CH2:3][N:4]([C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C(=O)N(CCBr)N=Cc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CN(C)C(=[NH2+])N(C)C
Solvent: CC(C)=O
Product: CCOC(=O)C(=O)N(CCN=[N+]=[N-])N=Cc1ccccc1

Procedure:
11 g. of the ethyl ester product from part (c) are added to acetone along with 5.7 g. of tetramethylguanidinium azide and 0.05 g. of 18-Crown-6. The mixture is refluxed for eight hours. After distilling off the solvent, the reaction mixture is stirred with 50 ml. of methylene chloride. The organic phase, after drying and concentrating, leaves an oil which crystallizes in the form of white crystals upon the addition of a small amount of isopropanol to yield [1-(2-azidoethyl)-2-(phenylmethylene)hydrazino]oxoacetic acid, ethyl ester; m.p. 59°-61°.
Reaction SMILES: [OH:1][CH:2]1[CH2:23][NH:22][CH2:21][CH2:20][C:3]21[C:7](=[O:8])[N:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)[CH2:5][CH2:4]2.[CH:24]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25]1>>[CH:24]1([S:27]([N:22]2[CH2:21][CH2:20][C:3]3([C:7](=[O:8])[N:6]([C:9]4[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:17])[F:18])=[CH:11][CH:10]=4)[CH2:5][CH2:4]3)[CH:2]([OH:1])[CH2:23]2)(=[O:29])=[O:28])[CH2:26][CH2:25]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2O
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)C1CC1)CC2O

Procedure:
The title compound was prepared in analogy to example 2 step B from a mixture of (5SR,6RS)-6-hydroxy-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 2 step A) and cyclopropanesulfonyl chloride. Colourless solid. MS (ESI): 435.3 (MH+)
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[N:33]=[C:34]([N:37]2[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]2)[S:35][CH:36]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[N:33]=[C:34]([N:37]2[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]2)[S:35][CH:36]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cn(-c2nc(C(=O)CC(=O)OC(C)(C)C)cs2)cn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Product: Cc1cn(-c2nc(C(=O)CC(=O)Nc3cc(-c4ccc(F)cc4)ccc3NC(=O)OC(C)(C)C)cs2)cn1

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) (151 mg, 0.5 mmol) and 3-[2-(4-methyl-imidazol-1-yl)-thiazol-4-yl]-3-oxo-propionic acid tert.-butyl ester (Example H20) (154 mg, 0.5 mmol) according to the general procedure K. Obtained as a yellow amorphous substance (225 mg).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[Br:20][C:21]1[CH:25]=[CH:24][S:23][C:22]=1[C:26](O)=[O:27]>>[Br:20][C:21]1[CH:25]=[CH:24][S:23][C:22]=1[C:26]([N:3]1[CH2:4][C@H:5]2[C@H:1]([CH2:6]2)[C@H:2]1[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10])=[O:27]
Reactant: O=C(O)c1sccc1Br
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1sccc1Br

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 3-Bromo-thiophene-2-carboxylic acid. LC-MS (basic): tR=1.22 min; [M+H]+=465.0.
Reaction SMILES: [OH-].[Na+].S(O)(O)(=O)=O.[CH3:8][S:9][C:10](=[NH:12])[NH2:11].[NH2:13][C:14]1[C:15]([C:22](OC(C)=CC(=O)NC(C)(C)C)=[O:23])=[N:16][C:17]([Cl:21])=[C:18]([NH2:20])[N:19]=1>C(Cl)Cl.O1CCCC1>[NH2:13][C:14]1[C:15]([C:22]([NH:12][C:10]([S:9][CH3:8])=[NH:11])=[O:23])=[N:16][C:17]([Cl:21])=[C:18]([NH2:20])[N:19]=1
Reactant: CSC(=N)N
Reactant: CC(=CC(=O)NC(C)(C)C)OC(=O)c1nc(Cl)c(N)nc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Yield: 83.6 %

Procedure:
To NaOH (1 M in water; 18.7 mL; 18.7 mmol) is added S-methylisothiourea sulphate (4.25 g; 15.3 mmol). The mixture is stirred until complete dissolution is achieved. CH2Cl2: tetrahydrofuran (1:1; 30 mL) and then 1-(tert-butylcarbamoyl)prop-1-en-2-yl 3,5-diamino-6-chloropyrazine-2-carboxylate (Intermediate 2; 2.00 g; 6.10 mmol) are added and the mixture is stirred at room temperature over night. The organic solvents are evaporated, then water (50 mL) is added. The precipitate formed is collected by filtration while applying suction, washed successively with water, methanol and then with diethyl ether and then dried at 50° C. to yield the title compound (1.33 g, 84% of theory).
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].N1C=CC=CC=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:32])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccccc2)CC1
Yield: 83.5 %

Procedure:
To a stirred solution of 1-(2-tert-butylphenyl)piperazine dihydrochloride (0.150 g, 0.52 mmol) and pyridine (0.166 g, 2.13 mmol) in dichloromethane (5 mL) was added benzoyl chloride (0.079 g, 0.56 mmol) at room temperature. After 16 h the reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 90:10 to 70:30 heptanes/ethyl acetate, gradient elution) to provide [4-(2-tert-butylphenyl)piperazin-1-yl](phenyl)methanone (0.140 g, 83%) as a white powder, mp 104-106° C.