Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[NH2:35][C@@H:36]([CH3:49])[CH2:37][O:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([NH:35][C@@H:36]([CH3:49])[CH2:37][O:38][C:39]2[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=2)=[O:23])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: COC(=O)c1ccc(OC[C@H](C)N)cc1
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OC[C@H](C)NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.6 %

Procedure:
A mixture of pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetate (505 mg, 1.05 mmol), methyl (S)-4-(2-amino-1-propoxy)benzoate (220 mg, 1.05 mmol), and Et3N (0.220 mL, 1.58 mmol) in DMF (8 mL) was stirred at room temp for 3 hr. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine and dried over Na2SO4. After removal of the solvent, the residue was recrystallized from MeOH—CHCl3-n-hexane to give 290 mg (55%) methyl (S)-4-[2-[3-methoxy-4-[N′-(2-methylphenyl) ureido]phenylacetylamino]-1-propoxy]benzoate as a white crystalline powder. 1H-NMR (DMSO-d6) δ 1.18 (d, 3 H, J=6.8 Hz), 2.24 (s, 3 H), 3.36 (s, 2H), 3.80 (s, 3H), 3.82 (s, 3H), 3.93–4.03 (m, 2H), 4.09–4.14 (m, 1H), 6.75–8.57 (series of m, total 13 H).
Reaction SMILES: [N+:1]([C:3](S(C1C=CC(C)=CC=1)(=O)=O)=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)#[C-:2].[N:23]1[CH:28]=[CH:27][C:26]([CH2:29]C(OCC)=O)=[CH:25][CH:24]=1.CC(C)([O-])C.[K+]>COCCOC>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:4]2[C:29]([C:26]3[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=3)=[CH:2][NH:1][CH:3]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)Cc1ccncc1
Reactant: [C-]#[N+]C(=Cc1cccc(OC)c1)S(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1cccc(-c2c[nH]cc2-c2ccncc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.1 %

Procedure:
1-[(1-isocyano-2-(3-methoxyphenyl)ethenyl)sulfonyl]-4-methylbenzene (9.0 g, 0.0285 mol) was dissolved in dry DME (200 mL) and added dropwise to a cooled (0° C.) mixture of ethyl 4-pyridylacetate (9.0 g, 0.545 mol) and potassium t-butoxide (7.1 g, 0.0633 mol) in dry DME (100 mL). After the addition was complete the reaction was warmed to 25° C. and stirred for 3 h. The reaction was then poured into ice water (1200 mL) and extracted into CH2Cl2 (3×500 mL). The combined organics were dried over Na2SO4, filtered and evaporated in vacuo to give a solid. This solid was then triturated with ether and filtered to give 3.0 g of pure 3-(3-methoxyphenyl)-4-(4-pyridyl)pyrrole. The filtrate was again evaporated in vacuo and then triturated with a 50/50 mixture of CH2Cl2 and ether to give an additional 1.5 g of pure product. Finally the filtrate was evaporated in vacuo and purified on SiO2 eluting with ethyl acetate to give another 0.5 g of pure product resulting in a 70% combined yield. 1HNMR (DMSO-d6) δ 11.38 (1H, br s, NH), 8.37 (2H, d, J=6.1), 7.24-7.17 (4H, m), 7.02-7.00 (1H, m), 6.80-6.77 (3H, m), 3.68 (3H, s).
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]([C@H:27]([CH3:50])[C@@H:28]([C:37]1[CH:42]=[CH:41][C:40]([O:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:39][CH:38]=1)[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:8]([C@@:10]1([C:22]([O:24]CC)=[O:23])[O:14][C@H:13]([C:15]([O:17]C(C)(C)C)=[O:16])[CH2:12][O:11]1)=[O:9])=[O:5])C>C(O)=O>[C:4]([CH2:6][N:7]([C@H:27]([CH3:50])[C@@H:28]([C:37]1[CH:38]=[CH:39][C:40]([O:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[CH:41][CH:42]=1)[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:8]([C@@:10]1([C:22]([OH:24])=[O:23])[O:14][C@H:13]([C:15]([OH:17])=[O:16])[CH2:12][O:11]1)=[O:9])([OH:5])=[O:3]
Reactant: CCOC(=O)CN(C(=O)[C@]1(C(=O)OCC)OC[C@@H](C(=O)OC(C)(C)C)O1)[C@H](C)[C@H](CCc1ccccc1)c1ccc(Oc2ccccc2)cc1
Solvent: O=CO
Product: C[C@H]([C@H](CCc1ccccc1)c1ccc(Oc2ccccc2)cc1)N(CC(=O)O)C(=O)[C@]1(C(=O)O)OC[C@@H](C(=O)O)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
310 mg of 4-tert-butyl 2-ethyl (2S*,4S)-2-[N-(ethoxycarbonylmethyl)-N-{(1R,2R)-1-methyl-2-(4-phenoxyphenyl)-4-phenylbutyl}carbamoyl]-1,3-dioxolane-2,4-dicarboxylate was dissolved in 4 ml of formic acid, followed by stirring at room temperature for 2 hours. The reaction solution was evaporated to dryness under reduced pressure, and then, the residue was dissolved in 6 ml of a 50% tetrahydrofuran aqueous solution. 3 ml of a 1N sodium hydroxide aqueous solution was added, followed by stirring at room temperature for 6 hours. The reaction solution was acidified with 1N hydrochloric acid and then extracted with ethyl ether. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by medium pressure liquid chromatography (Lobar column™, Size B, RP-8, manufactured by Merck Co.; acetonitrile/0.1% trifluoroacetic acid aqueous solution=1/1) to obtain 216 mg (yield: 84%) of the above identified compound as a colorless foam.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=1)=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>C(O)C>[CH3:28][S:25]([C:21]1[CH:20]=[C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:10]([NH2:9])=[S:11])[CH:24]=[CH:23][CH:22]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)c1cccc(-c2ccccc2NC(=S)NC(=O)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1cccc(-c2ccccc2NC(N)=S)c1

Procedure:
A mixture of N-benzoyl-N'-(3'-methanesulphonyl-2-biphenylyl)thiourea (8.2 g), sodium hydroxide (0.9 g) and ethanol (20 ml) was heated under reflux for 1.5 hours to give N-(3'-methanesulphonyl-2-biphenylyl)thiourea as a foamy solid.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.C(=O)=O.CC(C)=O.[Li]CCCC.[Si:22]([O:39][CH2:40]C(Cl)=O)([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>C1COCC1.C(OCC)C>[Si:22]([O:39][CH2:40][C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])([C:35]([CH3:36])([CH3:37])[CH3:38])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CC(C)(C)[Si](OCC(=O)Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 58.8 %

Procedure:
To a 1-L round-bottom flask equipped with a magnetic stir-bar, addition funnel, low temperature thermometer with thermometer adapter and a N2inlet was added monoethyl malonate (14.53g, 0.11moles, 2eq) in dry THF (150ml, 0.73M) and 20mg of 2,2′-dipyridyl. After cooling the reaction mixture to −78° C. (dry ice/acetone), n-BuLi (2.5M in Hexanes, 88ml, 0.22moles, 4eq) was added at a rate to maintain the internal temperature below −10° C. Once the addition was complete the reaction was allowed to warm to −10° C. by removal of the cold bath. The reaction remained a light pink color; this designates that there was ample amount of n-BuLi to deprotonate the monoethyl malonate. (If the color had turned yellow the reaction would have had to have been re-cooled to −78° C. and additional n-BuLi would have had to have been added followed be re-warming to −10° C.) At this point the reaction mixture was cooled to −78° C. followed by the dropwise addition of neat {[tert-Butyl(diphenyl)silyl]oxy}acetyl chloride (18g, 54mmoles, 1eq) over a period of 15minutes maintaining the internal reaction temperature below 60° C. This was allowed to stir at −78° C. for 10minutes at which point the reaction was transferred to a separatory funnel containing diethyl ether (900ml) and 1N HCl (450ml). This was agitated and vented until further gas evolution ceased after which the phases were separated and the organic phase washed with saturated sodium bicarbonate, brine and dried over Na2SO4. This was then filtered, concentrated in vacuo and purified by silica gel chromatography (5% EtOAc/Hexanes to 20% EtOAc/Hexanes) to yield 12.2g (60%) of product.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]=[C:14]([NH2:16])[C:13]3[CH:12]=[C:11]([CH3:17])[S:10][C:9]=3[NH:8][C:7]=2[CH:18]=1.[CH3:19][N:20]1[CH2:25][CH2:24]N[CH2:22][C@@H:21]1[CH2:26][CH2:27][S:28][CH3:29].C(N(C(C)C)CC)(C)C>CS(C)=O.C1(C)C=CC=CC=1.C(OCC)(=O)C.[OH-].[Na+]>[ClH:1].[ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]=[C:14]([N:16]3[CH2:24][CH2:25][N:20]([CH3:19])[C@@H:21]([CH2:26][CH2:27][S:28][CH3:29])[CH2:22]3)[C:13]3[CH:12]=[C:11]([CH3:17])[S:10][C:9]=3[NH:8][C:7]=2[CH:18]=1
Reactant: Cc1cc2c(s1)Nc1cc(F)ccc1N=C2N
Reactant: CSCC[C@H]1CNCCN1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CSCC[C@H]1CN(C2=Nc3ccc(F)cc3Nc3sc(C)cc32)CCN1C
Yield: 71.3 %

Procedure:
Heat a mixture of 6-fluoro-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride salt (0.135 g, 0.476 mmol), (S)-1-methyl-2-(2-methylsulfanyl-ethyl)-piperazine (0.166 g, 0.95 mmol) and diisopropyl ethylamine (0.083 mL, 0.476 mmol) in DMSO (0.2 mL) and toluene (0.8 mL) at 110° C. for 46 hours. Dilute the reaction mixture with ethyl acetate and 0.1N sodium hydroxide solution. The ethyl acetate extract gives 0.196 g. of the crude product. Silica gel chromatography, eluting with methylene chloride:methanol (100:5), gives 0.081 g of the title compound as an orange oil. The dihydrochloride salt precipitates in ethyl acetate as an orange solid: mp 194° C.; mass spectrum (ion spray): m/z=405 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:12][NH2:13])[C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6]1)=[O:4].[OH-].[Li+].O>CO>[NH2:13][CH2:12][C:5]1([C:3]([OH:4])=[O:2])[C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6]1
Reactant: COC(=O)C1(CN)CC12CCCC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NCC1(C(=O)O)CC12CCCC2
Yield: 38.8 %

Procedure:
To a solution of 1-aminomethyl-spiro[2.4]heptane-1-carboxylic acid methyl ester (3.40 g, 18.6 mmol) was added methanol (75 mL) and lithium hydroxide-water (LiOH—H2O) (1.55 g, 37.1 mmol). The mixture was heated to reflux under nitrogen for 48 hours. The solvent was removed by evaporation under reduced pressure and the residue was dissolved in water (50 mL). With ice bath cooling, concentrated HCl (˜2.5 mL) was added until the pH was adjusted to 6. A white precipitate was isolated by filtration and dried under vacuum to yield 1.22 g (39%) of 1-aminomethyl-spiro[2.4]heptane-1-carboxylic acid as an off-white solid: mp 231–235° C. (decomposition); 1H NMR (300 MHz, D2O) δ 0.78 (d, J=4.7 Hz, 1H), 1.32 (d, J=4.7 Hz, 1H), 1.40 (m, 1H), 1.54–1.77 (m, 7H), 2.86 (d, J=13.2 Hz, 1H), 3.43 (d, J=13.2 Hz, 1H); MS (APCI) m/z 170 [M+H]+. Anal. Calcd. For C9H15NO2 −1.1H2O: C, 57.18; H, 9.17; N, 7.41. Found: C, 57.38; H, 8.82; N, 7.09.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]O)=[CH:6][CH:5]=1)[CH3:2].[ClH:12]>>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Cl:12])=[CH:6][CH:5]=1)[CH3:2]
Reactant: Cl
Reactant: CCOc1ccc(CO)cc1
Product: CCOc1ccc(CCl)cc1

Procedure:
4-Ethoxybenzyl alcohol (5 g) and concentrated hydrochloric acid (8.5 cm3) were vigorously stirred together for 30 minutes. The 2 phases were then allowed to separate, and the lower layer separated off, and diluted with chloroform. The organic solution was dried over anhydrous magnesium sulphate, and removal of the solvent by evaporation gave 4-ethoxybenzyl chloride (5.6 g). (This product is not stable on keeping, so was converted immediately to the phosphonium salt--see Example 12).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([C:19]3([CH2:31][CH2:32][CH3:33])[CH2:23][CH2:22][CH2:21][N:20]3C(OC(C)(C)C)=O)=[O:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([C:19]3([CH2:31][CH2:32][CH3:33])[CH2:23][CH2:22][CH2:21][NH:20]3)=[O:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: CCCC1(C(=O)c2ccc3c(ccn3C(=O)OC(C)(C)C)c2)CCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC1(C(=O)c2ccc3[nH]ccc3c2)CCCN1
Yield: 71.6 %

Procedure:
To a stirred solution of 5-(1-tert-butoxycarbonyl-2-propyl-pyrrolidine-2-carbonyl)-indole-1-carboxylic acid tert-butyl ester (0.132 g, 0.289 mmol) in DCM (3 mL) at 20° C. under nitrogen was added TFA (1 mL). After 14 hours the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with DCM. The combined organic phases were concentrated in vacuo then purified by chromatography (silica, 0 to 30% MeOH in DCM) to furnish (1H-indol-5-yl)-(2-propyl-pyrrolidin-2-yl)-methanone (0.053 g, 0.207 mmol, 72%) as a beige foam, MS=257 [M+H]+.
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6](F)[CH:5]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([NH:2][CH3:1])[CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methylamine (2 M in tetrahydrofuran, 11.4 mL) was added to a mixture of 4-bromo-2-fluoro-1-nitro-benzene (2.50 g) and K2CO3 (1.90 g) in dimethylformamide (40 mL). The resulting mixture was stirred at ambient temperature overnight. Then, the mixture was concentrated under reduced pressure and dichloromethane was added. The resulting mixture was washed with 0.5 M aqueous HCl solution and brine and dried (MgSO4). The solvent was removed to give the product as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:38])[CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:49](=[O:54])[C:50]([O:52][CH3:53])=[O:51]>ClCCl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:38])[CH2:23][CH2:24][CH:25]1[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:29][CH2:30]1)[C:49](=[O:54])[C:50]([O:52][CH3:53])=[O:51])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2ccccc2NCCCNC(=O)OCc2ccccc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C(=O)N(CCCNC(=O)OCc1ccccc1)c1ccccc1C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the compound prepared in Example 326 (620 mg) in dichloromethane (10.0 mL) at 0° C. was added diisopropylethylamine (0.82 mL) followed by methyl 2-chloro-2-oxoacetate (0.22 mL). The reaction was allowed to warm to room temperature and then stirred for 2 hours. The solution was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and brine. The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 50% ethyl acetate/hexane) to furnish the title compound (722 mg) with the following physical properties.
Reaction SMILES: [CH:1]1([CH:4]([NH2:8])[CH:5]2[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[Cl:9][CH2:10][CH2:11][N:12]=[C:13]=[O:14]>O1CCCC1>[CH:1]1([CH:4]([CH:5]2[CH2:7][CH2:6]2)[NH:8][C:13]([NH:12][CH2:11][CH2:10][Cl:9])=[O:14])[CH2:3][CH2:2]1
Reactant: NC(C1CC1)C1CC1
Reactant: O=C=NCCCl
Solvent: C1CCOC1
Product: O=C(NCCCl)NC(C1CC1)C1CC1
Reaction time: 15 h

Procedure:
A solution made from 13.4 g of dicyclopropylmethylamine in 30 ml tetrahydrofuran is added dropwise to a solution of 13 g of β-chloroetyl isocyanate in 15 ml tetrahydrofuran while maintaining the inner temperature from 0° to +5° C. Then, the reaction mixture is kept at room temperature for 15 hours. Afterwards, the solution is evaporated to dryness and the dry residue, weighing 26.5 g, is used as such for the next step of the synthesis. For analytical purpose, a sample of the raw urea is recrystallised from acetonitrile. The N-(dicyclopropylmethyl) N-(β-chloroethyl) urea occurs as white crystals melting at 103°-104° C. with decomposition.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]([NH2:16])=[O:15])[N:7]=3.[CH3:19][N:20]([CH:22](OC)OC)[CH3:21]>O1CCOCC1>[CH3:19][N:20]([CH3:22])/[CH:21]=[N:16]\[C:14]([C:8]1[N:7]=[C:6]2[N:10]([CH2:11][CH2:12][O:13][C:4]3[CH:3]=[C:2]([Br:1])[CH:18]=[CH:17][C:5]=32)[CH:9]=1)=[O:15]
Reactant: NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: COC(OC)N(C)C
Solvent: C1COCCO1
Product: CN(C)/C=N\C(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 100 °C
Yield: 94.2 %

Procedure:
To a suspension of 8-bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide (7.67 g, 24.9 mmol) in dioxane (150 mL) was added DMF-DMA (9.92 mL, 74.7 mmol) and the reaction mixture heated at 100° C. for 1 h. During the reaction the solids dissolved to give a brown solution. The reaction mixture was concentrated in vacuo and the solid residue triturated with diethyl ether (˜150 mL). The product was collected by filtration and dried in vacuo at 45° C. for 3 h to yield 8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid 1-dimethylamino-meth-(Z)-ylideneamide as a buff coloured solid (8.52 g, 94%). 1H NMR (400 MHz, d6-DMSO) 8.56 (1H, s), 8.34 (1H, d, J=8.6 Hz), 7.96 (1H, s), 7.32 (1H, dd, J=8.6, 2.0 Hz), 7.26 (1H, d, J=2.1 Hz), 4.51-4.46 (4H, m), 3.16 (3H, s), 3.08 (3H, s). 1H NMR showed product to contain 5% 8-iodo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid 1-dimethylamino-meth-(Z)-ylideneamide.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].S(OC(C#C)C)([C:16]1[CH:22]=CC(C)=[CH:18][CH:17]=1)(=O)=O>CN(C=O)C>[C:1]1(=[O:11])[N:5]([CH:17]([C:16]#[CH:22])[CH3:18])[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C#CC(C)OS(=O)(=O)c1ccc(C)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: C#CC(C)N1C(=O)c2ccccc2C1=O

Procedure:
To a solution of potassium phthalimide (0.275 mole) in DMF (20 ml), 2-tosyloxy-3-butyne (0.25 mole) is added and allowed to react for 3 hours at 70° C. After cooling, the reaction mixture is extracted with chloroform and the chloroform layer is washed and dried. Removal of the chloroform, in vacuo, yields crude 2-phthalimido-3-butyne.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([CH3:15])([CH3:14])[C:7](=[O:13])[N:8]2[CH3:12])=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][N:25]=1)[C:20](O)=[O:21]>>[F:11][C:10]1[C:2]([NH:1][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][N:25]=[C:17]([CH3:16])[CH:18]=2)=[CH:3][CH:4]=[C:5]2[C:9]=1[N:8]([CH3:12])[C:7](=[O:13])[C:6]2([CH3:15])[CH3:14]
Reactant: Cc1cc(C(=O)O)ccn1
Reactant: CN1C(=O)C(C)(C)c2ccc(N)c(F)c21
Product: Cc1cc(C(=O)Nc2ccc3c(c2F)N(C)C(=O)C3(C)C)ccn1

Procedure:
Prepared in analogy to example 26 from 6-amino-7-fluoro-1,3,3-trimethylindolin-2-one (example 13d) and 2-methylisonicotinic acid. The title compound was obtained as light yellow crystals.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[N+:24]([CH2:27][CH2:28][C:29]1[CH:42]=[CH:41][C:32]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[CH:31][CH:30]=1)([O-])=[O:25].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CN(C)C1C=CN=CC=1.O1CCCC1>[N:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[O:34][CH2:33][C:32]1[CH:41]=[CH:42][C:29]([CH2:28][C:27]2[CH:2]=[C:1]([C:3]3[C:4]([N:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=3)[O:25][N:24]=2)=[CH:30][CH:31]=1
Reactant: O=[N+]([O-])CCc1ccc(COc2ccccn2)cc1
Reactant: C#Cc1cccnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Yield: 70 %

Procedure:
To a solution of di-tert-butyl (3-ethynylpyridin-2-yl)imidodicarbonate (12 g) described in Manufacturing Example 2-4-1, 2-(4-(2-nitro-ethyl)-benzyloxy)pyridine (19.4 g) described in Manufacturing Example 2-1-4, 4-dimethylaminopyridine (230 mg) and tetrahydrofuran (200 mL) was added di-tert-butyl dicarbonate (28.8 g) in 4 portions over the course of 8 hours at room temperature with stirring. After addition was complete, this was stirred at room temperature for a further 22 hours. Silica gel was added to the reaction solution, and the solvent was concentrated under a reduced pressure. The resulting silica gel was purified by silica gel chromatography (heptane:ethyl acetate=3:1 then 2:1) to obtain an oily product (11.8 g, containing about 70% of title compound) containing the title compound.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:22][CH2:21][C@@:12]34[C:13]5[CH:14]=[C:15]([OH:20])[CH:16]=[CH:17][C:18]=5[CH2:19][C@@H:6]2[C@:7]3([OH:23])[CH2:8][CH2:9][O:10][CH2:11]4)[CH2:3][CH2:2]1.Cl.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1.N1C=CC=CC=1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]2[CH2:22][CH2:21][C@@:12]34[C:13]5[CH:14]=[C:15]([O:20][C:25](=[O:32])[C:26]6[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=6)[CH:16]=[CH:17][C:18]=5[CH2:19][C@@H:6]2[C@:7]3([OH:23])[CH2:8][CH2:9][O:10][CH2:11]4)[CH2:2][CH2:3]1
Reactant: Oc1ccc2c(c1)[C@]13CCN(CC4CC4)[C@H](C2)[C@]1(O)CCOC3
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Oc1ccc2c(c1)[C@]13CCN(CC4CC4)[C@H](C2)[C@]1(O)CCOC3)c1cccnc1

Procedure:
Equimolar amounts of 17-cyclopropylmethyl-3,14β-dihydroxy-6-oxamorphinan (XVI), nicotinoyl chloride hydrochloride and pyridine are mixed together in dry methylene chloride and the mixture is heated at reflux for 3 hours to produce the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[C:5]([O:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][C:14]([O:17]CC)=[CH:13][C:12]1=[O:20])=[O:6]>C(Cl)Cl.C(OCC)C>[CH3:1][NH:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[C:5]([O:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][C:12]1=[O:20])=[O:6]
Reactant: CCOC1=CC(=O)C(CCCOC(=O)c2ccccc2NC)CC1
Solvent: ClCCl
Solvent: CCOCC
Product: CNc1ccccc1C(=O)OCCCC1CCC(=O)CC1=O

Procedure:
Compound 4 was stirred in a mixture of THF/3N HCl (1/1) at rt for 3 h and the mixture was concentrated. The crude product was washed with EtOAc/hexane/MeOH (1/2/0.5) to afford 6 as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.83 (1H, m), 7.34 (1H, m), 6.55 (2H, m), 4.22 (2H, t, J=6.3 Hz), 3.60 (2H, m), 2.84 (3H, s), 2.52-1.50 (9H, m); 13C NMR (75MHz, CDCl3) δ 204.3, 203.8, 168.6, 151.6, 134.9, 131.7, 131.5, 115.2, 111.6, 110.5, 64.1, 58.4, 49.1, 39.9, 30.1, 26.4, 26.0, 24.7; ESI MS m/z 326 (M++Na+).