Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][CH:7]=[N:6]1)[CH3:2].[C:19]([C:21]1[CH:22]=[C:23]([S:40]([N:43]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][C:51]=2[O:58][CH3:59])[C:44]2[S:48][N:47]=[CH:46][N:45]=2)(=[O:42])=[O:41])[CH:24]=[CH:25][C:26]=1[O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][C:29]=1I)#[N:20]>>[C:19]([C:21]1[CH:22]=[C:23]([S:40]([N:43]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][C:51]=2[O:58][CH3:59])[C:44]2[S:48][N:47]=[CH:46][N:45]=2)(=[O:42])=[O:41])[CH:24]=[CH:25][C:26]=1[O:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][C:35]([F:37])([F:36])[F:38])=[CH:32][C:33]=1[C:9]1[N:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]=[CH:7][CH:8]=1)#[N:20]
Reactant: CCOCn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(OC(F)(F)F)cc3I)c(C#N)c2)c(OC)c1
Product: CCOCn1nccc1-c1cc(OC(F)(F)F)ccc1Oc1ccc(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ncns2)cc1C#N
Yield: 29 %

Procedure:
Prepared according to Method U (below) using 1-(ethoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 337, 197 mg, 0.714 mmol), and 3-cyano-N-(2,4-dimethoxybenzyl)-4-[2-iodo-4-(trifluoromethoxy)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 497, 210 mg, 0.42 mmol). The material was purified by column chromatography eluting with ethyl acetate:heptane (1:1, by volume) to furnish the title compound as a white solid, 70 mg, 29% yield.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].CS[C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17]>CO>[CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:14]([NH:15][N+:16]([O-:18])=[O:17])=[NH:19]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CSC(=N)N[N+](=O)[O-]
Solvent: CO
Product: Cc1nc[nH]c1CSCCNC(=N)N[N+](=O)[O-]
Reaction time: 48 h

Procedure:
A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole (1.7 g.) and S-methyl-N-nitroisothiourea (1.45 g.) in methanol (35 ml.) was heated at 50°-60° for 2.5 hours and then set aside at room temperature for 48 hours. The crystalline product was filtered off and recrystallised from methanol to give N-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N'-nitroguanidine, m.p. 184°-186°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:6](O)=O)[CH3:2].C=O.N1CCCCC1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:20])[C:5](=[CH2:6])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[CH3:2]
Reactant: CCOC(=O)C(CCCCOC1CCCCC1)C(=O)O
Agent: C=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: C=C(CCCCOC1CCCCC1)C(=O)OCC

Procedure:
4.9 g of 6-cyclohexyloxy-2-methylenehexanoic acid ethyl ester, in the form of a colourless oil, which is purified by chromatography on silica gel (migrating agent: 90:10 petroleum ether/ethyl acetate), are obtained by the procedure described in Example (1b) from 7.4 g of [4-(cyclohexyloxy)-butyl]-malonic acid ethyl ester, 0.85 g of paraformaldehyde, 5.2 ml of pyridine and 0.3 ml of piperidine.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]2=[N:6][C:7]=1[Cl:8].B(O)(O)[C:25]1[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].N#N>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.O1CCOCC1>[Cl:8][C:7]1[N:6]=[C:5]2[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:10][CH2:11][CH2:12][C:4]2=[N:3][C:2]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCOC(=O)CCCCCCN1CCCc2nc(Br)c(Cl)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccc(C)cc3)c(Cl)nc21
Temperature: 150 °C

Procedure:
A mixture of ethyl 7-(2-bromo-3-chloro-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (Intermediate EB) (200 mg, 0.494 mmol), p-tolylboronic acid (Aldrich) (73.9 mg, 0.544 mmol) and potassium carbonate (205 mg, 1.482 mmol) were combined in a microwave vial. Dioxane (2 ml) was added and the flask was sealed and deoxygenated by evacuation/N2 purge (×3). Pd(Ph3P)4 (57.1 mg, 0.049 mmol) was added and the mixture was de-oxygenated by evacuation/N2 purge (×3) and heated at 150° C. for 3 hours using microwave radiation. The mixture was diluted with water and extracted with EtOAc (×2). The extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 20-100% EtOAc in iso-hexane followed by 10% MeOH in DCM to elute the bis product. Further purification by chromatography on silica eluting with 0-70% EtOAc in iso-hexane afforded a mixture of the titled compound (mono adduct) and the bis adduct (2:1 ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([CH3:32])[CH:24]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Reactant: Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cccc(-c2ccccc2C(=O)NCCc2c[nH]c3ccc(Cl)cc23)c1
Yield: 29.2 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methylbiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), m-tolylboronic acid (0.025 g; 0.176 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 10% ethyl acetate in dichloromethane) furnished 0.020 g (30%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methylbiphenyl-2-carboxamide as a white solid.
Reaction SMILES: [Br:1][C:2]1(C2C=CC=CN=2)[CH:7]=[CH:6][CH:5]=[C:4](Br)[NH:3]1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[N:26]=[N:25][C:24]([Sn](CCCC)(CCCC)CCCC)=[CH:23][CH:22]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[N:3]=[C:4]([C:24]2[N:25]=[N:26][C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=3)=[CH:22][CH:23]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: BrC1=CC=CC(Br)(c2ccccn2)N1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(-c2ccccn2)nn1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2ccc(-c3ccccn3)nn2)n1

Procedure:
The 3-(6-bromopyridin-2-yl)-6-(pyridin-2-yl)pyridazine was prepared according to the general Stille coupling method, starting from a mixture of 1.6 g (6.74 mmol) of 2,6-dibromobipyridine 42, 3 g (6.74 mmol) of 6-(pyridin-2-yl)-3-(tributylstannyl)pyridazine 39, 546 mg (0.47 mmol) of tetrakis(triphenylphosphine)-palladium(0) and 50 ml of freshly distilled toluene. The mixture is refluxed for 24 h. The residue obtained is chromatographed on a silica gel (eluent: ethyl acetate/petroleum ether=1/9). The brominated product 43 is isolated with a yield of 72%.
Reaction SMILES: [S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]1[C:11](=O)[CH2:12][NH:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1(C)C=CC=CC=1>[F:23][C:22]([F:25])([F:24])[O:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[S:37][C:11]([CH:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[S:1]3)=[CH:12][N:13]=2)=[CH:16][CH:17]=1
Reactant: O=C(NCC(=O)C1C=Cc2ccccc2S1)c1ccc(OC(F)(F)F)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1ccc(-c2ncc(C3C=Cc4ccccc4S3)s2)cc1
Yield: 88.4 %

Procedure:
In a manner similar to Step E of Example 1, the reaction of 1.0 g (0.0026 mole) of N-[2-(thianaphthalene-2-yl)-2oxoethyl]-4-trifluoromethoxybenzamide with 0.53 g (0.0013 mole) of Lawesson's reagent in 25 ml of toluene yielded 0.45 g of 2-(4-trifluoromethoxyphenyl)-5-(thianaphthalene-2-yl)thiazole as a solid, mp 65-69, compound 40 of Table 1.
Reaction SMILES: [Br:1][C:2]1[S:11][C:5]2[N:6]=[CH:7][N:8]=[C:9](Cl)[C:4]=2[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C.[N:27]1([CH2:32][CH2:33][O:34][CH2:35][CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:31][CH2:30][CH2:29][CH2:28]1>C1COCC1.O>[Br:1][C:2]1[S:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([N:39]3[CH2:40][CH2:41][CH:36]([CH2:35][O:34][CH2:33][CH2:32][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:37][CH2:38]3)[C:4]=2[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C1CCN(CCOCC2CCNCC2)C1
Reactant: Clc1ncnc2sc(Br)c(-c3ccccc3)c12
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Brc1sc2ncnc(N3CCC(COCCN4CCCC4)CC3)c2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
To a stirred solution of 6-bromo-4-chloro-5-phenyl-thieno[2,3-d]pyrimidine (0.820 g, 2.52 mmol) in THF (50 mL), was added diisopropylethylamine (0.65 mL, 3.78 mmol) and 4-(2-pyrrolidin-1-ylethoxymethyl)piperidine (0.801 g, 3.78 mmol) in one portion, and the reaction left to stir at room temperature overnight. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The reaction was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography using DCM: MeOH (0-25%) as eluent to afford the named product (0.828 g, 66%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCCCCCBr
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: CCCCCCCn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.72 g) and 1-bromoheptane (0.283 mL) as starting materials, 5-benzyloxy-N-[(1-heptylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.86 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, N-[(1-heptylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.62 g) was obtained.
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[C:25]([NH:26][C:27](=[O:29])[CH3:28])=[CH:24][CH:23]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:17]=1[OH:30])(C1C=CC(C)=CC=1)(=O)=O.[H-].[Na+].O>C1COCC1.C(OCC)(=O)C>[C:27]([NH:26][C:25]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][O:30][C:17]=2[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=1)(=[O:29])[CH3:28]
Reactant: COC(=O)c1ccc(NC(C)=O)c(CCCCOS(=O)(=O)c2ccc(C)cc2)c1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(C)=O)c2c1OCCCC2
Reaction time: 24 h

Procedure:
To a solution of 5 g (14.6 mmol) of methyl 3-(4'-tosyloxybutyl)-4-acetylaminosalicylate in 50 ml of THF is added 0.64 g (16.1 mmol) of sodium hydride (60% dispersion in mineral oil) portionwise at room temperature. After addition is complete stirring is continued 24 hours at room temperature. Water is added dropwise to decompose excess NaH. The reaction mixture is diluted with ethyl acetate and washed with water. The organic layer is dried over MgSO4, filtered and concentrated. Flash chromatography (5% EtOAc/hexanes) provides methyl 6-acetylamino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate.
Reaction SMILES: [BrH:1].C([N:9]1[CH2:14][C@@H:13]([CH2:15][OH:16])[C@H:12]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C@@H:11]([OH:24])[CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[BrH:1].[OH:16][CH2:15][C@@H:13]1[CH2:14][NH:9][CH2:10][C@H:11]([OH:24])[C@H:12]1[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1
Reactant: OC[C@@H]1CN(Cc2ccccc2)C[C@H](O)[C@H]1c1ccc(O)cc1
Agent: [Pd]
Agent: Br
Solvent: CO
Product: OC[C@@H]1CNC[C@H](O)[C@H]1c1ccc(O)cc1
Yield: 89.1 %

Procedure:
The solution of 18.6 g (47.2 mmol) of crude (3R,4R,5S)-1-benzyl-5-hydroxymethyl-4-(4-hydroxy-phenyl)-piperidin-3-ol hydrobromide in 250 ml of methanol was flushed with argon, treated with 1.5 g of palladium-on-charcoal (10%) and exhaustively hydrogenated at room temperature under normal pressure during 18 hours The reaction mixture was filtered over Dicalit and the residue washed twice with 100 ml of warm methanol. The methanol solutions were combined and evaporated under reduced pressure to yield 12.79 g of (3R,4R,5S)-5-hydroxymethyl-4-(4-hydroxy-phenyl)-piperidin-3-ol hydrobromide [MS: 223 (M)+] as a yellowish foam which was used in the next step without further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH:13]=[CH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CCCCCCCCCCNC(=O)C=C)C=CC=CC=1.C(NC(=O)C=C)CC1C=CC=CC=1>>[CH2:10]([NH:11][C:12](=[O:15])[CH:13]=[CH2:14])[CH2:9][CH2:8][CH2:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=CC(=O)NCCCCc1ccccc1
Agent: C=CC(=O)NCCCCCCCCCCc1ccccc1
Agent: C=CC(=O)NCCc1ccccc1
Product: C=CC(=O)NCCCCCCCCCC

Procedure:
The same procedure as in Example 18 was repeated except that N-(4-phenylbutyl)acrylamide, N-(10-phenyldecyl)acrylamide and N-phenethylacrylamide were used, respectively, in place of N-decylacrylamide to obtain N-cyclopropylmethyl-7α-(4-phenylbutylcarbamoyl)-6,14-endoethenotetrahydronormorphide 25.methanesulfonic acid salt (39%), N-cyclopropylmethyl-7β-(4-phenylbutylcarbamoyl)-6,14-endoethenotetrahydronormorphide 26.methanesulfonic acid salt (5%), N-cyclopropylmethyl-7α-(10-phenyldecylcarbamoyl)-6,14-endoethenotetrahydronormorphide 27.methanesulfonic acid salt (21%), and N-cyclopropylmethyl-7β-phenethylcarbamoyl-6,14-endoethenotetrahydronormorphide 28.methanesulfonic acid salt (3%), respectively.
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][S:13](=[O:24])(=[O:23])[N:12]=2)=[CH:7][CH:6]=1.Cl>C1(C)C=CC=CC=1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]2([CH3:1])[C:11]([C:8]3[CH:7]=[CH:6][C:5]([Cl:4])=[CH:10][CH:9]=3)=[N:12][S:13](=[O:24])(=[O:23])[NH:14]2)=[CH:17][CH:18]=1
Reactant: O=S1(=O)N=C(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)=N1
Reactant: C[Mg]Br
Agent: Cl
Solvent: Cc1ccccc1
Product: CC1(c2ccc(Cl)cc2)NS(=O)(=O)N=C1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl magnesium bromide (0.89 M tetrahydrofuran solution, 43.1 ml) was added dropwise to a toluene (200 ml) suspension of the compound (10.0 g, 29.5 mmol) obtained in Step 1 above at 0° C. The resulting mixture was stirred at room temperature for 1 hour and then 1 N aqueous hydrochloric acid solution was added, followed by extraction with ethyl acetate. Then, the organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine and dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give the title compound (11.1 g, quantitative) as a colorless oil.
Reaction SMILES: [Cl:1][N:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[O:20][CH:19]=[N:18][CH:17]=3)=[C:12]([O:21][CH3:22])[CH:11]=2)[NH:3]1.[CH3:23][NH2:24].C1COCC1>C(COC)OC>[Cl:1][N:2]1[N:7]=[C:6]([NH:24][CH3:23])[CH:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[O:20][CH:19]=[N:18][CH:17]=3)=[C:12]([O:21][CH3:22])[CH:11]=2)[NH:3]1
Reactant: CN
Reactant: COc1cc(NC2=CC(Cl)=NN(Cl)N2)ccc1-c1cnco1
Solvent: C1CCOC1
Solvent: COCCOC
Product: CNC1=NN(Cl)NC(Nc2ccc(-c3cnco3)c(OC)c2)=C1
Reaction time: 3 h
Yield: 77 %

Procedure:
2,4-Dichloro-6-(4-oxazol-5-yl-3-methoxyphenylamino)triazine 214A (1.8 g, 5.4 mmol) was suspended in dimethoxyethane (50 mL). 2 M Methylamine in THF (27 mL, 54 mmol) was added dropwise and the reaction mixture stirred for 3 h. The crude product was filtered and triturated with ethanol (20 mL) and dried to yield 1.37 g (77%) of the title compound. LCMS Condition A retention time=2.61 min (>95%), M+H+=333.16 (100%).
Reaction SMILES: [CH3:1][C@:2]([NH:26]C(=O)OC(C)(C)C)([C:5](=[O:25])[NH:6][C:7]1[CH:8]=[N:9][C:10]([O:13][C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH2:16][CH:17]([CH3:24])[CH2:18][O:19]3)=[CH:11][CH:12]=1)[CH2:3][CH3:4].C(O)(C(F)(F)F)=O>ClCCl>[NH2:26][C@:2]([CH3:1])([CH2:3][CH3:4])[C:5]([NH:6][C:7]1[CH:8]=[N:9][C:10]([O:13][C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH2:16][CH:17]([CH3:24])[CH2:18][O:19]3)=[CH:11][CH:12]=1)=[O:25]
Reactant: CC[C@@](C)(NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2cccc3c2CC(C)CO3)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@](C)(N)C(=O)Nc1ccc(Oc2cccc3c2CC(C)CO3)nc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
In a 50 mL round-bottomed flask tert-butyl N-[(1R)-1-methyl-1-[[6-(3-methylchroman-5-yl)oxy-3-pyridyl]carbamoyl]propyl]carbamate (Intermediate 146, 55.8 mg, 0.104 mmol) was dissolved in Dichloromethane (3 mL) to give a pale yellow solution. The reaction mixture was cooled at 0° C. and TFA (2 mL, 26.0 mmol) was added. The reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was evaporated in vacuo to give the crude product as a yellow oil. The sample was charged on a 2 g SCX cartridge. It was then flushed with 36 mL of MeOH followed by 25 mL of 2M solution of ammonia in MeOH. The ammonia eluate was evaporated in vacuo affording the title compound (32.9 mg) as pale yellow oil.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:6][O:5]1)[CH:2]=[CH2:3].[C:7](=[O:17])([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:8].[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O>CC(OC)(C)C>[CH2:10]([O:9][C:7](=[O:17])[NH:8][CH2:6][C@H:4]([OH:5])[CH2:1][CH:2]=[CH2:3])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=CCC1CO1
Reactant: NC(=O)OCc1ccccc1
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: COC(C)(C)C
Product: C=CC[C@@H](O)CNC(=O)OCc1ccccc1
Yield: 59.5 %

Procedure:
To a solution of 2-allyl-oxirane (Synthesis 1986, 309; 918 mg, 10.9 mmol) in TBME (12 mL) were added benzyl carbamate (750 mg, 4.96 mmol), 4-nitrobenzoic acid (146 mg, 0.87 mmol) and (1S,2S)-(+)-N—N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II) 264 mg, 0.44 mmol) at RT, then after 72 h the reaction mixture was partitioned between TBME and sat. aq. NaHCO3 solution. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; heptane-EtOAc gradient) produced the title compound (694 mg, 48%). Brown oil, MS: 236.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12](/[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:22][CH:21]=3)\[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>>[CH3:38][O:37][C:35]([CH2:34][NH:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12](/[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]4)=[CH:22][CH:21]=3)\[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1)=[O:36]
Reactant: COC(=O)CBr
Reactant: Nc1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Product: COC(=O)CNc1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinone and methyl bromoacetate
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]([CH3:17])([CH3:16])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:18]4[CH2:19][CH2:20][C:21](=[O:24])[NH:22][N:23]=4)[CH:13]=3)[N:8]=2)=[CH:3][CH:2]=1>[O-2].[O-2].[Mn+4].O1CCOCC1>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]([CH3:16])([CH3:17])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:18]4[CH:19]=[CH:20][C:21](=[O:24])[NH:22][N:23]=4)[CH:13]=3)[N:8]=2)=[CH:3][CH:2]=1
Reactant: CC1(C)C(c2ccncc2)=Nc2ccc(C3=NNC(=O)CC3)cc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CC1(C)C(c2ccncc2)=Nc2ccc(-c3ccc(=O)[nH]n3)cc21

Procedure:
1.75 g. (5.5 mMole) 2-(4-pyridyl)-3,3-dimethyl-5-(3-oxo-2,3,4,5-tetrahydro-6-pyridazinyl)-3H-indole (see Example 2 b)) was stirred with 25 g. manganese dioxide in 260 ml. dioxan for 20 hours at 90° C. The reaction mixture was subsequently filtered off with suction, the residue stirred up with methanol/methylene chloride and the combined filtrates evaporated to dryness. After crystallisation from methanol, there was obtained 1 g. (58% of theory) of the title compound; m.p. 305°-307° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[N:6]=1)=[O:4].[OH-].[Na+]>CO>[CH:12]1([CH2:11][O:10][C:8]2[N:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:9]=2)[CH2:13][CH2:14]1
Reactant: COC(=O)c1cc(OCC2CC2)n(-c2ccccc2F)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(OCC2CC2)n(-c2ccccc2F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
The crude compound obtained in step 1 was dissolved in 10 ml of methanol. 1.4 ml of an aqueous 1 M solution of sodium hydroxide were added and the mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the residue purified by preparative HPLC to give 102 mg (58%) of the title compound