Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:17][C:18]1[C:26]([F:27])=[C:25]2[C:21]([C:22]([CH3:31])([CH3:30])[C:23](=[O:29])[N:24]2[CH3:28])=[CH:20][C:19]=1[F:32]>CN(C=O)C.C([O-])(O)=O.[Na+]>[F:32][C:19]1[CH:20]=[C:21]2[C:25](=[C:26]([F:27])[C:18]=1[NH:17][C:1](=[O:9])[C:2]1[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=1)[N:24]([CH3:28])[C:23](=[O:29])[C:22]2([CH3:31])[CH3:30]
Reactant: O=C(O)c1ccncc1
Reactant: CN1C(=O)C(C)(C)c2cc(F)c(N)c(F)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1C(=O)C(C)(C)c2cc(F)c(NC(=O)c3ccncc3)c(F)c21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of isonicotinic acid (70 mg, 0.569 mmol) in DMF (2 ml) were added triethylamine (0.24 ml, 1.7 mmol) and Mukaiyama reagent (312 mg, 1.13 mmol) followed by the addition of 6-amino-5,7-difluoro-1,3,3-trimethyl-1,3-dihydro-indol-2-one (154 mg, 0.682 mmol). The resultant reaction mixture was stirred at 25° C. for 12 hours. The mixture was diluted with saturated aqueous NaHCO3 solution (10 ml), and extracted with dichloromethane (2×20 ml). The combined organic layers were washed with brine (15 ml), dried over anhydrous Na2SO4 and the solvent was evaporated. The crude material was purified by column chromatography with amine functionalized silica gel using ethyl acetate/heptane as eluent, followed by purification by prep-HPLC. The title compound was obtained as off-white solid (45 mg).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[I:13][C:14]1[CH:25]=[CH:24][C:17]([O:18][CH2:19][C:20]([NH:22][NH2:23])=[O:21])=[CH:16][CH:15]=1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:23][NH:22][C:20](=[O:21])[CH2:19][O:18][C:17]1[CH:24]=[CH:25][C:14]([I:13])=[CH:15][CH:16]=1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)COc1ccc(I)cc1
Solvent: CC(=O)O
Product: O=C(COc1ccc(I)cc1)NN=C1C(=O)Nc2ccc(I)cc21
Temperature: 100 °C
Yield: 79 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 2-(4-iodophenoxy)acetohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 173 mg of the title compound (79%) as a yellow solid in 96.4% purity by HPLC (Rt: 6.41, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:23][CH2:22][CH2:21][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.[OH:24]O.N>C(O)(=O)C>[Cl:1][C:2]1[C:3]2[S:23](=[O:24])[CH2:22][CH2:21][C:4]=2[N:5]=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[CH2:12][CH2:13]2)[N:7]=1
Reactant: Clc1ccc(N2CCN(c3nc(Cl)c4c(n3)CCS4)CC2)cc1
Reactant: OO
Agent: N
Solvent: CC(=O)O
Product: O=S1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(Cl)c21
Temperature: 10 °C
Reaction time: 2 h

Procedure:
14.69 g 4-chloro-2-[4-(4-chloro-phenyl)-piperazin-1-yl]-6,7-dihydro-thieno[3,2-d]pyrimidine are placed in 140 ml glacial acetic acid and cooled to 10° C. cooled. 3.79 ml hydrogen peroxide (35%) are added dropwise, then the mixture is stirred for 2 hours. A further 1 eq hydrogen peroxide is added, the mixture is stirred for 8 hours at ambient temperature. Then the reaction mixture is stirred into ice water, made basic with ammonia solution. The precipitate formed is suction filtered, washed with water and dried. 11.90 g of the product are obtained as a powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:41]([NH:53][NH2:54])(=[O:52])[CH2:42][NH:43][C:44]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:45]>>[C:44]([NH:43][CH2:42][C:41]([NH:53][NH:54][C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:52])(=[O:45])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: NNC(=O)CNC(=O)c1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NNC(=O)CNC(=O)c1ccccc1
Yield: 18.9 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (100 mg, 0.18 mmol) and hippuric acid hydrazide (42 mg, 0.22 mmol) according to Method C with HPLC purification to give the title compound (24 mg). IR (KBr) 3274, 1652, 1616 cm−1; HRMS m/z 705.2640 (calc. of monoisotopic mass for C35H39N5O11 gives 705.2646).
Reaction SMILES: [CH3:1][CH:2]([OH:13])[CH2:3][CH2:4][CH:5](O)[CH2:6][CH2:7][CH:8]=[CH:9][CH2:10][CH3:11].OS([O-])(=O)=O.[K+]>>[CH2:6]([CH:5]1[CH2:4][CH2:3][CH:2]([CH3:1])[O:13]1)[CH2:7][CH:8]=[CH:9][CH2:10][CH3:11]
Reactant: CCC=CCCC(O)CCC(C)O
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: CCC=CCCC1CCC(C)O1

Procedure:
Undec-8-ene-2,5-diol (obtained as detailed above) was heated to 150° C. with KHSO4. The resulting mixture was distilled to provide the product 2-(hex-3-enyl)-5-methyl-tetrahydro-furan.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH2:24][CH3:25])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)=[O:12])=[CH:4][C:3]=1[CH3:26].Cl[CH2:28][C@@H:29]([OH:32])[CH2:30][OH:31]>CC(O)C.[OH-].[Na+].O>[OH:32][C@@H:29]([CH2:30][OH:31])[CH2:28][O:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH2:24][CH3:25])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)=[O:12])=[CH:4][C:3]=1[CH3:26]
Reactant: CCc1sc(C(=O)CCc2cc(C)c(O)c(C)c2)cc1-c1ccccc1
Reactant: OC[C@H](O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCc1sc(C(=O)CCc2cc(C)c(OC[C@@H](O)CO)c(C)c2)cc1-c1ccccc1
Temperature: 70 °C
Reaction time: 15 h
Yield: 22.3 %

Procedure:
A solution of 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-(5-ethyl-4-phenyl-thiophen-2-yl)-propan-1-one (52 mg, 0.143 mmol) in 2-propanol (1 mL) and 3 N aq. NaOH (0.3 mL) is treated with (S)-3-chloro-propane-1,2-diol (79 mg, 0.71 mmol) and the mixture is stirred at 70° C. for 15 h. The reaction mixture is diluted with water and extracted with DCM. The solvent of the organic extract is evaporated and the crude product is purified on prep. TLC plates with heptane:EA 1:3 to give 3-[4-((S)-2,3-dihydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(5-ethyl-4-phenyl-thiophen-2-yl)-propan-1-one (14 mg) as a colourless resin; LC-MS: tR=1.03 min, [M+1]+=439.25; 1H NMR (CDCl3): δ 7.58 (s, 1H), 7.45-7.30 (m, 5H), 6.88 (s, 2H), 4.11-4.04 (m, 1H), 3.87-3.80 (m, 4H), 3.67-3.60 (m, 2H), 3.60-3.56 (m, 1H), 3.48-3.40 (m, 1H), 3.20-3.10 (m, 2H), 2.98-2.87 (m, 4H), 2.25 (s, 6H), 1.30 (t, J=7.6 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:13]([CH3:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:24][O:25][C:26]1(OC)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][O:19][C:26]3([O:25][CH3:24])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[C:13]([CH3:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(C)cc(Sc2c(C(C)C)nc(C)n2COCCO)c1
Reactant: COC1(OC)CCCCC1
Product: COC1(OCCOCn2c(C)nc(C(C)C)c2Sc2cc(C)cc(C)c2)CCCCC1
Yield: 62.7 %

Procedure:
The compound 1 (33.4 mg, 0.1 mmol) was converted to the acetal with 1,1-dimethoxycyclohexane (144 mg, 1.00 mmol) in the same manner as the example 1 to give the compound 3 (28 mg, 60 %). Rf 0.57 (Al2O3 60, Type E, 2:1 hexane -EtOAc).
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20](=[O:30])[CH:21]([CH3:29])[CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[CH:14]=[CH:13]2)C1C=CC=CC=1.Cl.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[ClH:1].[OH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20](=[O:30])[CH:21]([CH3:29])[CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[CH:14]=[CH:13]2
Reactant: CC(CN1CCCCC1)C(=O)c1ccc2cc(OCc3ccccc3)ccc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(CN1CCCCC1)C(=O)c1ccc2cc(O)ccc2c1
Temperature: 90 °C
Yield: 38.5 %

Procedure:
A mixture of 3.3 g of 6'-benzyloxy-2-methyl-3-piperidino-2'-propionaphthonehydrochloride, 5 ml of concentrated hydrochloric acid and 40 ml of acetic acid was agitated under heating at 90° C. for 6 hours. Aqueous solution of sodium bicarbonate was added thereto, and the mixture was extracted with ether-ethyl acetate (2:1). After washing with water, 1% hydrochloric acid was added to move the object product to aqueous phase. It was washed with ether-ethyl acetate and made to be alkaline by aqueous solution of sodium bicarbonate, and then extracted by ether. After washingwith water and drying, purification by silica gel column chromatography andactive carbon treatment were conducted. Crystals obtained by concentrating under reduced pressure were recrystallized from ethanol-ether, thus producing 1.0 g of 6'-hydroxy-2-methyl-3-piperidino-2'-propionaphthone hydrochloride of light-brown crystals.
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][O:9][N:10]=[C:6]2[CH2:5][CH:4]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:3]1[OH:19].N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>C(Cl)Cl.C(OCC)C>[Si:25]([O:1][CH:2]1[CH:7]2[CH2:8][O:9][N:10]=[C:6]2[CH2:5][CH:4]([O:11][Si:12]([C:15]([CH3:16])([CH3:18])[CH3:17])([CH3:13])[CH3:14])[CH:3]1[OH:19])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)[Si](C)(C)OC1CC2=NOCC2C(O)C1O
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OC1CC2=NOCC2C(O[Si](C)(C)C(C)(C)C)C1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
4,5-Dihydroxy-6-(tert-butyldimethylsilyloxy)-3,3a,4,5,6,7-hexahydro-2,1-benzoisooxazole (287 mg) was dissolved in 10 ml of methylene chloride, and 200 mg of imidazole and 226 mg of tert-butyldimethylsilyl chloride were added under ice cooling, followed by stirring the mixture overnight at room temperature. The reaction mixture was diluted with diethyl ether, washed with dilute hydrochloric acid, a sodium hydrogen carbonate aqueous solution and a sodium chloride aqueous solution in sequence, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 265 mg of 4,6-bis(tert-butyldimethylsilyloxy)-5-hydroxy-3,3a,4,5,6,7-hexahydro-2,1-benzoisooxazole having the following property (yield 66%).
Reaction SMILES: [O-][N+:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[N:12]3[C@@H:18]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:17][O:16][CH2:15][C:13]3=[N:14][C:4]=2[CH:3]=1.[NH4+:28].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl>[NH2:28][C:3]1[C:4]2[N:14]=[C:13]3[CH2:15][O:16][CH2:17][C@H:18]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[N:12]3[C:5]=2[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:2]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)NC[C@H]1COCc2nc3c[n+]([O-])c4ccccc4c3n21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NC[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Reaction time: 2 h

Procedure:
tert-Butyl [(11S)-5-oxido-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]methylcarbamate (1.69 g, 4.57 mmol) was dissolved in 20 mL of CH2Cl2 and treated with 2 mL of concentrated NH4OH solution. The mixture was stirred rapidly and then p-toluenesulfonyl chloride (958 mg, 5.02 mmol) was carefully added. Rapid stirring was continued for 2 hours. The reaction mixture was treated with 25 mL of CH2Cl2 and 25 mL of H2O. The layers were separated and the organic portion was washed with 2% Na2CO3 solution (3×20 mL), H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 10-30% CMA/CHCl3) gave tert-butyl [(11S)-6-amino-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]methylcarbamate (1.39 g) as a salmon colored foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].Cl.Cl[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:21][CH2:22][N:23]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[CH2:24][CH2:25]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NCC1CCNCC1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NCC1CCN(c2ccncc2)CC1
Yield: 14.6 %

Procedure:
Using a similar procedure to that described in Example 52, 5-chloro-N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethyl)aminobenzamide (400 mg, 1.05 mmol), 4-chloropyridine hydrochloride (791 mg, 5.27 mmol), triethylamine (533 mg, 5.27 mmol), and ethanol (3 mL) yielded 70 mg (15%) of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][CH2:27][O:28][C:21]=3[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][CH2:27][O:28][C:21]=4[CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Cc1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Product: Cc1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[C@H:10]([CH2:21][CH3:22])[CH2:11][C:12]2=[O:20])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:23][CH3:24])[CH:4]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].[N:31]#CBr>C(Cl)(Cl)Cl>[C:19]([N:18]1[CH2:17][CH2:16][C@:14]23[C:15]4[C:2]5[O:1][C@H:13]2[C:12](=[O:20])[CH2:11][C@@H:10]([CH2:21][CH3:22])[C@H:9]3[C@H:8]1[CH2:7][C:6]=4[CH:5]=[CH:4][C:3]=5[O:23][CH3:24])#[N:31]
Reactant: CC[C@@H]1CC(=O)[C@@H]2Oc3c(OC)ccc4c3[C@@]23CCN(C)[C@H](C4)[C@H]13
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC[C@@H]1CC(=O)[C@@H]2Oc3c(OC)ccc4c3[C@@]23CCN(C#N)[C@H](C4)[C@H]13
Yield: 94 %

Procedure:
4,5α-Epoxy-8α-ethyl-3-methoxy-17-methylmorphinan-6-one 3 (6.50 g, 19.8 mmole) was dissolved in chloroform (100 ml). After the addition of K2CO3 (4.12 g, 29.8 mmole), the stirred suspension was treated dropwise with a solution of cyanogen bromide (2.50 g, 23.8 mmole) in 50 ml of chloroform. After the addition was complete, the mixture was heated to reflux and refluxed for 2 hours. Cooling was followed by removal of the insoluble material by filtration. The filtrate was evaporated to a residue which crystallized on coevaporation with ethanol. The crystals were suspended in hot ethanol, the mixture cooled and the crystals collected to give 6.30 g (94%) of 5 as white needles, mp 212°-217°, in two crops.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:47]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])(=[O:50])[NH:48][NH2:49]>CN(C=O)C>[C:52]([O:51][C:47]([NH:48][NH:49][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:11]=1[F:10])=[O:50])([CH3:55])([CH3:54])[CH3:53]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NNC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 57.3 %

Procedure:
N, N-Diisopropylethylamine (14.1 ml, 0.081 mol) is added to 2-fluoro-4-nitrobenzoic acid (5 g, 0.027 mol) and O-(7-azabenzotriazol-1-yl)-N, N, N′, N′-tetramethyluronium hexafluorophosphate (10.8 g, 0.0284 mol) in DMF (100 ml) and the mixture stirred at room temperature for 20 minutes. tert-Butyl carbazate (3.57 g, 0.0270 mol) is added in one portion and the reaction stirred overnight at room temperature. The mixture is concentrated and diluted with water (100 ml). The resulting precipitate is filtered, washed well with water, and dried under vacuum to give the title compound as a white solid (4.63 g, 57%), [M+H]+=300.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[CH2:2]1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC=CC=1.N1CCCCC1>[CH:12](=[C:2]1[C:1](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CC(=O)c2ccccc21
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: O=C1C(=Cc2ccccc2)C(=O)c2ccccc21
Reaction time: 24 h
Yield: 72.1 %

Procedure:
To a solution of 1,3-indandione (43.8 g) and piperidine (44 mg) in dry benzene (500 ml) was added benzaldhyde (31.8 g). The mixture was heated to reflux and the water generated was removed by Dean-Stark trap. After 24 hours, the mixture was evaporated to dryness. The residue was recrystallized from ethanol (200 ml) to give 2-benzylidene-1,3-indandione as a yellow solid (50.6 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([CH:6]=[C:7](B(O)O)[N:8]2[CH3:11])=[CH:4][CH:3]=1.Br[C:16]1[C:21]([CH:22]=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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[N:10]=[C:9]2[N:8]([CH3:11])[C:7]([C:19]3[CH:20]=[C:21]([CH:22]=[O:23])[CH:16]=[N:17][CH:18]=3)=[CH:6][C:5]2=[CH:4][CH:3]=1
Reactant: O=Cc1cccnc1Br
Reactant: Cn1c(B(O)O)cc2ccc(Cl)nc21
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: C1COCCO1
Product: Cn1c(-c2cncc(C=O)c2)cc2ccc(Cl)nc21
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To 6-chloro-N-methyl-7-aza indole-2-boronic acid (1.00 g, 4.75 mmol) in dioxane (40 mL) under N2 was added 5 bromo-3-pyridine carbaldehyde (0.589 g, 3.17 mmol), aqueous Na2CO3 (2M, 4.75 mL, 9.50 mmol) and polymer bound Pd(PPh3)4 (1.760 g, 0.158 mmol). The reaction was stirred for 2 hours at 85° C. The reaction mixture was cooled to room temperature. The solids were filtered off and the precipitate was washed thoroughly with methanol. The filtrate was concentrated in vacuo to give a brown color oil. The crude was purified by silica gel flash chromatography using DCM-MeOH (90-10, v/v) to afford pure product 5-(6-Chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-pyridine-3-carbaldehyde as a solid. ESI-MS: m/z 272.1 (M+H)+
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=3)[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:19][C@@H:20]([C:23]1[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[CH2:21][OH:22].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:19][C@@H:20]([C:23]4[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=4)[CH2:21][OH:22])[C:3]=3[CH2:11]2)=[N:13][CH:14]=1
Reactant: Clc1ccc(N2CCc3ncnc(Cl)c3C2)nc1
Reactant: COc1ccc([C@H](N)CO)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc([C@@H](CO)Nc2ncnc3c2CN(c2ccc(Cl)cn2)CC3)cn1

Procedure:
A reaction mixture of 4-chloro-6-(5-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (55 mg, 0.20 mmol) and (S)-2-amino-2-(6-methoxypyridin-3-yl)ethanol (33 mg, 0.20 mmol) in acetonitrile (2 mL) and N,N-diisopropylethylamine (68 μL, 0.39 mmol) was subjected to microwave irradiation at 180° C. for 2 h. The reaction mixture was concentrated and purified by semi-prep HPLC (100×20.2 mm, C18 column; 25-50% CH3CN-water [10 mM Et2NH]) to give an off-white solid.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:23])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[CH3:11]>>[CH2:10]([O:12][C:13](=[O:23])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:7]([C:5]2[O:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:9])[CH:17]=1)[CH3:11]
Reactant: CCOC(=O)COc1cccc(N)c1
Reactant: O=C(O)c1ccc(Br)o1
Product: CCOC(=O)COc1cccc(NC(=O)c2ccc(Br)o2)c1

Procedure:
5-Bromo-furan-2-carboxylic acid (245 mg, 1.28 mmol) was coupled to aniline (64) (250 mg, 1.28 mmol) using Method C. The residue was purified by column chromatography eluting with 15% EtOAc in heptane to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([CH3:25])([CH3:24])[C:17](=[O:23])[N:18]2[CH2:21][CH3:22])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([CH3:24])([CH3:25])[C:17](=[O:23])[N:18]2[CH2:21][CH3:22])=[CH:14][CH:13]=1)=[O:6]
Reactant: O=C(O)c1ccncc1Cl
Reactant: CCN1C(=O)C(C)(C)c2ccc(N)cc21
Product: CCN1C(=O)C(C)(C)c2ccc(NC(=O)c3ccncc3Cl)cc21

Procedure:
Prepared in analogy to example 26 from 3-chloroisonicotinic acid and 6-amino-1-ethyl-3,3-dimethylindolin-2-one (G. Georges et al., US2006/142247 A1). The title compound was obtained as white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][C:10]2[C:9]([NH:12][C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18](I)[CH:17]=3)=[O:14])=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+].C(OC(=O)C)C>C1COCC1.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>[OH:1][CH:2]1[CH2:11][C:10]2[C:9]([NH:12][C:13]([NH:15][C:16]3[CH:17]=[C:18]([C:26]4[CH:27]=[CH:28][C:23]([CH3:32])=[CH:24][CH:25]=4)[CH:19]=[CH:20][CH:21]=3)=[O:14])=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: O=C(Nc1cccc(I)c1)Nc1cccc2c1CC(O)CC2
Reactant: Cc1ccc(B(O)O)cc1
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: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2cccc(NC(=O)Nc3cccc4c3CC(O)CC4)c2)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 37.6 %

Procedure:
Next, to a solution of N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(3-iodophenyl)urea (9.0 mg, 0.02 mmol) and 4-tolylboronic acid (3.60 mg, 0.03 mmol) in THF was added tetrakis(triphenylphosphine)palladium(0) (2.55 mg) followed by 0.1 mL of saturated sodium bicarbonate solution. The mixture was stirred for 3 hours at 90° C., then ethylacetate was added. The mixture was passed through a short pad of silica gel and was concentrated under reduced pressure to afford N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(4′-methylbiphenyl-3-yl)urea (2.80 mg, 34% yield).