Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:43]=[C:44]([N+:46]([O-])=O)[CH:45]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[C:29](/[C:32]2[CH:40]=[CH:39][C:35]3[O:36][CH2:37][O:38][C:34]=3[CH:33]=2)\[C:30]#[N:31])=[CH:24][C:23]=1[O:41][CH3:42])=[O:8])([O-])=O>CN(C=O)C.O.[Zn]>[NH2:46][C:44]1[CH:43]=[C:6]([CH:5]=[C:4]([NH2:1])[CH:45]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[C:29](/[C:32]2[CH:40]=[CH:39][C:35]3[O:36][CH2:37][O:38][C:34]=3[CH:33]=2)\[C:30]#[N:31])=[CH:24][C:23]=1[O:41][CH3:42])=[O:8]
Reactant: COc1cc(/C=C(\C#N)c2ccc3c(c2)OCO3)ccc1OCCCCCCCCCCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(/C=C(\C#N)c2ccc3c(c2)OCO3)ccc1OCCCCCCCCCCCOC(=O)c1cc(N)cc(N)c1
Yield: 61.4 %

Procedure:
5 g (7.6 mmol) of 11-{4-[(Z)-2-(1,3-benzodioxol-5-yl)-2-cyanoethenyl]-2-methoxyphenoxy}undecyl 3,5-dinitrobenzoate are dissolved in a mixture of 84 ml of DMF and 9 ml of water. 15.7 g (58 mmol) of ferric chloride hexahydrate are added. 6.31 g (97 mmol) of zinc powder are added portionwise within 30 min. The mixture is allowed to react for 2 hours. The reaction mixture is then partitioned between ethyl acetate and water and filtered. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Filtration of the residue on silica gel using toluene:ethyl acetate(1:3) as eluant and yielded 2.8 g (61%) of 11-{4-[(Z)-2-(1,3-benzodioxol-5-yl)-2-cyanoethenyl]-2-methoxyphenoxy}undecyl 3,5-diaminobenzoate as a white powder.
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]2[C:6]3[C:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)=[CH:9][N:8]([C:14]1[N:15]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[N:16]=[CH:17][N:18]=1)[N:7]=3.ClC1N(C2C=CC(F)=CC=2F)N=CN=1.[Br:43]C1C=CC2OCCC3C(=NNC=3)C=2C=1.C(OCC)(=O)C>C1CCCCC1>[Br:43][C:28]1[CH:2]=[CH:3][C:4]2[O:13][CH2:12][CH2:11][C:10]3[C:6](=[N:7][N:8]([C:14]4[N:15]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=5[F:26])[N:16]=[CH:17][N:18]=4)[CH:9]=3)[C:5]=2[CH:27]=1
Reactant: Brc1ccc2c(c1)-c1n[nH]cc1CCO2
Reactant: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2ccc(Br)cc2OCC3)c(F)c1
Agent: Fc1ccc(-n2ncnc2Cl)c(F)c1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2cc(Br)ccc2OCC3)c(F)c1
Yield: 62 %

Procedure:
9-Bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene was prepared similarly to 8-bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene from 5-chloro-1-(2,4-difluoro-phenyl)-1H-[1,2,4]triazole (1.33 g, 6.16 mmol) and 9-bromo-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene (1.36 g, 5.13 mmol), the crude product was subjected to flash chromatography (SiO2, gradient 0 to 35% ethyl acetate in cyclohexane) to give 9-Bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen (1.42 g, 62%). LCMS RT=4.80 M+H+=444/446.
Reaction SMILES: [N:1]([CH:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]C)[CH3:5])=[C:2]=[O:3].[CH2:15](C1CCC(C(O)=O)CC1)CCCC>>[N:1]([CH:4]1[CH2:5][CH2:15][CH:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:7][CH2:6]1)=[C:2]=[O:3]
Reactant: CCCCCC1CCC(C(=O)O)CC1
Reactant: CCCCCCCCCC(C)N=C=O
Product: CCCCCC1CCC(N=C=O)CC1

Procedure:
The title compound was prepared in a similar manner as described in the preparation of 2-isocyanatoundecane (compound 81, example 17), except commercially available 4-pentylcyclohexanecarboxylic acid was used in the place of 2-methylundecanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH2:13][N:14]3[CH2:20][CH2:19][CH2:18][CH2:17][N:16]4[C:21]([C:24]5[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=5)=[N:22][N:23]=[C:15]34)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:30]S(OC(C1N=C(C2C=CC=C(Cl)C=2)ON=1)C)(=O)=O.N1C=CC(C2N3CCCCNC3=NN=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH:13]([N:14]3[CH2:20][CH2:19][CH2:18][CH2:17][N:16]4[C:21]([C:24]5[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=5)=[N:22][N:23]=[C:15]34)[CH3:30])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(OS(C)(=O)=O)c1noc(-c2cccc(Cl)c2)n1
Reactant: Clc1cccc(-c2nc(CN3CCCCn4c(-c5ccncc5)nnc43)no2)c1
Agent: c1cc(-c2nnc3n2CCCCN3)ccn1
Product: CC(c1noc(-c2cccc(Cl)c2)n1)N1CCCCn2c(-c3ccncc3)nnc21
Yield: 4 %

Procedure:
The title compound was prepared analogous to 9-{[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]methyl}-3-pyridin-4-yl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a][1,3]diazepine from 1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl methanesulfonate (186 mg, 0.61 mmol), 3-pyridin-4-yl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a][1,3]diazepine (200 mg, 0.56 mmol) to give 8.1 mg (4%) of the title compound. 1H NMR: 1.83 (d, 3H), 1.86-1.95 (m, 4H), 3.16-3.27 (m, 1H), 3.43-3.53 (m, 1H), 3.75-3.87 (m, 1H), 3.95-4.07 (m, 1H), 5.54 (q, 1H), 7.41-7.52 (m, 3H), 7.52-7.58 (m, 1H), 8.01 (m, 1H), 8.12 (m, 1H), 8.73 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([O:11][CH3:12])[CH:8]=[CH:9][CH:10]=1.C([Li])CCC.[B:18](OC)([O:21]C)[O:19]C.[NH4+].[Cl-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(OCC)(=O)C>[CH3:12][O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:6]=1[B:18]([OH:21])[OH:19]
Reactant: COCOc1cccc(OC)c1
Reactant: COB(OC)OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCOc1cccc(OC)c1B(O)O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 12.0 g (100 mmol) of 3-methoxyphenol in 100 mL of methylene chloride at 0° C. was added 29.5 g (229 mmol) of diisopropylethylamine followed by dropwise addition of 10 g of chloromethyl methyl ether. The reaction mixture was stirred at room temperature overnight, washed with 1N HCl (3×75 mL), 1N NaOH (3×75 mL) and brine and was dried over anhydrous MgSO4. The mixture was filtered and concentrated in vacuo to give 3-methoxymethyloxy-anisole. 6.0 g (36 mmol) of 3-methoxymethyloxy-anisole was dissolved in 100 mL dry THF and was cooled to −78° C. To the solution was added dropwise 20 mL (50 mmol) of 2.5M n-butyl lithium in hexanes. The solution was stirred at −78° C. for 1 hour, the ice bath was removed and the solution stirred at room temperature for a further 1 hour. The reaction mixture was cooled to −78° C. and treated with 5.56 g (54 mmol) of trimethyl orthoborate. The solution was stirred for 1 hour and then allowed to warm to room temperature over 1 hour. The solution was treated with 30 mL of saturated NH4Cl solution and 100 mL of ethyl acetate with stirring. The pH was immediately adjusted to 5.0 by addition of aliquots of 5% citric acid solution. The aqueous phase was promptly extracted with ethyl acetate (3×50 mL). The combined ethyl acetate phases were extracted with 1N NaOH solution (3×50 mL). The combined basic extracts were acidified with rapid stirring by dropwise addition of concentrated hydrochloric acid to pH 5.0. The mixture was extracted by ethyl acetate (3×75 mL). The combined EtOAc phases were dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 2-methoxy-6-(methoxymethyloxy)phenylboronic acid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:8]=[CH:7][NH:6][C:5]=1[C:9]([O:11][CH3:12])=[O:10].C1(P(O[NH2:28])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C=O)C>[NH2:28][N:6]1[CH:7]=[CH:8][C:4]([Cl:3])=[C:5]1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1[nH]ccc1Cl
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)ccn1N
Reaction time: 0.42 h
Yield: 91.5 %

Procedure:
To a suspension of sodium hydride (60 percent, 1.5 g, 37.5 mmol) in DMF (250 mL) was added methyl 3-chloro-1H-pyrrole-2-carboxylate (5.0 g, 31.3 mmol) at 0° C., and the mixture was stirred for 25 min, followed by the addition of O-(diphenylphosphoryl)hydroxylamine (10.0 g, 43.75 mmol). The reaction mixture was stirred at RT for 4 h and quenched by aq. Na2SO3 solution. After stirred for another 5 min, the mixture was extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give crude product as a brown oil, which was purified by chromatography purification on silica gel (PE:EA=4:1) to obtain the title compound (5.00 g, 91%) as a white solid. MS (ES+) C6H7ClN2O2 requires: 174, 176. found: 175, 177 [M+H]+.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:11]3[N:12]=[CH:13][C:14]([C:15]#[N:16])=[C:10]3[NH:9][C:8]=2[C:17]2[C:26]([O:27][CH3:28])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH2:29]>CS(C)=O.[Cl-].[Na+].O>[NH2:9][C:10]1[N:11](/[C:7](=[N:6]/[CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)/[C:8]([C:17]2[C:26]([O:27][CH3:28])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[O:29])[N:12]=[CH:13][C:14]=1[C:15]#[N:16]
Reactant: COc1cc2ccccc2cc1-c1[nH]c2c(C#N)cnn2c1NC1CCCC1
Reactant: O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc2ccccc2cc1C(=O)/C(=N\C1CCCC1)n1ncc(C#N)c1N
Yield: 23 %

Procedure:
A light yellow solution of 3-(cyclopentylamino)-2-(3-methoxynaphthalen-2-yl)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile (150 mg, 0.404 mmol) in DMSO (6 mL) was stored for 40 days at RT. Then, it was poured into a mixture of water and brine solution (˜150 mL) and the organic compound was extracted into ethyl acetate (2×50 mL). The combined extracts were washed with brine solution and dried over anhydrous MgSO4. Filtration and concentration gave the light yellow oil which was purified using an ISCO (40 g) column chromatography eluting with 0-60% ethyl acetate in hexanes. The desired fractions were combined and the solvent was removed under vacuum to isolate 36 mg (23% yield) of (E)-5-amino-1-(1-(cyclopentylimino)-2-(3-methoxynaphthalen-2-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.42-1.64 (br m, 4H), 1.64-1.80 (br, 4H), 3.75 (p, 1H), 3.77 (s, 3H), 7.45 (t, J=2.4 Hz, 1H), 7.48 (s, 1H), 7.64 (s, 1H), 7.65 (t, J=2.4 Hz, 1H) 7.88 (d, 1H), 8.10 (br s, 2H), 8.12 (d, 1H), 8.62 (s, 1H). LC/MS calcd. for C22H21N5O2 (m/e) 387.441, obsd. 388.0 (M+H, ES+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=2)[N:5]=[C:4]([CH3:15])[CH:3]=1.C(OC([NH:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)=O)(C)(C)C.C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH:23][C:24]3[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=3)=[O:14])[CH:10]=2)[N:5]=[C:4]([CH3:15])[CH:3]=1
Reactant: Cc1cc(N)c2cc(C(=O)O)ccc2n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(N)c2cc(C(=O)Nc3ccc(N)cc3)ccc2n1
Reaction time: 1 h
Yield: 29.4 %

Procedure:
To a solution of 270 mg (1.0 mmol) 4-amino-2-methyl-6-quinolincarboxylic acid, 220 mg (1.1 mmol) 4-t-butoxycarbonylaminoaniline, and 0.56 ml (4.0 mmol) triethylamine in 10 ml DMF was added 4.42 mg (1.0 mmol) BOP reagent. After 1 h stirring at room temparature the solution was evaporated. The residue was dissolved in 1M solution of NaOH and extracted with ethyl acetate and the organic layer was washed with water and brine, dried (MgSO4) and evaporated. The residue was treated with 4M HCl in dioxane at room temperature for 1 h. After evaporation the residue was purified by HPLC and lyophilized to give 86 mg (17%) of the title compound. MS 293.3 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[C:11]1[C:26](=[O:27])[N:25]([O:28][CH3:29])[C:14]2[N:15]=[C:16]([NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[N:17]=[CH:18][C:13]=2[CH:12]=1>CCO.Cl.[Fe]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([C:11]2[C:26](=[O:27])[N:25]([O:28][CH3:29])[C:14]3[N:15]=[C:16]([NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[N:17]=[CH:18][C:13]=3[CH:12]=2)=[C:2]([Cl:1])[CH:7]=1
Reactant: COn1c(=O)c(-c2ccc([N+](=O)[O-])cc2Cl)cc2cnc(NCCN(C)C)nc21
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: COn1c(=O)c(-c2ccc(N)cc2Cl)cc2cnc(NCCN(C)C)nc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
To a solution of 6-(2-chloro-4-nitrophenyl)-2-(2-(dimethylamino)ethylamino)-8-methoxypyrido[2,3-d]pyrimidin-7(8H)-one (8.36 mmol) in EtOH (300 mL) and conc. hydrochloric acid (20 mL), iron powder (91 mmol) was added and the mixture was stirred at 80° C. for 2 h. The mixture was then allowed to cool to room temperature and filtered through a pad of Celite. The filtrate was diluted with EtOAc (300 mL) and washed with sat. aq. NaHCO3 (300 mL). The aqueous layer was backextracted with EtOAc (8×150 mL). The organic layers were combined and washed with brine (1×300 mL). Drying of the organic layer over Na2SO4, filtration and evaporation of the solvent gave 6-(4-amino-2-chlorophenyl)-2-(2-(dimethylamino)ethylamino)-8-methoxypyrido[2,3-d]pyrimidin-7(8H)-one as a solid (43%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4](I)[C:3]=1[C:16]([F:19])([F:18])[F:17].[Si:20]([C:24]#[CH:25])([CH3:23])([CH3:22])[CH3:21]>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([C:25]#[C:24][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:3]=1[C:16]([F:19])([F:18])[F:17]
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1C#C[Si](C)(C)C
Temperature: 50 °C

Procedure:
A triethylamine (2.2 mL) solution of N-[4-chloro-2-iodo-3-(trifluoromethyl)phenyl]-2,2-dimethylpropanamide (0.413 g, 1.02 mmol) was treated with TMS acetylene (0.158 mL, 1.12 mmol) followed by copper iodide (0.019 g, 0.102 mmol) and PdCl2(PPh3)2 (0.021 g, 0.031 mmol). The reaction vessel was purged with N2, sealed and heated to 50° C. for 14 h. TLC at this time showed excellent conversion to the desired product. The cooled mixture was filtered through a plug of celite and partitioned between EtOAc (10 mL) and H2O (10 mL). The organic portion was dried (Na2SO4), filtered, and concentrated. Column chromatography (SiO2, EtOAc/hexanes) afforded the title compound as a light brown solid: 1H NMR (CDCl3) δ 8.72 (bs, 1H), 8.64 (d, J=6.0 Hz, 1H), 7.41 (d, J=6.0 Hz, 1H), 1.34 (s, 9H), 0.29 (s, 9H).
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].[CH:6]([NH2:9])([CH3:8])[CH3:7]>>[CH:6]([NH:9][CH2:1][CH:2]([OH:3])[CH2:4][OH:5])([CH3:8])[CH3:7]
Reactant: OCC1CO1
Reactant: CC(C)N
Product: CC(C)NCC(O)CO
Reaction time: 8 h
Yield: 79.6 %

Procedure:
A mixture of 37 g (0.5 mole) of glycidol and 35.4 g (0.6 mole) of isopropylamine was stirred at 25° overnight. Excess isopropylamine was evaporated in vacuo and the mixture was distilled to give 53 g of product: b.p. 80° C./0.1 mm Hg. The NMR and IR spectra were consistent with the assigned structure and the elemental analysis was consistent with the empirical formula C6H15O2N.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)(C)(C)C.[NH2:28][C:29]1[CH:30]=[C:31]([C:35]#[CH:36])[CH:32]=[CH:33][CH:34]=1>>[NH2:28][C:29]1[CH:30]=[C:31]([C:35]#[C:36][C:13]2[CH:12]=[C:11]3[C:16]([C:7](=[N:6][OH:5])[CH:8]=[C:9]([C:18]4[N:19]=[CH:20][C:21]5[C:26]([CH:27]=4)=[CH:25][CH:24]=[CH:23][CH:22]=5)[O:10]3)=[CH:15][CH:14]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Reactant: C#Cc1cccc(N)c1
Product: Nc1cccc(C#Cc2ccc3c(=NO)cc(-c4cc5ccccc5cn4)oc3c2)c1

Procedure:
7-(3-aminophenyl)ethynyl-2-isoquinolin-3-yl-chromen-4-one oxime was prepared in 17% overall yield using the method described in example 24, starting from 7-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (example 2B) and 3-aminophenylacetylene. The title compound was isolated as a yellow solid and as a 95/5 mixture of Z/E oxime isomers.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.C(N(CC)CC)C.[NH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>C(O)C>[CH3:21][P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH3:22])=[O:20]
Reactant: NN1CCOCC1
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(NN3CCOCC3)n2)cc1
Yield: 12 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol was added 50 L of triethylamine and 4-Aminomorpholine (12 mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (6 mg, 12% yield.) MS/ES+: m/z=416.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][O:14][C:15]([C:17]1[S:18][CH:19]=[CH:20][C:21]=1[N:22]([CH:32]1[CH2:41][CH2:40][C:35]2([O:39][CH2:38][CH2:37][O:36]2)[CH2:34][CH2:33]1)[C:23]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)=[O:24])=[O:16].C(B(CCCC)CCCC)CCC.C([Cu])#N.Br[CH:59]1[CH2:64][CH2:63][CH2:62][CH:61]=[CH:60]1.[OH-].[Na+].OO>C1COCC1.CCOC(C)=O>[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([CH:64]2[CH2:63][CH2:62][CH2:61][CH:60]=[CH:59]2)=[CH:20][C:21]=1[N:22]([CH:32]1[CH2:41][CH2:40][C:35]2([O:39][CH2:38][CH2:37][O:36]2)[CH2:34][CH2:33]1)[C:23]([C@H:25]1[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]1)=[O:24])=[O:16]
Reactant: COC(=O)c1sccc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC2(CC1)OCCO2
Reactant: BrC1C=CCCC1
Agent: N#C[Cu]
Agent: CCCCB(CCCC)CCCC
Agent: OO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: COC(=O)c1sc(C2C=CCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
In a small RB flask THF (1.5 mL) was placed followed by diisopropylamine (80 μl, 0.57 mmol) and the mixture was cooled to −40° C. n-BuLi (1.6 M, 0.34 mL, 0.54 mmol) was added dropwise. It was stirred at this temperature for 20 min. The mixture was cooled to −78° C. and 3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (200 mg, 0.47 mmol) in THF (2 mL) was added dropwise. Stirring at −78° C. was continued for 30 min. Tributyl borane (1M in ether, 0.48 mL,) was added and the mixture was allowed to come to room temperature over a period of 1 h. This solution was added to a suspension of CuCN (47 mg) in THF (1 mL) cooled to −30° C. The mixture was stirred at this temperature for 20 min. 3-Bromocyclohexene (90%, 60 μl, 0.47 mmol) was added and the mixture was allowed to come to room temperature slowly. It was stirred at this temperature for 16 h. The mixture was cooled to 0° C. and 10% NaOH (0.8 mL) was added followed by dropwise addition of 30% H2O2 (0.27 mL). The mixture was stirred for 10 min. It was diluted with EtOAc, washed with water and brine, dried (MgSO4) and evaporated. Pure 5-cyclohex-2-enyl-3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester was obtained on chromatography over silica gel (hexane:EtOAc-9:1, 4:1 and 7:3 eluents) (153 mg, 64%).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10](=[O:42])[O:11][C@:12]2([C@:36]3([CH3:37])[C@H:22]([C@H:23]4[C@:33]([F:39])([C@@H:34]([OH:38])[CH2:35]3)[C@:31]3([CH3:32])[C:26](=[CH:27][C:28](=[O:40])[CH:29]=[CH:30]3)[CH2:25][CH2:24]4)[CH2:21][C@@H:20]2[CH3:41])[C:13](=[O:19])[CH2:14][O:15]C(=O)C)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.C(Cl)(Cl)Cl>[C:1]1([C@H:7]([NH:9][C:10](=[O:42])[O:11][C@:12]2([C@:36]3([CH3:37])[C@H:22]([C@H:23]4[C@:33]([F:39])([C@@H:34]([OH:38])[CH2:35]3)[C@:31]3([CH3:32])[C:26](=[CH:27][C:28](=[O:40])[CH:29]=[CH:30]3)[CH2:25][CH2:24]4)[CH2:21][C@@H:20]2[CH3:41])[C:13](=[O:19])[CH2:14][OH:15])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OCC(=O)[C@@]1(OC(=O)N[C@H](C)c2ccccc2)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C[C@@H](NC(=O)O[C@]1(C(=O)CO)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C)c1ccccc1
Temperature: 25 °C
Reaction time: 24.5 h
Yield: 57.9 %

Procedure:
(11β,16β)-21-(acetyloxy)-9-fluoro-11-hydroxy-16-methyl-3,20-dioxopregna-1,4-dien-17-yl (1R)-1-phenylethylcarbamate (42 mg, 0.064 mmol) was dissolved in 1.25 mL of a pre-mixed solution of methanol/chloroform/6N HCl (10:2:1) and stirred at room temperature for 24.5 hours. The solution was then partitioned between ethyl acetate and water and the organic phase was washed with water (twice) and brine and dried over Na2SO4. Filtration and evaporation under vacuum gave a white film which was purified by preparative thin layer chromatography on silica gel, eluting with ethyl acetate/hexane/dichloromethane/methanol (95:95:95:15), to yield 20 mg of (11β,16β)-9-fluoro-11,21-dihydroxy-16-methyl-3,20-dioxopregna-1,4-dien-17-yl (1R)-1-phenylethylcarbamate as a white solid.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.C[O:20][C:21](=[O:25])[CH2:22][CH2:23][NH2:24].[OH-].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:24][CH2:23][CH2:22][C:21]([OH:25])=[O:20])=[CH:13][CH:12]=1
Reactant: COC(=O)CCN
Reactant: O=Cc1ccc(Oc2nc3ncccc3s2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCNCc1ccc(Oc2nc3ncccc3s2)cc1
Reaction time: 4 h
Yield: 31.1 %

Procedure:
To a mixture of 4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)-benzaldehyde (100 mg, 0.39 mmol) and β-alanine methyl ester (54 mg, 0.39 mmol, 1 equiv.) was added methanol (2 mL) followed by 1 N NaOH (430 μL). The reaction was allowed to stir at rt for 1 h before the addition of sodium triacetoxyborohydride (95 mg, 0.39 mmol, 1 equiv.). Stirring was allowed to continue for 4 h before the reaction was concentrated and purified using preparative reversed phase HPLC to afford the product as white powder (40 mg, 31%). 1H NMR (400 MHz, CD3OD): 8.49 (d, J=4.8, 1H), 8.33 (d, J=7.9, 1H), 8.27 (s, 1H), 7.65 (d, J=8.2, 2H), 7.55 (d, J=8.2, 2H), 7.38-7.33 (m, 1H), 4.28 (s, 2H), 3.24 (t, J=6.4, 2H), 2.58 (t, J=6.4, 2H). MS (ESI): Mass calcd for C16H15N3O3S, 329.08; m/z found, 330.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[CH2:15][CH2:14][CH2:13][C:12](=[O:17])[C:11]=2[CH:10]=[CH:9][C:8]1=[O:18])[CH:2]1OCC[CH2:3]1>C(Cl)(Cl)Cl.C(O)C>[CH2:1]([N:7]1[C:16]2[CH2:15][CH2:14][CH2:13][C:12](=[O:17])[C:11]=2[CH:10]=[CH:9][C:8]1=[O:18])[CH2:2][CH3:3]
Reactant: O=C1CCCc2c1ccc(=O)n2CC1CCCO1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCCn1c2c(ccc1=O)C(=O)CCC2

Procedure:
1-tetrahydrofurfuryl-7,8-dihydro-2,5(1H,6H)-quinolinedione oil, Rf-value: 0.58 (Polygram silica gel plates SIL G/UV254 of Messrs. Machery-Nagel, system: chloroform/ethanol=19/1 by volume).
Reaction SMILES: COCCOC[C:7]1[CH:17]=[CH:16][C:10]([O:11][CH2:12][CH:13]2[O:15][CH2:14]2)=[CH:9][CH:8]=1>ClCCl.CO>[C:10]1([O:11][CH2:12][CH:13]2[O:15][CH2:14]2)[C:9]2[C:8](=[CH:17][CH:7]=[CH:8][CH:9]=2)[CH:7]=[CH:17][CH:16]=1
Reactant: COCCOCc1ccc(OCC2CO2)cc1
Solvent: CO
Solvent: ClCCl
Product: c1ccc2c(OCC3CO3)cccc2c1

Procedure:
1-[4-(2-methoxyethoxy-methyl)phenoxy]-2,3-epoxypropane Rf value: 0.78 (silica gel, dichloromethane/methanol=30:1).