Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:40]1[S:48][C:43]2=[N:44][CH:45]=[CH:46][CH:47]=[C:42]2[CH:41]=1)CCC>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(O)=O.[Na+].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>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:40]2[S:48][C:43]3=[N:44][CH:45]=[CH:46][CH:47]=[C:42]3[CH:41]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2cccnc2s1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
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: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(-c2cc3cccnc3s2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Yield: 35.5 %

Procedure:
A solution of tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (200 mg, 0.401 mmol), 2-(tributylstannyl)thieno[2,3-b]pyridine (340 mg, 0.802 mmol) and tetrakis(triphenylphosphine)palladium(0) (463 mg, 0.401 mmol) in toluene (3 mL) was heated to 102° C. overnight. The reaction mixture was diluted with EtOAc (50 mL) and saturated aqueous NaHCO3 (100 mL). The organic layer was separated and the aqueous layer was washed with EtOAc (50 mL). The organic layers were combined, dried over Na2SO4, and the solvent was removed in vacuo. The crude product was purified by silica gel column chromatography, eluting with a gradient of 5-50% EtOAc and hexane over a period of 120 minutes. The fractions were collected to give the title compound (85 mg, 35%). ESI-MS m/z [M+H]+ calc'd for C30H36FN5O5S, 598. found, 598.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:22])=O>>[Cl:22][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=1
Reactant: OC(c1ccccc1)c1cccc(OC(F)(F)F)c1
Reactant: O=S(Cl)Cl
Product: FC(F)(F)Oc1cccc(C(Cl)c2ccccc2)c1
Yield: 44 %

Procedure:
A solution of phenyl(3-(trifluoromethoxy)phenyl)methanol (300 mg, 1.12 mmol) in thionyl chloride (50 mL) was refluxed for 5 h. The solvent was removed and the residue was purified by silica gel chromatography (eluting with petroleum ether/EtOAc=100/1) to give the target compound (140 mg, 44%) as a pale yellow oil. 1H-NMR (500 MHz, DMSO-d6): δ 7.56-7.49 (m, 5H), 7.42-7.40 (m, 2H), 7.35-7.32 (m, 2H), 6.62 (m, 1H).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5]C[CH2:3][CH2:2]1.[CH3:8][O:9][CH:10](OC)[O:11][CH3:12].C[O-].[Na+]>OS(O)(=O)=O.CO>[CH3:8][O:9][C:10]1([O:11][CH3:12])[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1
Reactant: COC(OC)OC
Reactant: O=C1CCCCC1
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC1(OC)CCCCC1

Procedure:
A mixture of cyclohexanone (52 ml, 0.5 mol), trimethylorthoformate (66 ml, 0.6 mol), methanol (51 ml, 1.26 mol) and concentrated H2SO4 (1 drop) was refluxed for 18 hours. A solution sodium methoxide in methanol was added until the mi was neutral, and the mixture was fractionally distilled. 1,1-Dimethoxycyclohexane was obtained from the fraction b.p. 162°-164° C. (50.6 g, 70%).
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][CH:10]([CH:13]3[CH2:18][CH:17]([OH:19])[CH:16]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[C:22]([F:29])[C:21]=4F)[CH2:15][CH2:14]3)[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1.O.Cl>CCCCC.C1(C)C=CC=CC=1.CN(C=O)C>[O:6]1[C:7]2([CH2:8][CH2:9][CH:10]([C@H:13]3[CH2:18][C@H:17]4[O:19][C:21]5[C:22]([F:29])=[C:23]([O:26][CH2:27][CH3:28])[CH:24]=[CH:25][C:20]=5[C@@H:16]4[CH2:15][CH2:14]3)[CH2:11][CH2:12]2)[O:3][CH2:4][CH2:5]1
Reactant: CCOc1ccc(C2CCC(C3CCC4(CC3)OCCO4)CC2O)c(F)c1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCC
Product: CCOc1ccc2c(c1F)O[C@@H]1C[C@H](C3CCC4(CC3)OCCO4)CC[C@@H]21
Temperature: 90 °C
Reaction time: 20 h

Procedure:
30.0 g (0.75 mol) of sodium hydride (60% suspension in mineral oil) are washed repeatedly with n-pentane and suspended in 2500 ml of toluene. The suspension is heated to 90° C., and a solution of 101.5 g (0.26 mol) of 5-(1,4-dioxaspiro[4.5]dec-8-yl)-2-(4-ethoxy-2,3-difluorophenyl)cyclohexanol in 500 ml of DMF is metered in slowly. The batch is stirred at 90° C. for 20 h, cooled and hydrolysed using water. The mixture is neutralised by addition of 2 N hydrochloric acid, and the organic phase is separated off. The aqueous phase is extracted with toluene, and the combined organic phases are washed with sat. sodium chloride solution. The solution is dried using sodium sulfate and concentrated to dryness under reduced pressure. The crude product obtained is firstly purified by column chromatography (SiO2, toluene:ethyl acetate=8:2) and then recrystallised successively from toluene and toluene:ethanol (3:1), giving (±)-(3R*,4aR*,9bS*)-3-(1,4-dioxaspiro[4.5]dec-8-yl)-7-ethoxy-6-fluoro-1,2,3,4,4a,9b-hexahydrodibenzofuran as colourless, crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[N:55]1([CH2:60][C@H:61]2[CH2:65][CH2:64][CH2:63][NH:62]2)[CH2:59][CH2:58][CH2:57][CH2:56]1>CN(C=O)C.O.C([O-])(O)=O.[Na+]>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:62]2[CH2:63][CH2:64][CH2:65][C@@H:61]2[CH2:60][N:55]2[CH2:59][CH2:58][CH2:57][CH2:56]2)=[O:32])[C:25]=1[CH3:33])(=[O:11])=[O:12]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(F)cccc4F)cc32)c(C)c1C(=O)O
Reactant: C1CN[C@@H](CN2CCCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(F)cccc4F)cc32)c(C)c1C(=O)N1CCC[C@@H]1CN1CCCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-[5-(2,6-difluoro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (138 mg, 0.33 mmol), EDAC (97 mg, 0.51 mmol) and HOBt (67 mg, 0.5 mmol) in DMF (4 mL) was added (R)-2-pyrrolidin-1-ylmethyl-pyrrolidine (106 mg, 0.68 mmol) and TEA (0.1 mL). The mixture was stirred at rt for 20 hours. The reaction was diluted with water and NaHCO3, extracted with DCM. The combined DCM was concentrated and the residue was purified on a silica gel column to give the titled compound.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])=[CH:5][N:4]=1)[NH2:2].N(C1C=CC=CC=1)=[C:16]=[S:17].BrC1C=CC2N(C(S)=NN=2)C=1>>[CH3:14][O:13][CH2:12][CH2:11][O:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]2[N:4]([C:16]([SH:17])=[N:2][N:1]=2)[CH:5]=1
Reactant: S=C=Nc1ccccc1
Reactant: COCCOCc1ccc(NN)nc1
Agent: Sc1nnc2ccc(Br)cn12
Product: COCCOCc1ccc2nnc(S)n2c1

Procedure:
The title compound was prepared from 2-hydrazinyl-5-((2-methoxyethoxy)methyl)pyridine and isothiocyanatobenzene following the procedure described in the synthesis of compound 4A.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][S:8][C:4]=2[CH:3]=[N:2]1.[OH-].[K+].[I:11]I>CN(C=O)C>[I:11][C:3]1[C:4]2[S:8][CH:7]=[CH:6][C:5]=2[NH:1][N:2]=1
Reactant: c1cc2[nH]ncc2s1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Ic1n[nH]c2ccsc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
To a solution of 1H-thieno[3,2-c]pyrazole (1.0 g, 8.05 mmol) in DMF (65 ml) at room temperature was added potassium hydroxide (1.36 g, 24.2 mmol) and iodine (3.07 g, 12.1 mmol). The maroon reaction mixture was stirred at room temperature for 3 h then quenched with 10% aqueous Na2S2O3 and diluted with water. The mixture was extracted with EtOAc (2×). The combined organics were washed with water, sat LiCl, and sat NaCl, then dried over MgSO4 and concentrated to afford 2.0 g (99%) of 3-iodo-1H-thieno[3,2-c]pyrazole as a light brown solid. 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 13.38 (br. s., 1H), 7.68 (d, J=5.3 Hz, 1H), 7.21 (d, J=5.3 Hz, 1H).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([NH:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:18]=2)[CH2:12]1)=O)C1C=CC=CC=1>[Pd].C(O)C>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][NH:24][C:19]1[CH:18]=[C:17]([CH:13]2[CH2:14][CH2:15][CH2:16][NH:11][CH2:12]2)[CH:22]=[CH:21][C:20]=1[CH3:23])[CH3:30]
Reactant: CCOC(=O)CNc1cc(C2CCCN(C(=O)OCc3ccccc3)C2)ccc1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CNc1cc(C2CCCNC2)ccc1C
Reaction time: 2 h
Yield: 123.2 %

Procedure:
A 100 mL Parr bottle was charged with 30 mg of 10% palladium on carbon (50% water) and covered with 10 mL ethanol. 3-[3-(ethoxycarbonylmethyl-amino)-4-methyl-phenyl]-piperidine-1-carboxylic acid benzyl ester (152 mg, 0.37 mmol) was dissolved in 10 mL ethanol and added to the catalyst suspension. The reaction was hydrogenated at 45 psi for 2 h. The catalyst was filtered through a celite plug. The filter cake was washed with 30 mL ethanol and the filtrate concentrated under reduced pressure to yield 126 mg (100%) of (2-methyl-5-piperidin-3-yl-phenylamino)-acetic acid ethyl ester as a clear oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[CH3:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1.C([O-])(=O)C.[K+].CN(C=O)C>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.O>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:30]5[C:25]([CH3:24])=[N:26][CH:27]=[CH:28][CH:29]=5)=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: Cc1ncccc1B(O)O
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncccc1-c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)sc1CCO2
Temperature: 105 °C
Reaction time: 24 h
Yield: 28.7 %

Procedure:
To 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 (0.388 g, 0.992 mmol), 2-methylpyridin-3-ylboronic acid (0.176 g, 1.29 mmol), potassium acetate (0.389 g, 3.96 mmol), and tetrakis(triphenylphosphine)palladium(0) (57 mg, 0.049 mmol) was added DMF (20 mL) and water (1 mL). Nitrogen was bubbled through the reaction mixture for 5 minutes. The reaction mixture was allowed to stir at 105° C. for 24 hours before cooling, diluting with EtOAc, and filtering through a pad of celite. The filtrate was concentrated under reduced pressure and diluted with EtOAc. The solution was washed sequentially with water, and brine, before drying over MgSO4 and concentrating under reduced pressure. The crude material was dissolved in DMF and purified by reverse phase HPLC to provide 128 (115 mg, 28%). 1H NMR (400 MHz, DMSO) δ 8.44 (dd, J=24.8, 2.7, 2H), 8.10 (s, 1H), 7.69 (t, J=8.1, 1H), 7.35 (ddd, J=12.5, 7.9, 3.6, 2H), 7.19 (d, J=8.3, 1H), 5.74 (dt, J=13.2, 6.7, 1H), 4.44 (t, J=4.9, 2H), 3.49 (t, J=4.9, 2H), 2.53 (s, 3H), 1.48 (d, J=6.6, 6H). MS (ESI(+)): m/z 404.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH2:21][O:22][CH3:23])=[C:19]([C:24](O)=[O:25])[C:18]([CH2:27][O:28][CH3:29])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[CH2:30]([N:32]([CH2:38][CH3:39])[CH:33]1[CH2:37][CH2:36][NH:35][CH2:34]1)[CH3:31]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH2:21][O:22][CH3:23])=[C:19]([C:24]([N:35]4[CH2:36][CH2:37][CH:33]([N:32]([CH2:38][CH3:39])[CH2:30][CH3:31])[CH2:34]4)=[O:25])[C:18]([CH2:27][O:28][CH3:29])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: COCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(COC)c1C(=O)O
Reactant: CCN(CC)C1CCNC1
Product: CCN(CC)C1CCN(C(=O)c2c(COC)nn(-c3cccc(/C=C/c4ccc(Cl)cc4)c3)c2COC)C1

Procedure:
In analogy to the procedure described for example 1, 1-{3-[(E)-2-(4-chloro-phenyl)-vinyl]-phenyl}-3,5-bis-methoxymethyl-1H-pyrazole-4-carboxylic acid (intermediate 3) and [rac]-diethyl-pyrrolidin-3-yl-amine gave the title compound as brown solid. MS: 537.3 (MH+, 1 Cl).
Reaction SMILES: C(=O)(O)[O-].[K+].CO.[H][H].[O:10]([CH2:17][C:18]([NH:20][CH:21]1[C:41](=[O:42])[N:23]2[CH:24]([C:29]3[N:33](CC4C=CC=CC=4)[N:32]=[N:31][N:30]=3)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]12)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[Pd].C(OCC)(=O)C.O>[O:10]([CH2:17][C:18]([NH:20][CH:21]1[C:41](=[O:42])[N:23]2[CH:24]([C:29]3[NH:33][N:32]=[N:31][N:30]=3)[C:25]([CH3:27])([CH3:28])[S:26][C@H:22]12)=[O:19])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: [H][H]
Reactant: CC1(C)S[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1c1nnnn1Cc1ccccc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC1(C)S[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1c1nnn[nH]1
Reaction time: 5 h
Yield: 51 %

Procedure:
A mixture of 100 mg. (1 mmole) of potassium bicarbonate and 2.3 g. of 10% palladium-on-carbon, in a mixture of 12 ml. of methanol and 3 ml. of water, is stirred under an atmosphere of hydrogen until hydrogen uptake ceases. A solution of 464 mg. of 6-(2-phenoxyacetamido)-2,2-dimethyl-3-(1-benzyltetrazol-5-yl)penam in 10 ml. of ethyl acetate is then added, and stirring under an atmosphere of hydrogen is continued for an additional 5 hours. At this point the reaction mixture is filtered, and the residue is washed with aqueous methanol. The washings and the filtrate are combined and evaporated in vacuo. To this latter residue is added chloroform and water and the pH is adjusted to 8.0. The chloroform is removed and discarded, and fresh chloroform is added to the aqueous phase. The pH is lowered to 2.5 and the chloroform layer is separated. The dried chloroform is evaporated in vacuo, leaving 190 mg. (51% yield) of 6-(2-phenoxyacetamido)-2,2-dimethyl-3 -(5-tetrazolyl)penam.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl-].[CH3:14][O:15][CH2:16][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:36]([N:43]1[CH2:48][CH2:47][CH:46]([CH:49]=O)[CH2:45][CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCCC1.C(OCC)(=O)C>[CH2:36]([N:43]1[CH2:44][CH2:45][CH:46]([CH:49]=[CH:14][O:15][CH3:16])[CH2:47][CH2:48]1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC=CC1CCN(Cc2ccccc2)CC1
Temperature: -40 °C

Procedure:
A solution of di-isopropylamine (4.38 g, 6.1 mL, 43.3 mmol) in anhydrous tetrahydrofuran (50 mL) was cooled to 0° C. with stirring. A solution of n-butyl lithium in hexanes (2.4 M, 17.3 mL, 43.3 mmol) was added dropwise; the resulting solution was stirred for 15 minutes. The reaction mixture was transferred via cannula to a suspension of methoxymethyl triphenyl phosphonium chloride (14.9 g, 43.3 mmol) in anhydrous tetrahydrofuran (100 mL), stirred at -20° C. The reaction mixture was stirred at -20° C. for 35 minutes, then it was cooled to -40° C. A solution of 1-benzyl-4-formylpiperidine (8 g, 39.4 mmol) in anhydrous tetrahydrofuran (50 mL) was added dropwise. The reaction mixture was warmed gradually to ambient temperature over 21 hours, then it was poured onto water (500 mL) mixed and extracted three times with ethyl acetate (500 mL). The combined organic layers were dried over magnesium sulfate, treated with decolorizing charcoal and filtered through Celite®. Solvent was removed in vacuo to give an orange oil. Column chromatography (ethyl acetate) gave the product as a mixture of E- and Z- isomers (Rf=0.41, 5.06 g):1H-NMR:7.4-7.2(m,5H), 6.3(d,0.6H,J=13), 5.8(d,0.4H,J=6), 4.65(dd,0.6H,J=13,6), 4.2(dd,0.4H,J=6,5), 3.5(s,1.2H), 3.45(s,1.8H), 2.9-2.7(m,2H), 2.5-2.3(m,1H), 2.1-1.3(m,7H); HR-MS:Calcd for C15H21NO:231.1623; Found:231.1633.
Reaction SMILES: N#N.[CH3:3][NH:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:12].[CH2:13](C(CC)(CC)C([O-])([O-])[O-])[CH3:14]>C(O)C>[CH3:3][N:4]1[C:5]2[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=2[N:12]=[C:13]1[CH3:14]
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: CNc1c(N)cccc1F
Agent: N#N
Solvent: CCO
Product: Cc1nc2cccc(F)c2n1C

Procedure:
Following the procedure of Preparation O-1, 3.0 g of N2 -methyl-3-fluorophenylenediamine and 3.9 ml of triethylorthoacetate in 100 ml of ethanol gave 3.0 g of product.
Reaction SMILES: [OH:1][C:2]([P:8](=[O:11])([OH:10])[OH:9])([P:4](=[O:7])([OH:6])[OH:5])[CH3:3].[CH:12](Cl)(Cl)Cl.[N+](=C)=[N-]>CCOCC>[CH3:12][O:11][P:8]([C:2]([P:4](=[O:6])([OH:5])[OH:7])([OH:1])[CH3:3])(=[O:9])[OH:10]
Reactant: ClC(Cl)Cl
Reactant: CC(O)(P(=O)(O)O)P(=O)(O)O
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: COP(=O)(O)C(C)(O)P(=O)(O)O
Reaction time: 1 h
Yield: 42 %

Procedure:
Finely ground (1-hydroxyethylidene)bisphosphonic acid (0.005 moles) was mixed with 100 ml of chloroform and to the mixture 25 ml of an appr. 2% ether solution of diazomethane were slowly added at room temperature. After the addition, the mixing was continued for 1 hour, whereafter the solution was evaporated at reduced pressure (yield 42%, 31-P NMR 17.25/24.84 ppm, J=27.3; D2O).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=N[N:18]([CH2:29]OCC[Si](C)(C)C)[C:15]3=[N:16][CH:17]=2)[CH:7]=1)[C:3]([OH:5])=O.C(Cl)(=O)C(Cl)=O.C[N:44](C=O)C>ClCCl>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[CH:29][NH:18][C:15]3=[N:16][CH:17]=2)[CH:7]=1)[C:3]([NH2:44])=[O:5]
Reactant: CN(C)C=O
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(O)C(=O)O)c3)cc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C(O)C(N)=O)c3)cc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
Hydroxy-{3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-acetic acid (92 mg, 0.19 mmol) was dissolved in dichloromethane (1 mL) and oxalyl chloride (145 mg, 1.14 mmol) and DMF (10 μL) were added. The resulting solution was heated to 60° C. with stirring overnight. The mixture was concentrated and ammonium hydroxide (30% w/v in water, 1 mL) was added and the stirring was continued for 15 minutes. The mixture was neutralized to pH 7 and extracted with ethyl acetate (5 mL×5). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. To the residue was added trifluoroacetic acid (2 mL) and the resulting mixture was sonicated until the residue was completely dissolved. The volatiles were evaporated and the residue was treated with ethylene diamine (0.2 mL). The resulting mixture was directly purified by mass-triggered reverse-phase HPLC to afford 2-hydroxy-2-{3-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acetamide as a white solid (32 mg, 45%). MS: m/z 374 (M+H+). 1H NMR (500 MHz, DMSO-d6) δ 3.86 (s, 3H), 4.95 (s, 1H), 6.09 (s, 1H), 7.11 (t, 1H), 7.21 (s, br, 1H), 7.23 (d, 1H), 7.47 (m, 4H), 7.67 (d, 2H), 7.81 (s, 1H), 8.31 (d, 1H), 8.83 (d, 1H), 8.73 (s, 1H), 13.82 (s, 1H).
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:13][C:14]([Br:18])([Br:17])[CH:15]=O>O>[Br:13][C:14]([Br:18])([Br:17])[CH:15]([C:9]1[CH:10]=[CH:11][C:6]([OH:12])=[CH:7][CH:8]=1)[C:9]1[CH:10]=[CH:11][C:6]([OH:12])=[CH:7][CH:8]=1
Reactant: O=CC(Br)(Br)Br
Reactant: Oc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: Oc1ccc(C(c2ccc(O)cc2)C(Br)(Br)Br)cc1

Procedure:
A 4-necked 3-L flask, is equipped with a mechanical stirrer, a nitrogen inlet, and thermometer, is charged with 83% sulfuric acid (640 g) and phenol (354 g). To the resulting milky mixture, tribromoacetaldehyde (380 g) in an additional funnel is added dropwise. The reaction temperature is maintained below 30° C. After the addition, the mixture is allowed to stir at the room temperature for 18 hours, before water (640 g) is added. The resulting mixture is filtered and washed with more water to afford 1,1,1-tribromo-2,2-bis(4-hydroxyphenyl)ethane.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2.O.[OH-].[Na+].Cl>CO>[N:11]1[C:12]2[C:7](=[CH:6][C:5]([CH2:4][C:3]([OH:15])=[O:2])=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc2ncccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1ccc2ncccc2c1
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
Sulphuric acid (67.5 ml) was added to 4-Aminophenylacetic acid (45 g, 297 mmol), glycerol (61.7 g, 67 mmol), and iodine (1.14 g, 4 mmol) drop-wise at rt. The mixture was heated to 140° C. for 24 h. After that reaction mixture cooled to rt and pH adjusted to 5 using 10% sodium hydroxide solution. To this methanol (350 ml) and sulphuric acid (3 ml) was added and heated to 100° C. for 24 h. Reaction mixture filtered through celite and filtrate was evaporated on rotavapour to obtain the residue. pH of the residue was adjusted to 5 using 4% NaOH solution and extracted with EtOAc. EtOAc layer was dried on anhydrous Na2SO4 and EtOAc removed on rotavapour to obtain the crude. Crude was purified by column using EtOAc and Petether as eluent to obtain methyl-2-(quinolin-6-yl)acetate (11.2 g). Methyl-2-(quinolin-6-yl)acetate (11.2 g) was dissolved in Methanol (8 ml) and water (8 ml) and added sodium hydroxide (3.3 g, 82 mmol). This mixture stirred for 30 mins and methanol removed on rotavapour to obtain the residue. Residue was acidified to pH 5 using 0.8 N HCl to obtain the solid. Solid was filtered and dried to obtain the title compound (8.2 g).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][CH2:7][C:8]1[C:17]2[O:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:14]([CH3:24])[C:13](=[O:25])[C:12]=2[CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.O>ClCCCl>[Cl:1][CH2:2][C:3]([NH:6][CH2:7][C:8]1[C:17]2[O:16][C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:14]([CH3:24])[C:13](=[O:25])[C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: Cc1c(-c2ccccc2)oc2c(CN)cccc2c1=O
Reactant: O=C(Cl)CCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1c(-c2ccccc2)oc2c(CNC(=O)CCl)cccc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3.2 ml of chloracetyl chloride in 32 ml of 1,2-dichloroethane was added dropwise, under stirring at -5° C., to a mixture of 10 g of Intermediate XXIV and 5.5 ml of triethylamine in 80 ml of 1,2-dichloroethane. The reaction mixture was stirred at ambient temperature for 1 hour and then 150 ml of water was added. The phases were separated; the aqueous phase was extracted with 1,2-dichloroethane and the extracts were added to the organic phase which was then washed with a cold saturated solution of sodium bicarbonate, washed with water, dried on anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was crystallized from ethanol to give 10.7 g of the title compound, m.p. 152°-155° C.