Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=1)\[C:13](O)=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:63][C@@H:64]1[C:67](=[O:68])[NH:66][C@@H:65]1[CH2:69][N:70]1[CH:74]=[N:73][C:72]([CH2:75][NH:76][C:77](=[O:83])[O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[N:71]1>C(Cl)Cl.CN(C=O)C.O.CCOC(C)=O>[C:79]([O:78][C:77]([NH:76][CH2:75][C:72]1[N:73]=[CH:74][N:70]([CH2:69][C@@H:65]2[C@H:64]([NH:63][C:13](=[O:14])/[C:12](=[N:11]\[O:10][C:7]([CH3:9])([CH3:8])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:29])/[C:16]3[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=3)[C:67](=[O:68])[NH:66]2)[N:71]=1)=[O:83])([CH3:80])([CH3:82])[CH3:81]
Reactant: CC(C)(C)OC(=O)NCc1ncn(C[C@H]2NC(=O)[C@H]2N)n1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ncn(C[C@H]2NC(=O)[C@H]2NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c2csc(NC(=O)OC(C)(C)C)n2)n1
Reaction time: 1 h
Yield: 554.8 %

Procedure:
To a slurry of (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (47 mg, 0.109 mmol) in DCM:DMF (12:1, 6.5 mL) at 0° C. was added DIPEA (505 μL, 2.89 mmol) followed by HATU (440 mg, 1.16 mmol). To the resulting solution was added a solution of tert-butyl ((1-(((2R,3S)-3-amino-4-oxoazetidin-2-yl)methyl)-1H-1,2,4-triazol-3-yl)methyl)carbamate (286 mg, 0.964 mmol) in DCM:DMF (14:1, 7.5 mL). After 1 h of stirring it was diluted with water/EtOAc and the layers separated. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine (3×), dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (Acetone-DCM, 70%) to afford the title compound (428 mg, 63%). LCMS: Rt=0.99 min, m/z=708.2 (M+1) Method 2m_acidic.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][N:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1>[Pd].CO>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[N:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(C2=CCC3(CC2)OCCO3)nc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(C2CCC3(CC2)OCCO3)nc1
Reaction time: 16 h
Yield: 87.6 %

Procedure:
Wet 50% palladium on carbon (750 mg) was added to a solution of 2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-5-nitropyridine (3.96 g, 15.11 mmol), prepared as above, in MeOH (500 mL). The reaction mixture was deoxygenated by evacuation and placed under an atmosphere of hydrogen (5 cycles) then stirred for 16 h. The mixture was filtered, and the filtrate concentrated to give the title compound (3.10 g, 87%) as a solid;
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2CO)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:32]([OH:37])(=[O:36])[C:33]([CH3:35])=[CH2:34]>C1COCC1>[C:32]([OH:37])(=[O:36])[C:33]([CH3:35])=[CH2:34].[CH:4]1[C:5]2[C:14](=[CH:13][C:12]3[C:7]([CH:6]=2)=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:1]=[CH:2][CH:3]=1
Reactant: OCc1c2ccccc2cc2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C=C(C)C(=O)O
Solvent: C1CCOC1
Product: c1ccc2cc3ccccc3cc2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
208 g of 9-anthracene methanol (1 mol), 309 g of dicyclohexyl carbodiimide (1.5 mol) and a methacrylic acid were stirred and dissolved in 2,000 g of a THF solution to form a preliminary mixture. 183 g of 4-dimethyl amino pyridine (1.5 mol) was injected into the preliminary mixture at a temperature of 0° C. to obtain a mixture. The mixture was stirred at room temperature for 6 hours. A solvent was then removed from the stirred mixture. The mixture without the solvent was repeatedly re-crystallized using methanol to obtain 163 g of an anthracene methacrylate monomer. 82 g of the anthracene methacrylate monomer, 34 g of p-tert-butoxystryne and 43 g of methacrylic acid were dissolved in 380 g of propylene glycol monomethyl ether acetate (PMA) to obtain a polymerization mixture. The polymerization mixture was heated at a temperature of 60° C. for 2 hours under a nitrogen atmosphere to synthesize a preliminary copolymer resin. 1 l of n-hexane was injected into the preliminary copolymer resin to remove non-polymerized portions from the preliminary copolymer resin, thereby synthesizing 120 g of copolymer resin. Here, the copolymer resin had a weight-average molecular weight of 5,600 and a dispersion degree of a molecular weight distribution of 2.4.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[N:21]1([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[CH:25]=[CH:24][N:23]=[CH:22]1>>[N:21]1([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:16][CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)=[CH:28][CH:27]=2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: Oc1ccc(-n2ccnc2)cc1
Reactant: CCOC(=O)C(Cc1ccc(OCCCBr)cc1)OC
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(-n3ccnc3)cc2)cc1)C(=O)O

Procedure:
3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 173, Step A) and 4-(imidazol-1-yl)phenol were treated under ester J to give the title compound. 1H-NMR (CDCl3, 200.15 MHz): δ 8.11 (s, 1H), 7.31–7.16 (m, 7H), 6.99 (d, 2H, J=8.9), 6.82 (d, 2H, J=8.6), 4.19 (t, 2H, J=6.2), 4.12 (t, 2H, J=5.9), 3.95 (dd, 1H, J=7.3, 4.8), 3.39 (s, 3H), 3.08 (dd, 1H, J=14.4, 4.8), 2.96 (dd, 1H, J=14.2, 7.6), 2.26 (qn, 2H, J=5.9).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:31][N:30]([C:32]3[N:36]([CH3:37])[N:35]=[C:34]([CH:38]([CH3:40])[CH3:39])[CH:33]=3)[CH2:29][CH2:28][C:4]=2[N:5]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10]([CH3:27])=[CH:11][N:12]3[S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:7]=1.[Cl:41]N1C(=O)CCC1=O>CC#N.C(OCC)C.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[C:3]2[CH2:31][N:30]([C:32]3[N:36]([CH3:37])[N:35]=[C:34]([CH:38]([CH3:40])[CH3:39])[C:33]=3[Cl:41])[CH2:29][CH2:28][C:4]=2[N:5]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10]([CH3:27])=[CH:11][N:12]3[S:17]([C:20]2[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=2)(=[O:18])=[O:19])[N:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc(Cl)c5c(n4)CCN(c4cc(C(C)C)nn4C)C5)cccc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc(Cl)c5c(n4)CCN(c4c(Cl)c(C(C)C)nn4C)C5)cccc32)cc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a solution of 4-chloro-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (90 mg, 0.156 mmol) in MeCN (2.0 mL) at 0° C. was added N-chlorosuccinimide (21 mg, 0.156 mmol). The reaction was permitted to stir for 2.5 h at 0° C., and then was diluted with diethyl ether and saturated aqueous sodium bicarbonate. The layers were separated and the organic layer was washed once with brine, dried over MgSO4, filtered and concentrated to furnish 4-chloro-6-(4-chloro-3-isopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine without the need for further purification. MS (ESI+) m/z 609.2 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH3:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].N1C=CC=CC=1.[Cl:17][CH2:18][C:19](Cl)=[O:20]>CN(C1C=CN=CC=1)C.C1COCC1>[Cl:17][CH2:18][C:19]([O:1][CH:2]([CH3:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:20]
Reactant: CCOC(=O)/C=C/C(C)O
Reactant: O=C(Cl)CCl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C(C)OC(=O)CCl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
21 (rac-Ethyl (2E)-4-hydroxypent-2-enoate) (crude, HPLC: ˜94 area %, 9.20 g, 60 mmol), pyridine (9.7 ml, 0.12 mol) and DMAP (1.47 g, 12 mmol) are dissolved in THF (300 ml) and cooled to 0° C. Chloroacetylchloride (9.6 ml, 0.12 mol) in THF (60 ml) is added dropwise under stirring at ≦2° C. over 10 min. The reaction mixture is stirred 40 min at 0° C. The resulting suspension is then poured onto H2O (250 ml) and extracted with tBuOMe (1 l). The organic phase is washed with saturated NaHCO3 (100 ml), 1 M HCl (100 ml), H2O (3×100 ml) and brine (100 ml) successively. The organic phase is dried with Na2SO4 and evaporated under reduced pressure at 40° C. The residue is purified by HPLC (tBuOMe:hexane fraction 5:95) and yields 30 (rac-Ethyl (2E)-4-(chloroacetoxy)pent-2-enoate) (9.81 g, 74%) as a yellowish oil.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([C:22]3[CH:23]=[N:24][NH:25][CH:26]=3)=[N:8][C:7]=2[N:6]([CH2:27][CH2:28][CH3:29])[C:5]1=[O:30])[CH2:2][CH3:3].[CH:31]([C:34]1[CH:39]=[CH:38][C:37]([N:40]2[C:44](=[O:45])[CH2:43][CH:42]([CH2:46]OS(C)(=O)=O)[CH2:41]2)=[CH:36][CH:35]=1)([CH3:33])[CH3:32].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH:31]([C:34]1[CH:39]=[CH:38][C:37]([N:40]2[C:44](=[O:45])[CH2:43][CH:42]([CH2:46][N:25]3[CH:26]=[C:22]([C:9]4[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:21])[CH3:19])[C:11]5[C:12](=[O:13])[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:30])[N:6]([CH2:27][CH2:28][CH3:29])[C:7]=5[N:8]=4)[CH:23]=[N:24]3)[CH2:41]2)=[CH:36][CH:35]=1)([CH3:33])[CH3:32]
Reactant: CCCn1c(=O)c2c(nc(-c3cn[nH]c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Reactant: CC(C)c1ccc(N2CC(COS(C)(=O)=O)CC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(nc(-c3cnn(CC4CC(=O)N(c5ccc(C(C)C)cc5)C4)c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Temperature: 77.5 °C
Yield: 80.5 %

Procedure:
A mixture of 1,3-dipropyl-8-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.100 g, 0.23 mmol), methanesulfonic acid 1-(4-isopropyl-phenyl)-5-oxo-pyrrolidin-3-ylmethyl ester (0.107 g, 0.34 mmol), K2CO3 (0.048 g, 0.34 mmol) and DMF (1 ml) were heated at 75-80° C. for 16 hrs. Reaction mixture was cooled to 20-25° C. and water was added (10 ml). The aqueous layer was extracted with ethyl acetate, washed with saturated brine solution. The organic layer was dried over Na2SO4 and evaporated to obtain crude product (0.2 g). The crude product was purified by preparative TLC to obtain pure 8-{1-[1-(4-isopropyl-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazol-4-yl}-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.12 g, 80%) as a light yellow oil.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:14]=2[NH:13][C:12]([C:15]([NH2:17])=O)=[CH:11]3)[CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCCC1>[CH:1]1([CH2:4][N:5]([S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:14]=2[NH:13][C:12]([C:15](=[S:35])[NH2:17])=[CH:11]3)[CH2:3][CH2:2]1
Reactant: NC(=O)c1cc2cccc(N(CC3CC3)S(=O)(=O)c3cccs3)c2[nH]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: NC(=S)c1cc2cccc(N(CC3CC3)S(=O)(=O)c3cccs3)c2[nH]1
Temperature: 60 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
A mixture of 7-[(cyclopropylmethyl)(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (264 mg), Lawesson's reagent (339 mg) and tetrahydrofuran (5 ml) was stirred at 60° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of ethyl acetate-hexane (1:1) to give the title compound (243 mg, yield 88%) as an amorphous solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:5]=[C:4](Cl)[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(#N)C.ClCCl.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.[Pd]>[C:23]1([C:2]2[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=3)[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:3]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(Nc2cc(Cl)nc(Cl)c2)cc1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ccc(Nc2cc(-c3ccccc3)nc(-c3ccccc3)c2)cc1
Yield: 172.4 %

Procedure:
To a mixture of (2,6-dichloro-pyridin-4-yl)-p-tolyl-amine (100.4 mg, 0.4 mmol) dissolved in acetonitrile (6 mL) and 2 M Na2CO3 (6 mL) was added phenylboronic acid (122.5 mg, 1 mmol) and palladium tetrakis(triphenylphosphine) (46.3 mg, 0.04 mmol). The resulting mixture was allowed to stir at reflux for 12 hours. The sample was diluted in dichloromethane and filtered through Celite™. The Celite™ was washed with dichloromethane, and the filtrate was washed two times with water and one time with brine. The organic phase was dried over potassium carbonate and concentrated by rotary evaporation. The resulting sample was dried for 12-18 hours under vacuum. Purification (Biotage Horizon HPFC chromatography system, SiO2, 70:30 hexanes:ethyl acetate) gave a brown solid (2,6-diphenyl-pyridin-4-yl)-p-tolyl-amine (116 mg, 86%).
Reaction SMILES: [CH:1]([C:3]1[O:8][CH2:7][N:6]([C:9]([CH3:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C:5](=[O:18])[C:4]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O.Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>C(O)C>[OH:27][N:26]=[CH:1][C:3]1[O:8][CH2:7][N:6]([C:9]([CH3:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C:5](=[O:18])[C:4]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NO
Reactant: CC(C)(c1ccccc1)N1COC(C=O)=C(c2ccccc2)C1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(c1ccccc1)N1COC(C=NO)=C(c2ccccc2)C1=O
Reaction time: 1 h
Yield: 86 %

Procedure:
6-Formyl-3-(1-methyl-1-phenylethyl)-5-phenyl-2,3-dihydro-4H-1,3-oxazin-4-one (Compound No. 121, 2.87 g) was dissolved in ethanol (30 ml), and an aqueous solution (15 ml) of hydroxylamine hydrochloric acid (0.65 g) and sodium acetate (1.30 g) was added slowly thereto at room temperature. After stirring for one hour, ethanol was removed by evaporation, and filtered after adding water. The solid product obtained was rinsed with water and dried to afford the captioned compound (2.59 g, yield 86%).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-])=O)[CH:3]=1.O.O.Cl[Sn]Cl>Cl>[I:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:6])=[CH:7][CH:8]=1
Reactant: Nc1ccc(I)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: Nc1ccc(I)cc1N
Temperature: 65 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
4-Iodo-2-nitroaniline (35.2 g, 0.133 mol) was added in batches via an open funnel over 25 mM to a heated (65° C.) mixture of SnCl2.2H2O (106.86 g, 0.465 mol) and 12N HCl (200 ml). An additional 12N HCl (30 ml) was added and the reaction mixture was heated at 65° C. for an additional 1 h, and stirred at room temperature for 1 h. It was placed in a refrigerator for 15 h, and the precipitate was filtered. The resultant solid was transferred into a flask containing water (210 ml), cooled (ice/water), and a solution of NaOH (aq) (35 g in 70 ml of water) was added to it over 10 min with stirring. The cooling bath was removed, and vigorous stirring was continued for 45 min. The mixture was filtered and the solid was washed with water and dried in vacuo to provide 4-iodobenzene-1,2-diamine as a tan solid (25.4 g). The product was used in the next step without further purification. 1H NMR (DMSO-d6, =2.5 ppm, 500 MHz): 6.79 (d, J=2.1H), 6.63 (dd, J=1.9, 8.1, 1H), 6.31 (d, J=8.1, 1H), 4.65 (br s, 2H), 4.59 (br s, 2H). LC/MS: Anal. Calcd. for [M+H]+ C6R8IN2: 234.97; found: 234.9.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][C:13]1[O:14][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:16][N:17]=1)C1C=CC=CC=1>CO.[Pd]>[CH:18]([C:15]1[O:14][C:13]([CH2:12][CH2:11][NH2:10])=[N:17][CH:16]=1)([CH3:20])[CH3:19]
Reactant: CC(C)c1cnc(CCNC(=O)OCc2ccccc2)o1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1cnc(CCN)o1
Reaction time: 5 h

Procedure:
6.50 g (22.54 mmol) benzyl[2-(5-isopropyl-oxazol-2-yl)-ethyl]-carbamate are placed in 130 ml of methanol, 3.50 g palladium/charcoal 10% are added, then the mixture is hydrogenated for 5 hours at ambient temperature under a pressure of 14 psi. Then the catalyst is removed by suction filtering, the solution is evaporated down. The residue is extracted with dichloromethane and potassium carbonate solution, the organic phase is dried and evaporated to dryness.
Reaction SMILES: C(N1CCC(OC2C=CC3N4CCCNC(=O)C4=CC=3C=2)CC1)(C)C.[CH3:26][O:27][C:28]([C:30]1[N:46](C(OC(C)(C)C)=O)[C:33]2=[N:34][CH:35]=[C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:37]=[C:32]2[CH:31]=1)=[O:29].[C:54]([O:58][C:59]([N:61]1[CH2:65][CH2:64]OS1(=O)=O)=[O:60])([CH3:57])([CH3:56])[CH3:55].CC(C)([O-])C.[K+]>>[CH3:26][O:27][C:28]([C:30]1[N:46]([CH2:64][CH2:65][NH:61][C:59]([O:58][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:60])[C:33]2=[N:34][CH:35]=[C:36]([O:38][CH2:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:37]=[C:32]2[CH:31]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCOS1(=O)=O
Reactant: COC(=O)c1cc2cc(OCc3ccccc3)cnc2n1C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCCNC2=O)CC1
Agent: [K+]
Product: COC(=O)c1cc2cc(OCc3ccccc3)cnc2n1CCNC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized in analogy to example 1, intermediate b), from 5-benzyloxy-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (intermediate M), 2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (prepared according to WO02/072584) and potassium tert-butoxide, to give the product as a colorless foam (89%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]([C:19]1[C:24]([O:25][CH3:26])=[CH:23][C:22]([O:27][CH3:28])=[CH:21][C:20]=1[OH:29])=[O:18]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:28][O:27][C:22]1[CH:23]=[C:24]([O:25][CH3:26])[C:19]([C:17](=[O:18])[CH3:16])=[C:20]([O:29][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:21]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: COc1cc(O)c(C(C)=O)c(OC)c1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc(OC)c(C(C)=O)c(Oc2ccnc3cc(OC)c(OC)cc23)c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (56 mg), 2-hydroxy-4,6-dimethoxyacetophenone (196 mg), and 4-dimethylaminopyridine (122 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure. The residue was purified by column chromatography using acetone-hexane to give the title compound (25 mg, yield 27%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=1)([O-:3])=[O:2].Br.C(O)(=O)C>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)([O-:3])=[O:2]
Reactant: COc1ccc(Oc2cccc([N+](=O)[O-])c2)cc1
Agent: Br
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc(Oc2ccc(O)cc2)c1

Procedure:
m-nitrophenol and bromoanisole yield p-(m-nitrophenoxy)anisole of m.p. 69°-71° C. and reaction with hydrobromic acid/acetic acid yields p-(m-nitrophenoxy)phenol which distils in the bulb-tube at 95°-97° C./0.04 Torr;
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[O:10][CH:7]([O:8][CH3:9])[C@H:6]([OH:11])[C@@H:5]1[OH:12].[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CO>CN(C)C=O>[CH3:1][O:2][CH2:3][C@H:4]1[O:10][CH:7]([O:8][CH3:9])[C@H:6]([O:11][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:5]1[O:12][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC[C@H]1OC(OC)[C@H](O)[C@@H]1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC[C@H]1OC(OC)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of methyl 5-O-methyl-D-ribofuranoside (Dubois L. et al. Tetrahedron 1993, 49(4), 901-910, 2 g, 11.2 mmol) in dimethylformamide (10 mL) was added dropwise to a suspension of sodium hydride (60% in oil, 2.25 g, 563 mmol) in dimethylformamide (54 mL). After stirring at rt for 45 minutes, a solution of benzyl bromide (4 mL, 33.6 mmol) was added dropwise in dimethylformamide (4 mL). The reaction mixture was stirred at rt overnight, quenched with methanol and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, hexanes/ethyl acetate 70/30 to 50/50) to provide the a anomer (2.86 g, 71%) and the β anomer (0.86 g, 21%); α anomer Rf=0.5, β anomer Rf=0.4 (silica, hexanes/ethyl acetate 50/50).
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([C:14]#[N:15])([CH2:12][CH3:13])[CH2:9]1)=O)(C)(C)C.[F:16][C:17]([F:22])([F:21])[C:18]([OH:20])=[O:19]>ClCCl>[F:16][C:17]([F:22])([F:21])[C:18]([OH:20])=[O:19].[C:14]([C:10]1([CH2:12][CH3:13])[CH2:11][NH:8][CH2:9]1)#[N:15]
Reactant: CCC1(C#N)CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC1(C#N)CNC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a round-bottomed flask, 3-cyano-3-ethyl-azetidine-1-carboxylic acid tert-butyl ester (0.40 g, 1.9 mmol) was dissolved in dichloromethane (12 mL). The light yellow solution was cooled to 0° C. and trifluoroacetic acid (4.4 mL) was slowly added. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated to afford 3-cyano-3-ethyl-azetidine trifluoroacetate as a light yellow oil which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][C:11]=2[NH:19][C:20]2[C:21]3[CH:29]=[CH:28][CH:27]=[N:26][C:22]=3[N:23]=[CH:24][N:25]=2)=[CH:5][CH:4]=1.[F:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][C:32]=1[CH3:38].FC(F)(F)C1C=C(C=CC=1)N>CO>[F:30][C:31]1[CH:37]=[CH:36][C:34]([NH:35][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][C:10]([S:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[C:11]([NH:19][C:20]3[C:21]4[CH:29]=[CH:28][CH:27]=[N:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH:12]=2)=[CH:33][C:32]=1[CH3:38]
Reactant: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3ncccc23)cc1
Reactant: Cc1cc(N)ccc1F
Agent: Nc1cccc(C(F)(F)F)c1
Solvent: CO
Product: COc1ccc(Sc2ccc(C(=O)Nc3ccc(F)c(C)c3)cc2Nc2ncnc3ncccc23)cc1

Procedure:
The product from Example 260B was reacted with 4-fluoro-3-methylaniline according to the procedure from Example 260C substituting 4-fluoro-3-methylaniline for 3-(trifluoromethyl)aniline to provide the title compound as an off white solid after trituration of the reaction product from methanol (44 mg, 52%).