Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([CH:11]([OH:16])[C:12](=[NH:15])[NH:13][OH:14])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]([CH:11]([OH:16])[C:12](=[NH:15])[NH:13][O:14][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:9][CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(O)c1ccccc1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(O)C(=N)NO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CCC(NC(=O)OC(C)(C)C)C(O)C(=N)NOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.2 %

Procedure:
A solution of {1-[hydroxy-(N-hydroxycarbamimidoyl)-methyl]-propyl}-carbamic acid tert-butyl ester (2) (2.5 g, 10 mmol) in dichloromethyl (125 ml) was treated with benzoic acid 1.36 g, 11 mmol), EDCI (2.14 g, 11 mmol), HOBT (1.37 g, 10 mmol) and triethylamine (1.35 mL, 11 mmol) and stirred at room temperature overnight. The reaction mixture was washed with saturated sodium bicarbonate solution, then water, then dried over Na2SO4 and then evaporated under reduced pressure. The residue was subjected to mplc eluting with 1% triethylamine in 2:3 v/v ethyl acetate and heptane mixture to give {1-[hydroxy-(N-benzoyloxycarbamimidoyl)-methyl]-propyl}-carbamic acid tert-butyl ester (850 mg) as a yellow solid. MS: MH+ 352.
Reaction SMILES: N(C(C)=O)(CNC(C)=O)CNC(C)=O.C=O.O.[C:18]([OH:21])(=[O:20])[CH3:19].N(CC(O)=O)CC(O)=O.[C:31]([NH:34][CH2:35][C:36]([OH:38])=[O:37])(=[O:33])[CH3:32]>CC(C)=O>[C:31]([N:34]([CH2:35][C:36]([OH:38])=[O:37])[CH2:19][C:18]([OH:21])=[O:20])(=[O:33])[CH3:32]
Reactant: CC(=O)NCC(=O)O
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)NCN(CNC(C)=O)C(C)=O
Agent: O=C(O)CNCC(=O)O
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)N(CC(=O)O)CC(=O)O
Temperature: 110 °C
Yield: 95 %

Procedure:
A 300 mL autoclave was charged with acetamide (VII)(11.8 g, 0.2 mole), 95% paraformaldehyde (13.6 g, 0.43 mole), water (12.9 g, 0.72 mole), acetic acid (2.1 g, 0.035 mole), acetone (90 mL) and Co2(CO)8 (2.1 g, 0.006 mol) and pressurized to 3200 psi (22,069 kPa) CO:H2 (95:5) at 25° C. This mixture was heated to 110° C. for 30 min. HPLC analysis of this stream indicated a 95% yield of (XVI), 0.5% (XIV), and 4.5% (XVIII).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C1C=CC=CC=1.[CH:18]([C:20]([CH3:22])=[O:21])=[CH2:19]>C(N(CC)CC)C>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:19][CH2:18][C:20](=[O:21])[CH3:22])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: C=CC(C)=O
Reactant: CCOC(=O)C1CCCC1=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)C1(CCC(C)=O)CCCC1=O

Procedure:
(B.) A mixture of 102.0 g of ethyl 2-oxocyclopentanecarboxylate, 300 ml of benzene, 67 ml of methyl vinyl ketone and 20 ml of triethylamine was allowed to stir magnetically at reflux for 2.5 hours. Concentration followed by Claisen distillation gave 128 g of product.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([OH:31])[CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:32]([C:35]1[CH:36]=[C:37](O)[CH:38]=[CH:39][CH:40]=1)(=[O:34])[CH3:33]>>[C:32]([C:35]1[CH:40]=[C:39]([CH:38]=[CH:37][CH:36]=1)[O:31][CH:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH2:2][CH2:3]2)[CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=2)[CH2:17][CH2:18]1)(=[O:34])[CH3:33]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc4c(c3)CCC4)CC2)c1
Product: CC(=O)c1cccc(OC(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc3c(c2)CCC3)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(2,3-dihydro-1H-inden-5-yl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3-acetylphenol: ESMS m/e: 539.2 (M+H)+.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([NH:15][NH2:16])=[O:14])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:30])=[C:25]([C:27](=O)[CH3:28])[CH:26]=1>CO.C(O)(=O)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:30])=[C:25](/[C:27](=[N:16]/[NH:15][C:13](=[O:14])[C:12]2[CH:17]=[CH:18][CH:19]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)/[CH3:28])[CH:26]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCCCC2)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 54.1 %

Procedure:
3-(piperidin-1-ylsulfonyl)benzohydrazide (65 mg, 0.229 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (39.1 mg, 0.229 mmol) was dissolved in methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the product (E)-N′-(1-(5-chloro-2-hydroxyphenyl)ethylidene)-3-(piperidin-1-ylsulfonyl)benzohydrazide (55 mg, 0.124 mmol, 53.9% yield) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.09 (m, 2H), 7.85 (d, 1H, J=8.0 Hz), 7.62 (t, 1H, J=8.0 Hz), 7.41 (d, 1H, J=2.4 Hz), 7.22 (d, 1H, J=8.0 Hz), 6.93 (d, 1H, J=8.8 Hz), 2.97 (m, 4H), 2.41 (s, 3H), 1.61 (m, 4H), 1.40 (m, 2H). Mass [M+H]+:436.9
Reaction SMILES: [N:1]#[C:2]Cl.[CH:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([CH3:11])[CH:5]=1.C1(O)C=CC=CC=1>>[OH:10][C:9]1[CH:4]=[CH:5][C:6]([CH2:11][C:2]#[N:1])=[CH:7][CH:8]=1
Reactant: Cc1ccc(O)cc1
Reactant: N#CCl
Solvent: Oc1ccccc1
Product: N#CCc1ccc(O)cc1
Yield: 55 %

Procedure:
There were fed into the 1 meter heated reactor having a diameter of 55 mm and an average temperature of 720° C. via line 1 per hour 46.1 grams (0.75 mole) of gaseous cyanogen chloride and via line 2 313.6 grams (2.9 moles) of gaseous p-cresol as well as 1-2 liters of gaseous nitrogen. From the reactor 3 the nitrile containing gas entered into column 5 via the cooled line 4. The column 5 consisted of a "Sambay-Evaporator" having an inner surface area of 0.1 m and an erect packed column 20 cm long. At the foot of the column there were fed in per hour 2-3 liters of gaseous nitrogen, the temperature of the oil in the double jacket of the column is so regulated that the crude product condensing in the column and having a temperature of about 180° C. can be withdrawn via line 8, while at the head of the column 5 the waste gas having a temperature of about 160° C. is led via line 7 into the fractionating column 8. The column 8 has a length of 50 cm, a diameter of 2 cm and is filled with Raschig rings. At the foot of column 8 per hour there were led in about 2-3 liters of gaseous nitrogen. The cooling over the double jacket is so regulated that at the foot of the column there prevails a sump temperature of up to 120° C. and at the column head a temperature of 20°-40° C. The p-cresol condensing in the column 8 contains 5-6% phenol. Only after distillation separation of the phenol can be recovered p-cresol mixed with fresh p-cresol for replacement of material consumed be returned into the reactor 3. The residual gas leaving the column 8 is led via line 10 into the separator 11 at -30° C., as well as to the activated carbon filter (not shown) and thereupon led into the washing column 14 in which there takes place the washing of the residual gas with water. There are obtained in the column 5 per hour 91.6 grams of crude product from which there is obtained by distillation in the column 18 at 160° C./l Torr 54.9 grams of p-hydroxyphenylacetonitrile. This corresponds to a yield of 55% based on the cyanogen chloride employed.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH2:12][NH2:13])[CH2:7][CH2:6][CH2:5]2.[CH2:14]([CH:16]1[O:18][CH2:17]1)Br>C(O)(C)C>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH2:12][N:13]1[CH2:17][CH:16]([OH:18])[CH2:14]1)[CH2:7][CH2:6][CH2:5]2
Reactant: BrCC1CO1
Reactant: NC[C@@H]1CCCc2cc(I)ccc21
Solvent: CC(C)O
Product: OC1CN(C[C@@H]2CCCc3cc(I)ccc32)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of C—((R)-6-iodo-1,2,3,4-tetrahydro-naphthalen-1-yl)-methylamine (0.79 g, 2.75 mmol) in isopropanol (6 mL) at ice bath temperature and under nitrogen atmosphere, was added dropwise epibromohydrin ((0.38 g, 2.8 mmol). The ice bath was removed and the reaction mixture was stirred for 18 hours at room temperature. Triethylamine ((0.39 mL, 2.8 mmol) was added, and the reaction mixture was stirred at room temperature for two hours, then at 60° C. for three hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was taken up in EtOAc. The EtOAc solution was washed with water and 0.5 M aqueous sodium carbonate, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting oil was chromatographed by HPLC (hexanes/EtOAc 1:1 to 50% hexanes/27% EtOA/15% MeOH/8% con. NH4OH) to 0.5 g (53%) of 1-((R)-6-Iodo-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-azetidin-3-ol, MS M+H=344
Reaction SMILES: [CH:1](=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH2:16](O)[CH2:17][OH:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:2]([CH:1]1[O:18][CH2:17][CH2:16][O:15]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC/C=C\CCCCCCC=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCC/C=C\CCCCCCC1OCCO1
Reaction time: 3 h

Procedure:
5.6 g (Z)-8-tetradecenal (6), 2.0 g ethylene glycol and 20 mg p-toluenesulphonic acid in 150 ml toluene were boiled in a water separator for 3 h. The reaction mixture was washed with sodium bisulphate solution and dried over sodium sulphate and the solvent was distilled off. Chromatography on silica gel gave 2-[(Z)-tridec-7-enyl]-1,3-dioxolane (7).
Reaction SMILES: BrCC1CC1(F)F.Br[CH2:9][CH2:10][CH2:11][C:12]([F:15])([F:14])[F:13].[CH3:16][C:17]1[N:18]=[C:19]([N:27]2[CH2:31][CH2:30][NH:29][C:28]2=[O:32])[S:20][C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH3:16][C:17]1[N:18]=[C:19]([N:27]2[CH2:31][CH2:30][N:29]([CH2:9][CH2:10][CH2:11][C:12]([F:15])([F:14])[F:13])[C:28]2=[O:32])[S:20][C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: FC(F)(F)CCCBr
Agent: FC1(F)CC1CBr
Product: CCOC(=O)c1sc(N2CCN(CCCC(F)(F)F)C2=O)nc1C
Yield: 98 %

Procedure:
Following the procedure as described in Preparation 13, making variations to replace bromomethyl-2,2-difluorocyclopropane with 4-bromo-1,1,1-trifluorobutane to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 98% yield: MS (ES+) m/z 366.1 (M+1).
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)[C:10]([NH2:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]([NH2:12])=[O:11])=[CH:19][CH:18]=1
Reactant: NC(=O)N(Cc1ccc([N+](=O)[O-])cc1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NC(=O)N(Cc1ccc(N)cc1)OCc1ccccc1
Yield: 42.5 %

Procedure:
10% Palladium carbon (0.3 g) was added to 80 ml of ethyl acetate solution containing 4.76 g of 1-benzyloxy-1-(4-nitrobenzyl)urea. The reaction mixture was stirred overnight under normal pressure in an atmosphere of hydrogen, and then insoluble materials were removed by filtration. After evaporating the solvent under a reduced pressure, the resulting residue was purified by silica gel column chromatography (eluant: chloroform:methanol=10:1) to obtain 1.82 g of 1-(4-aminobenzyl)-1-benzyloxyurea.
Reaction SMILES: C[O:2][CH2:3][CH2:4]OC.C([Zn]CC)C.ICI.[Br:15][C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/CO)=[CH:18][CH:17]=1>C(Cl)Cl>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]2[CH2:23][C@@H:4]2[CH2:3][OH:2])=[CH:18][CH:17]=1
Reactant: OC/C=C/c1ccc(Br)cc1
Reactant: COCCOC
Agent: CC[Zn]CC
Solvent: ICI
Solvent: ClCCl
Product: OC[C@H]1C[C@@H]1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of DME (24.39 mL, 235 mmol) in DCM (700 mL) under nitrogen atmosphere was cooled to −10° C., and diethylzinc (235 mL, 1M in hexane, 235 mmol) was added over 5-10 minutes followed by diiodomethane (37.9 mL, 469 mmol). The product from Example 8C (33.0 g, 122 mmol) in 100 mL DCM was added in 5-10 minutes. The temperature was maintained from −5° to −10° C. throughout the additions. The product from Example 8A, (E)-3-(4-bromophenyl)prop-2-en-1-ol (20 g, 94 mmol) in DCM (150 mL) was added dropwise, and the reaction mixture was stirred at ambient temperature for 16 hours. It was quenched with saturated aqueous NH4Cl (300 mL), HCl (1N, 480 mL) and diluted with ether (900 mL). The organic layer was separated. The aqueous layer was extracted with additional ether. The organic layers were combined and treated with NaOH (2N, 880 mL). To the solution, H2O2 (30%, 136 mL) was added dropwise while the reaction was cooled with an ice bath. The solution was stirred for 5-10 minutes. The organic layer was separated, washed with HCl (1N), saturated aqueous Na2S2O3, saturated aqueous NaHCO3, and brine, dried and concentrated. The residue was chromatographed on silica gel eluting with 5-15% EtOAc/Hexane to provide the title compound. 1H NMR (300 MHz, CDCl3): δ 0.92-1.0 (m, 2H), 1.45-1.48 (m, 2H), 1.76-1.85 (m, 1H), 3.61 (d, J=7.5 Hz, 2H), 6.95 (d, J=9 Hz, 2H), 7.37 (d, J=9 Hz, 2H). MS (DCI—NH3) m/z 228 (M+H)+. (ee 94%).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH2:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20](=[O:22])[CH3:21])[CH:18]=2)[C:13]([CH2:23][CH3:24])=[N:12]1)[CH3:10]>CN(C)C=O>[CH2:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20](=[O:22])/[CH:21]=[CH:3]/[N:4]([CH3:5])[CH3:6])[CH:18]=2)[C:13]([CH2:23][CH3:24])=[N:12]1)[CH3:10]
Reactant: COC(OC)N(C)C
Reactant: CCc1nn(CC)c2cc(C(C)=O)ccc12
Solvent: CN(C)C=O
Product: CCc1nn(CC)c2cc(C(=O)/C=C/N(C)C)ccc12
Temperature: 120 °C
Reaction time: 16 h
Yield: 1.7 %

Procedure:
1,1-dimethoxy-N,N-dimethylmethanamine (0.891 g, 0.0075 mol) was added to a solution of 1-(1,3-Diethyl-1H-indazol-6-yl)-ethanone (0.187 mg, 8.64 mmol) in N,N-dimethylformamide (8 mL), and the resulting mixture was shaken at 120° C. for 16 hours. 1,1-dimethoxy-N,N-dimethylmethanamine (0.618 g, 0.0052 mol) was added, and the reaction was refluxed at 140° C. for a further 16 hours. The solvent was removed in vacuo, and the residue extracted with ethyl acetate (30 mL) and water (10 mL). The aqueous layer was re-extracted with ethyl acetate (30 mL). The organic layers were combined, dried, filtered and concentrated. The resulting crude product was purified by silica-gel chromatography, using an eluent gradient of 0.25-0.5% methanol in dichloromethane (mobile phase contained 0.5% ammonium hydroxide solution) to afford 35 mg of (2E)-1-(1,3-diethyl-1H-indazol-6-yl)-3-(dimethylamino)prop-2-en-1-one.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[C:10]([O:25][CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[N:6]2[N:5]=1)=O.[OH-:34].[Na+].O>C(O)(=O)C>[OH:34][C:4]1[N:9]=[CH:8][C:7]2=[C:10]([O:25][CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:33])[CH3:31])[CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[N:6]2[N:5]=1
Reactant: [OH-]
Reactant: CN(c1ccccc1-c1cc(OCOCC[Si](C)(C)C)c2cnc(S(C)=O)nn12)S(C)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CN(c1ccccc1-c1cc(OCOCC[Si](C)(C)C)c2cnc(O)nn12)S(C)(=O)=O
Temperature: 120 °C
Yield: 45 %

Procedure:
Into a 8-dram vial, N-{2-[2-Methanesulfinyl-5-(2-trimethylsilanyl-ethoxymethoxy)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-N-methyl-methane sulfonamide (480 mg, 0.94 mmol) was added to heated solution of 19.10 M of Sodium hydroxide in Water (5.0 mL, 96 mmol) at 110° C. The reaction mixture was heated at 120° C. for 2 hours. 5 mL of Acetic acid was added to adjust pH to 5. The reaction was partitioned with water and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with DCM and NH3 in methanol as eluant (2 to 15% methanol). The collected fractions afforded N-{2-[2-Hydroxy-5-(2-trimethylsilanyl-ethoxymethoxy)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-N-methyl-methanesulfonamide as a red solid (195 mg, 45%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([S:30](Cl)(=[O:32])=[O:31])=[C:25]([CH3:34])[C:24]=1[CH3:35]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:13])[CH:4]([NH:5][S:30]([C:26]1[C:27]([CH3:29])=[CH:28][C:23]([O:22][CH3:21])=[C:24]([CH3:35])[C:25]=1[CH3:34])(=[O:32])=[O:31])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(Cc1ccccc1)NS(=O)(=O)c1c(C)cc(OC)c(C)c1C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of L-phenylalanine methyl ester (300 mg, 1.68 mmol) in anhydrous CH2Cl2 (10 mL) was cooled to 0° C. in an ice bath, then triethylamine (0.35 mL), 4-methoxy-2,3,6-trimethyl-benzenesulfonyl chloride (438 mg, 1.76 mmol) and catalytic amount of DMAP (25 mg) were added under a N2 atmosphere. The reaction mixture was stirred at room temperature for 12 h. After that period of time, the mixture was partitioned between water and CH2Cl2, the organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate and hexane (1:2) as eluent to obtain 2-(4-Methoxy-2,3,6-trimethyl-benzenesulfonylamino)-3-phenyl-propionic acid methyl ester as a white solid, 500 mg (77%). 1H NMR (CDCl3, 400 MHz): δ7.26-7.18 (m, 3H), 7.02-6.99 (m, 2H), 6.53 (s, 1H), 5.12 (d, 1H), 4.09-4.04 (m, 1H), 3.84 (s, 3H), 3.55 (s, 3H), 3.05 (dd, 1H), 3.03 (dd, 1H), 2.64, 2.38, 2.08 (3s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9]/[C:10]/2=[N:13]\[S:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:20]([O:23][CH3:24])(=[O:22])[CH3:21]>>[CH3:24][O:23][C:20](=[O:22])[CH2:21][C@:10]1([NH:13][S@@:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH2:8][CH2:9]1
Reactant: CC(C)(C)S(=O)/N=C1\CCc2ccc([N+](=O)[O-])cc21
Reactant: COC(C)=O
Product: COC(=O)C[C@@]1(N[S@](=O)C(C)(C)C)CCc2ccc([N+](=O)[O-])cc21

Procedure:
Starting from 2-methyl-propane-2-sulfinic acid [6-nitro-indan-(1E)-ylidene]-amide and methyl acetate, the product [(S)-1-((R)-2-methyl-propane-2-sulfinylamino)-6-nitro-indan-1-yl]-acetic acid methyl ester was obtained as a black oil. MS (ESI): m/z=355.5 [M+H]+.
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]([CH3:13])[CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[OH-].[Na+].Cl>O>[O:16]=[C:17]1[CH:22]=[CH:21][N:20]([C:2]2[CH:15]=[CH:14][C:5]([C:6]([CH:8]([CH3:13])[CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=2)[CH:19]=[CH:18]1
Reactant: CC(CC(=O)O)C(=O)c1ccc(F)cc1
Reactant: Oc1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(CC(=O)O)C(=O)c1ccc(-n2ccc(=O)cc2)cc1

Procedure:
A solution of 3-(4-fluorobenzoyl)butanoic acid (8 g), 4-hydroxypyridine (8 g) and sodium hydroxide (4.6 g) in water (80 ml) was heated in an autoclave at 140° C. for 20 hours. The reaction mixture was cooled and on acidification to pH3 with dilute hydrochloric acid afforded as a white crystalline precipitate 3-[4-(4-oxo -1,4-dihydropyridin-1-yl)benzoyl]butanoic acid, 9.45 g, m.p. 250-252° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH:12]1[O:16][CH2:15][CH2:14][O:13]1.O1CCCC1.C([Li])CCC.[CH:27]1[C:32]([CH:33]=[O:34])=[CH:31][C:30]2[O:35][CH2:36][O:37][C:29]=2[CH:28]=1>C(=O)=O.CC(C)=O>[O:13]1[CH2:14][CH2:15][O:16][CH:12]1[C:3]1[CH:4]=[C:5]([O:10][CH3:11])[C:6]([O:8][CH3:9])=[CH:7][C:2]=1[CH:33]([C:32]1[CH:27]=[CH:28][C:29]2[O:37][CH2:36][O:35][C:30]=2[CH:31]=1)[OH:34]
Reactant: COc1cc(Br)c(C2OCCO2)cc1OC
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1cc(C2OCCO2)c(C(O)c2ccc3c(c2)OCO3)cc1OC
Temperature: -78 °C
Yield: 30 %

Procedure:
To a flame dried four necked round bottom flask (100 mL) were added 2-(2-bromo-4,5-dimethoxyphenyl)-1,3-dioxolane (formula VII; 1.0 g, 0.9934 mole) and anhydrous tetrahydrofuran (25 ml) under nitrogen atmosphere. The flask was cooled to −78° C. in dry ice-acetone bath; n-Butyllithium (5.3 ml, 0.005 mole) was added drop wise with stirring at −78° C. and stirred for 15 minutes. A separate flame dried flask was charged with Piperonal (0.517 g, 1.0034 mole) and dry tetrahydrofuran (6 ml). The Piperonal solution was cannulated to the reaction mixture during 30 minutes and after the addition, reaction mixture was slowly warmed to room temperature and further stirred for 2.5 hours. After the consumption of all bromine compound, as confirmed by TLC (50:50, EtOAc:Hexane), reaction mixture was quenched by the addition of saturated ammonium chloride solution and extracted with ethyl acetate (3×20 ml). All the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to yield 80% of crude product. The crude product was purified by column chromatography using column of 2 meter length, diameter 2.5 cm and filled with silica gel 60-120 (column chromatographic grade). Finally column eluted with EtOAC:Hexane (50:50), to get pure product (2-(1,3-Dioxolane-2-yl)-4,5-dimethoxy phenyl) (benzo(d)(1,3)dioxol-5-yl)-methanol with 30% yield. The total time required was about 7 hours.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11](F)([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)=[O:27])=[CH:24][C:23]=4[O:38][CH3:39])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(C([O-])=O)CN>>[CH:1]1([N:6]2[CH2:12][CH:11]([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)=[O:27])=[CH:24][C:23]=4[O:38][CH3:39])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: NCC(F)C(=O)[O-]
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)C(=O)N2C

Procedure:
The title compound was synthesized using an analogous procedure to that described in connection with Compound 3 except that 2-fluoro-beta-alaninate was used as the starting material. The final product was purified on reversed phase HPLC as TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55-1.87 (m, 11 H) 1.91-2.08 (m, 3 H) 2.18 (s, 3 H) 2.79 (d, J=11.4 Hz, 2 H) 3.24 (s, 3 H) 3.61-3.83 (m, 3 H) 3.94 (s, 3 H) 4.77 (quin., J=8.3 Hz, 1 H) 5.52 (qd, 1 H) 7.47 (dd, J=1.8 Hz, 1 H) 7.49 (s, 1 H) 7.86 (s, 1 H) 8.11 (d, J=7.8 Hz, 1 H) 8.16 (s, 1 H) 8.33 (d, J=8.34 Hz, 1 H). [M+H] calc'd for C27H36FN7O3 526; found 526.