Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[CH:15]=[C:16]([CH:19]=[O:20])[NH:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.[CH2:22]1COCC1.[H-].[Na+].IC>O>[CH3:22][N:17]1[CH:18]=[C:14]([C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:21])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=3[CH:7]=2)[CH:15]=[C:16]1[CH:19]=[O:20]
Reactant: C1CCOC1
Reactant: CC1(C)CCC(C)(C)c2cc(-c3c[nH]c(C=O)c3)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cn1cc(-c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1C=O

Procedure:
1.3 g (4.6 mmol) of 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-pyrrolecarboxaldehyde and 50 ml of THF are introduced into a three-necked flask under a stream of nitrogen. 300 mg (10 mmol) of sodium hydride (80% in oil) are added portionwise and the mixture is stirred until the evolution of gas has ceased. 640 μl (10 mmol) of iodomethane are then added and the mixture is stirred at room temperature for one hour. The reaction medium is poured into water and extracted with ethyl acetate, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of dichloromethane and heptane (70/30). After evaporation of the solvents, 600 mg (44%) of the expected product are collected.
Reaction SMILES: [Cl:1][Si:2]([Cl:12])([Cl:11])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]=[CH:7][CH2:6]1.[Cl:13][SiH:14]([Cl:16])[Cl:15]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.C(O)(C)C>[Cl:1][Si:2]([Cl:11])([Cl:12])[CH2:3][CH2:4][C:5]1([Si:14]([Cl:16])([Cl:15])[Cl:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: Cl[Si](Cl)(Cl)CCC1CC=CCC1
Reactant: Cl[SiH](Cl)Cl
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: Cl[Si](Cl)(Cl)CCC1([Si](Cl)(Cl)Cl)CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 121.8 g (0.50 mol) of 4-(2-trichlorosilylethyl)-1-cyclohexene and 0.1 g of a 20 wt % isopropanol solution of chloroplatinic acid, which were heated at 80° C. After the internal temperature became constant, 74.5 g (0.55 mol) of trichlorosilane was added dropwise over 10 hours. After the completion of addition, the reaction solution was stirred for 8 hours at 80° C. The reaction solution was distilled, collecting 157.3 g of (2-trichlorosilylethyl)trichlorosilylcyclohexane as a fraction having a boiling point of 122-126° C./0.1 mmHg (yield 83.0%).
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:8]([CH2:9][NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC([O-])(C)C.[K+].Br[CH2:26][CH:27]([OH:32])[C:28]([F:31])([F:30])[F:29]>C(#N)C>[C:1]([C:5]1[CH:18]=[CH:17][C:8]([CH2:9][N:10]([CH2:26][CH:27]([OH:32])[C:28]([F:31])([F:30])[F:29])[C:11](=[O:16])[C:12]([F:15])([F:13])[F:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OC(CBr)C(F)(F)F
Reactant: CC(C)(C)c1ccc(CNC(=O)C(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)c1ccc(CN(CC(O)C(F)(F)F)C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 29.9 %

Procedure:
260 mg of N-(4-tert-butyl-benzyl)-2,2,2-trifluoro-acetamide (1 mmol) were dissolved in 10 ml acetonitrile and treated with 169 mg of potassium tert-butylate (1.5 mmol). After 5 min stirring at rt, 0.125 ml of [rac]-3-bromo-1,1,1-trifluoro-propan-2-ol (1.2 mmol) were added and the reaction mixture stirred at 75° C. bath temperature for 22 h. After cooling down to rt, the reaction mixture was concentrated in vacuo, dissolved in EtOAc/water and the phases separated. The organic phase was then washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (90 g silica gel; EtOAc/heptane 1:4) to give 111 mg of N-(4-tert-butyl-benzyl)-2,2,2-trifluoro-N-(3,3,3-trifluoro-2-hydroxy-propyl)-acetamide as a white solid (30%). MS (ISP) 301.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[OH:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36]([OH:40])[CH2:37][NH:38][CH3:39])=[CH:32][CH:31]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:38]([CH2:37][CH:36]([OH:40])[C:33]4[CH:34]=[CH:35][C:30]([O:29][CH2:28][CH2:27][OH:26])=[CH:31][CH:32]=4)[CH3:39])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCC(O)c1ccc(OCCO)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CN(C)CC(O)c2ccc(OCCO)cc2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 60 °C
Reaction time: 4 h
Yield: 57.5 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 1-[4-(2-hydroxyethoxy)phenyl]-2-(methylamino)ethanol (Preparation 83) (70 mg, 0.38 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 4 hours at that temperature. After cooling to room temperature, the solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (5 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (82 mg) as a white solid.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:27])[CH2:15][CH2:16][CH2:17][C@@H:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:33](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].Cl>CN(C)C=O>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:27])[CH2:15][CH2:16][CH2:17][C@H:18]([O:19][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCC[C@H](O)c1ccc(F)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 88 %

Procedure:
(4S)-4-Benzyl-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-1,3-oxazolidin-2-one (37.54 mmol) was dissolved in N,N-dimethylformamide (40 mL) and then imidazole (2.97 g, 43.6 mmol) and tert-butyldimethylsilyl chloride (6.12 g, 40.6 mmol) were added. The reaction was stirred at room temperature for 19 h, poured into 0.1 N hydrochloric acid (500 mL) and extracted with 1:1 ethyl acetate-hexane (500 mL). The organic layer was washed with water (2×500 mL), brine (300 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by crystallization from methanol (55 mL) by heating to a light boil and cooling slowly to room temperature over 18 h. The crystals were filtered cold and washed with cold methanol (45 mL) to afford (4S)-4-benzyl-3-[(5S)-5-{[tert-butyl(dimethyl)silyl]oxy}-5-(4-fluorophenyl)pentanoyl]-1,3-oxazolidin-2-one (16.04 g, 88% yield) as a white crystalline solid; mp 87.6° C.; Rf 0.66 (1:2 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.36-7.18 (m, 7H), 6.99 (t, J=8.7 Hz, 2H), 4.69-4.61 (m, 2H), 4.18-4.13 (m, 2H), 3.27 (dd, J=13.5, 3.2 Hz, 1H), 2.96-2.89 (m, 2H), 2.73 (dd, J=13.5, 9.7 Hz, 1H), 1.82-1.63 (m, 4H), 0.88 (s, 9H), 0.04 (s, 3H), −0.15 (s, 3H) ppm; MS [M−OSi(CH3)2C(CH3)3]+354.0.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][CH2:8][C:9]([O:11]C)=O)=[C:4]([Cl:15])[CH:3]=1.[CH2:16]([N:18]=[C:19]=[O:20])[CH3:17]>C(Cl)Cl>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:8][C:9](=[O:11])[N:18]([CH2:16][CH3:17])[C:19]2=[O:20])=[C:4]([Cl:15])[CH:3]=1
Reactant: CCN=C=O
Reactant: COC(=O)CNCc1ccc(Br)cc1Cl
Solvent: ClCCl
Product: CCN1C(=O)CN(Cc2ccc(Br)cc2Cl)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
Methyl 2-(4-bromo-2-chlorobenzylamino)acetate (2C3) (1.44 mmol, 420 mg) was dissolved in DCM (35 ml) and ethyl isocyanate (2C4) (2.87 mmol, 0.227 ml, 204 mg) added. The mixture was stirred at room temperature overnight. The mixture was concentrated and azeotroped with DCM three times and then re-dissolved in DCM (10 ml) and TFA (3 ml) added. The solution was stirred for 1.5 h then quenched with saturated sodium carbonate solution and the phases separated. The aqueous layer was washed with DCM twice and the combined organics dried over sodium sulphate, filtered and concentrated to give 1-(4-bromo-2-chlorobenzyl)-3-ethylimidazolidine-2,4-dione (2C5) 430 mg (90%); 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H) 7.42 (d, 1H) 7.22 (d, 1H) 4.65 (s, 2H) 3.79 (s, 2H) 3.59 (q, 2H) 1.23 (t, 3H).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([CH:10]=[O:11])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][Mg]Br.O>O1CCCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([CH:10]([OH:11])[CH3:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C=O)no1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1cc(C(C)(C)C)on1
Reaction time: 1 h

Procedure:
1.29 g of 5-t-butyl-isoxazole-3-carbaldehyde was dissolved in 10 ml of tetrahydrofuran, and 10 ml of a 0.93 M solution of methylmagnesium bromide in tetrahydrofuran was then added. The mixture was stirred for 1 hour under ice-cooling. After water was added, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.18 g of 1-(5-t-butyl-isoxazol-3-yl)ethanol.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][C@@H:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[B-](F)(F)(F)[F:21].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.FC(F)(F)S(O)(=O)=O.O>ClCCCl>[F:19][C:2]([F:18])([F:1])[C:3]([N:5]1[CH2:11][C@@H:10]([CH3:12])[C:9]2[C:13]([F:21])=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: C[C@@H]1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)cc21
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCCl
Solvent: O
Product: C[C@@H]1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)c(F)c21
Temperature: 75 °C
Reaction time: 60 h
Yield: 22.8 %

Procedure:
A solution of (S)-N-trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2.5 g, 8.5 mmol) in 1,2-dichloroethane (15 mL) was treated with Selectfluor (3.9 g, 11 mmol), trifluoromethanesulfonic acid (8 mL, 90 mmol) and stirred 60 hours at 75° C. The product mixture was poured into water (200 mL), extracted with EtOAc (200 mL), the organic phase washed with saturated aqueous NaHCO3 (2×100 mL), brine (100 mL), dried with Na2SO4 and concentrated. The crude product was purified by flash chromatography (6% EtOAc in hexane, silica) resulting in 0.6 g of a white solid. MS calculated for C13H12ClF4NO+H: 310, observed: 310.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH2:14][CH2:15][CH3:16])[CH2:8][N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1[O:33][CH3:34].C(O)C>Cl.O>[CH:17]1([N:7]2[CH2:8][CH:9]([CH2:14][CH2:15][CH3:16])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCCC1CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCCC1CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Yield: 69.5 %

Procedure:
step d A mixture of 0.208 g (0.00065 mole) of (rac)-2-chloro-9-cyclopentyl-5-methyl-7-propyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-16), 0.13 g (0.00078 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated at 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.205 g of (rac)-4-(9-cyclopentyl-5-methyl-7-propyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-16) as an off-white solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:20]([O:22][CH3:23])=[O:21])[CH2:3]1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].Cl>ClCCl>[CH3:31][S:32]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:8])[C@H:4]([C:20]([O:22][CH3:23])=[O:21])[CH2:3]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
To a solution of crude (2S,4R)-4-hydroxy-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine (86.1 g) in dichloromethane (1 liter) under ice cooling are added triethylamine (52 ml) and then methanesulfonyl chloride (21.6 ml), and the mixture is stirred for 25 minutes. The reaction mixture is acidified with diluted hydrochloric acid and stirred. The organic layer is taken, washed with aqueous sodium hydrogen carbonate and water, dried over sodium sulfate, and concentrated in vacuo to give (2S, 4R)-4-methanesulfonyloxy-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine (2:90.0 g) as an organge oil. This product can be used in the next step without further purification.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:18]([CH2:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:17][C@@H:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C@@H:6]1[O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)C=C>CO.C1(C)C=CC=CC=1.Cl[Pd]Cl>[CH2:38]([O:37][C@@H:6]1[C@@H:5]([OH:4])[C@@H:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@@H:18]([CH2:28][O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:17][C@H:7]1[O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: C=CCO[C@H]1[C@@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](Oc2ccc(OC)cc2)[C@@H]1OCc1ccccc1
Agent: Cl[Pd]Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc(O[C@@H]2O[C@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@H](O)[C@H]2OCc2ccccc2)cc1
Yield: 94 %

Procedure:
Compound 9 (2.67 g, 4.49 mmol) was dissolved in a mixture of anhydrous methanol and toluene (21 mL, v/v 3:1) and reacted with PdCl2 (˜100 mg) under nitrogen and at room temperature. After 4 hours of reaction, the reaction mixture was filtrated over a pad of Celite and the solvents were evaporated. Purification of the residue by chromatography on silica gel (ethyl acetate-petroleum ether, v/v 1:4) afforded 10 as white crystals in 94% yield (2.35 g). mp=84-86° C.; [αD]24 =−11° (c 1, CHCl3); 1H NMR (500 MHz, CDCl3): δ3.66-3.73 (m, 3H, H-5, H-6a and H-6b), 3.74 (t, 1H, J2,3 9.5 Hz, J3,4 2.9 Hz, H-3), 3.76 (s, 3H, OMe), 3.83 (dd, 1H, J1,2 7.7 Hz, H-2), 3.90 (d, 1H, J4,5<1.5 Hz, H-4), 4.44, 4.49, 4.66, 4.78, 4.81 and 5.05 (6 d, 1H each, JA,B 11.8 Hz, CH2Ph), 4.84 (d, 1H, H-1), 6.78 and 7.02 (2 d, 2H each, C6H4), 7.22-7.40 (m, 15H, 3C6H5). Anal. Calcd for C34H36O7 (556.7): C 73.36, H 6.52; found: C 72.96, H 6.63.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][O:33][C:34]1[CH:67]=[CH:66][C:37]([C:38]([O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64]O)([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)=[CH:36][CH:35]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:46][O:45][C:42]1[CH:41]=[CH:40][C:39]([C:38]([O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:37]2[CH:36]=[CH:35][C:34]([O:33][CH3:32])=[CH:67][CH:66]=2)=[CH:44][CH:43]=1
Reactant: COc1ccc(C(OCCOCCOCCOCCO)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(OCCOCCOCCOCCON2C(=O)c3ccccc3C2=O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 8 h
Yield: 81.8 %

Procedure:
N-hydroxyphthalimide (0.7 g, 4.3 mmol) and triphenylphosphine (1.1 g, 4.2 mmol) were added to a solution of 11-(4,4′-dimethoxytrityloxy)-3,6,9-trioxaundecanol (2.0 g, 4.0 mmol) in THF (60 mL). Diethylazodicarboxylate (DEAD, 0.7 mL, 3.6 mmol) was added dropwise and the stirring was continued overnight at ambient temperature. The reaction mixture was evaporated to an oil, applied onto a silica gel column, and eluted with a linear gradient from neat CH2Cl2 to a 97:3 (v/v) mixture of CH2Cl2 and MeOH. The purification was repeated to yield 2.1 g (80%) of the title compound.
Reaction SMILES: [Sn](Cl)Cl.[Br:4][C:5]1[CH:6]=[CH:7][C:8]([N+:13]([O-])=O)=[C:9]([CH:12]=1)[CH:10]=O.O=[C:17]([CH3:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(OCC)C.C(O)C.[Cl-].[Zn+2].[Cl-]>[Br:4][C:5]1[CH:12]=[C:9]2[C:8](=[CH:7][CH:6]=1)[N:13]=[C:17]([CH3:24])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:10]2
Reactant: O=Cc1cc(Br)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(C)=O
Agent: Cl[Sn]Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1cc2cc(Br)ccc2nc1C
Temperature: 70 °C
Yield: 54.5 %

Procedure:
A 2.2 M solution of zinc(II)chloride (9.88 mL, 21.74 mmol) in diethyl ether was added to tin(II)chloride (4.12 g, 21.74 mmol) and activated 4 Å molecular sieve pellets (1.00 g) in ethanol (10 mL) under argon. Then, 5-bromo-2-nitro-benzaldehyde (1.00 g, 4.35 mmol) and ethyl 3-oxobutanoate (594.0 mg, 4.56 mmol) in ethanol (12 mL) were added to the reaction mixture via canula. The mixture was heated at 70° C. in an oil bath for three hours, then allowed to cool to room temperature, and carefully quenched with saturated sodium bicarbonate. Ethyl acetate was added and the mixture was filtered through Celite®. The filtrate was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 1:6 ethyl acetate:hexanes to give 697.9 mg (55%) of ethyl 6-bromo-2-methyl-3-quinolinecarboxylate as a solid. 1H NMR (400 MHz, d6-DMSO): δ 8.84 (s, 1H), 8.42 (d, J=2 Hz, 1H), 7.95 (dd, J=9, 2 Hz, 1H), 7.91 (d, J=9 Hz, 1H), 4.38 (q, J=7 Hz, 2H), 2.84 (s, 3H), 1.37 (t, J=7 Hz, 3H). ESI-LCMS m/z 294 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:13]2[S:12](=[O:15])(=[O:14])[N:11]=[C:10]([C:16]3[C:17](=[O:32])[N:18]([NH:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:19]4[C:24]([C:25]=3[OH:26])=[CH:23][CH:22]=[CH:21][CH:20]=4)[NH:9][C:8]=2[S:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>N1C=CC=CC=1.[OH-].[NH4+]>[NH2:1][CH2:4][C:5]1[C:13]2[S:12](=[O:14])(=[O:15])[N:11]=[C:10]([C:16]3[C:17](=[O:32])[N:18]([NH:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:19]4[C:24]([C:25]=3[OH:26])=[CH:23][CH:22]=[CH:21][CH:20]=4)[NH:9][C:8]=2[S:7][CH:6]=1
Reactant: [N-]=[N+]=NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Agent: [NH4+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To the solution of 3-[7-(azidomethyl)-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-1-[(cyclopropylmethyl)amino]-4-hydroxyquinolin-2(1H)-one (357 mg, 0.62 mmol) in pyridine (4.6 mL) and concentrated ammonium hydroxide (3 mL) was added triphenylphosphine (397 mg, 1.51 mmol) at room temperature. The solution was stirred at room temperature overnight and concentrated under reduced pressure. The residue was diluted with 30% hexane/toluene and the solid was filtered to give 3-[7-(aminomethyl)-1,1-dioxido-4H -thieno[2,3-e][1,2,4]thiadiazin-3-yl]-1-[(cyclopropylmethyl)amino]-4-hydroxyquinolin-2(1H)-one (250 mg, 90%). MS (ESI−) m/z 446 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ 0.21 (m, 2H) 0.46 (br d, J=8.09 Hz, 2H) 1.00 (m, 1H) 4.12 (s, 2H) 5.98 (t, J=6.43 Hz, 1H) 7.12 (m, 1H) 7.22 (s, 1H) 7.58 (m, 1H) 772 (d, J=7.72 Hz, 1H) 8.04 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:8]=[N+:9]([O-])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Cl:18][C:10]1[N:9]=[CH:8][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:12][CH:11]=1
Reactant: [O-][n+]1cccc(Oc2ccc(Cl)cc2)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Clc1ccc(Oc2ccc(Cl)nc2)cc1

Procedure:
A solution of 22 g of 3-(p-chlorophenoxy)pyridine N-oxide in 500 ml of chloroform is added dropwise to 77 g of refluxing phosphorous oxychloride. The mixture is refluxed 30 minutes, cooled and concentrated at reduced pressure. The resulting oil is dissolved in 400 ml of dichloromethane, washed with 40 ml ice cold concentrated ammonium hydroxide and the dichloromethane solution is dried over anhydrous MgSO4. The mixture is filtered, concentrated under reduced pressure and distilled to yield the mixture of desired chlorinated pyridines; bp 103°-105° C./0.1 mm. The oil is dissolved in 100 ml of toluene and chromatographed over 400 g of silica gel in toluene to yield in the first eluate, 6-chloro-3-(p-chlorophenoxy)pyridine. Continued elution with toluene yields 2-chloro 3-(p-chlorophenoxy)pyridine. Finally, elution with toluene-methanol (50:50) yields 4-chloro-3-(p-chlorophenoxy)pyridine.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:19])[C:9]=1[C:10]([O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[O:11])=[CH:2][CH3:3].[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24](S(C)(=O)=O)[N:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([O:19][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:1]=[CH:2][CH3:3])[C:9]=2[C:10]([O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:18])[CH3:17])=[O:11])[N:23]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: CC=Cc1cccc(O)c1C(=O)OCC[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC=Cc1cccc(Oc2nc(OC)cc(OC)n2)c1C(=O)OCC[Si](C)(C)C
Yield: 43.6 %

Procedure:
In a 50 ml round bottom-flask, there were charged 2-trimethylsilylethyl 6-(1-propenyl)salicylate (3.1 g, 11.0 mmol), 4,6-dimethoxy-2-methylsulfonylpyrimidine (2.4 g, 11.0 mmol), potassium carbonate (1.8 g, 13.0 mmol) and 10 ml of N,N-dimethylformamide (hereinafter referred to as "DMF"), and the resultant mixture was reacted for 1 hour at 80° C. After cooling the reaction mixture, DMF was distilled off under reduced pressure, and the residue thus obtained was dissolved in ethyl acetate, washed with water and a saturated salt water, dried with anhydrous sodium sulfate and concentrated. The resultant residue was purified by silica gel column chromatography to obtain 2.0 g (yield: 47.6%) of the aimed product (colorless transparent viscous liquid).