Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:17])[C:7](O)(O)[CH2:6][CH2:5][N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:3]1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1>[C:13]([O:12][C:10]([N:4]1[CH2:5][CH2:6][CH:7]([NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:2]([F:17])([F:1])[CH2:3]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(O)C(F)(F)C1
Reactant: NCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)C(F)(F)C1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 3,3-difluoro-4,4-dihydroxypiperidine-1-carboxylate (1 g, 3.36 mmol), and benzylamine (539 mg, 550 μL, 5.03 mmol) in dry toluene (70 mL) was heated to reflux with dean stark apparatus for 12 hours. Further benzyl amine (20 μL, 185 μmol) was added and heated to reflux with dean stark apparatus for another 12 hours. About 50 mL of toluene were distilled off, the residue was cooled to 55° C., ethanol (35 mL) and NaBH4 (508 mg, 13.4 mmol) were added and the reaction mixture stirred at 55° C. for 2 hours. Further NaBH4 (508 mg, 13.4 mmol) was added and stirred for another hour. Further NaBH4 (508 mg, 13.4 mmol) was added. After 2 hours the reaction mixture was concentrated, then 2 N Na2CO3 solution was added and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and the solvents were evaporated. The residue was purified by flash chromatography (70 g, 0% to 100% EtOAc in hexanes). The title compound was obtained as colorless oil (875 mg, 80%).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[S:15][C:14]=3[S:22]([NH:25]C(C)(C)C)(=[O:24])=[O:23])=[CH:9][CH:8]=2)[CH:5]=[N:4][CH:3]=[N:2]1.B(Cl)(Cl)Cl>ClCCl>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[S:15][C:14]=3[S:22]([NH2:25])(=[O:23])=[O:24])=[CH:9][CH:8]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)Cc1cc(-c2ccc(Cn3cncn3)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CC(C)Cc1cc(-c2ccc(Cn3cncn3)cc2)c(S(N)(=O)=O)s1
Reaction time: 1 h

Procedure:
3-(4-[1,2,4]Triazol-1-ylmethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (146.4 mg, 0.34 mmol, see step (b) above) was mixed with BCl3 (1M solution in hexane) (2 mL, 1.7 mmol) in 5 mL of dichloromethane at rt and stirred for 1 h. The reaction mixture was extracted with ethyl acetate and water and subsequently dried over K2CO3. The solvent was evaporated and the resultant product was sufficiently pure to be used directly in the next step.
Reaction SMILES: [CH2:1]([CH:17]([OH:38])[CH:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:19]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O1CCCC1.[CH3:44][S-:45].[Na+].C(OCC)(=O)C>CCCCCC.C(Cl)(Cl)Cl>[CH2:1]([CH:17]([OH:38])[CH:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:19][S:45][CH3:44])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOC(CBr)C(O)CCCCCCCCCCCCCCCC
Reactant: C[S-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCOC(CSC)C(O)CCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Racemic 1,2-O-dihexadecyl-3-bromo-1,2-propanediol (from Step 1), 2.0 g (3.3 mmoles), was dissolved into 100 ml of dry tetrahydrofuran in a 250 ml round bottom flask equipped with a magnetic stir bar. To this solution was added 2.33 g (33.2 mmoles) of sodium thiomethoxide powder and the reaction mixture was stirred overnight at room temperature. The reaction was monitored by TLC (silica gel, 5% ethyl acetate in hexane) and an additional 490 mg (7 mmoles) of sodium thiomethoxide was added to the reaction. After an additional 3 hr, the mixture was filtered and the filtrate was washed with 50 ml tetrahydrofuran. The combined filtrates were concentrated under vacuum using a rotary evaporator to afford a yellow residue. This residue was dissolved into 50 ml chloroform and the organic solution was washed twice with 25 ml of a concentrated solution of sodium bicarbonate. The organic phase was then dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator under vacuum to afford the crude product as a pale yellow oily residue. The crude product was purified by column chromatography on a silica gel 60 (E. Merck, Germany) column using a step gradient of 0 to 10% ethyl acetate in hexane. The fractions collected were screened by TLC. Those fractions containing pure product were pooled and concentrated to afford 1,2-O-dihexadecyl-3-methylthio-1,2-propanediol in 90% yield.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:19]1[CH:27]=[CH:26][C:25]([C:28]([NH2:30])=[O:29])=[C:24]2[C:20]=1[C:21]1[CH2:34][NH:33][CH2:32][CH2:31][C:22]=1[NH:23]2>C(OCCCC)(=O)C.CO.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[C:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:19]1[CH:27]=[CH:26][C:25]([C:28]([NH2:30])=[O:29])=[C:24]2[C:20]=1[C:21]1[CH:34]=[N:33][CH:32]=[CH:31][C:22]=1[NH:23]2
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4c(c23)CNCC4)cccc1-n1cnc2ccccc2c1=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCCCOC(C)=O
Solvent: CO
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4ccncc4c23)cccc1-n1cnc2ccccc2c1=O
Temperature: 110 °C
Reaction time: 60 h
Yield: 35.7 %

Procedure:
A mixture of 9-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxamide (10 mg, 0.022 mmol) and activated manganese dioxide (19.34 mg, 0.222 mmol) in butyl acetate (0.5 mL) was heated on an oil bath at 110° C. for 5.25 h, then at 90-100° C. for 2.5 days, then at 125° C. for 20 h. The mixture was cooled to room temperature, diluted with methanol, filtered and concentrated under vacuum. The residue was purified by preparative HPLC. The effluent containing the desired product was concentrated under vacuum to provide a fine aqueous suspension. This was extracted three times with EtOAc, and the combined organic phases were dried and concentrated to provide the desired product as an off-white solid (3.5 mg, 33% yield). LCMS (M+H)+ m/z 446.2. 1H NMR (400 MHz, methanol-d4) δ 8.31-8.47 (3.6 H, m), 8.06-8.16 (1.4 H, m), 7.87-7.96 (1 H, m), 7.76-7.87 (1 H, m), 7.55-7.70 (5 H, m), 7.24-7.36 (1 H, m), 1.90 (3 H, 2s).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[CH:11]=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=2[C:6]2[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:5]1=2)[CH:2]=[CH2:3].Br[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:13][C:9]1[CH:10]=[CH:11][C:12]2[N:4]([CH2:1]/[CH:2]=[CH:3]/[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[C:5]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][C:6]=3[C:7]=2[CH:8]=1
Reactant: C=CCn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Reactant: Brc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCc2c(c3cc(Cl)ccc3n2C/C=C/c2ccncc2)C1
Temperature: 25 °C

Procedure:
5-Allyl-8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (400 mg, 1.52 mmol, 1 equiv.) and 4-bromopyridine (240 mg, 1.52 mmol, 1 equiv.) were heated to 100° C. with palladium acetate (10 mg, 0.046 mmol), triphenyl phosphine (24 mg, 0.092 mmol) and triethyl amine (0.44 mL, 2 equiv.) in 10 mL of THF for 14 h. The reaction mixture was cooled to RT and diluted with THF (10 mL), filtered over a Celite bed and concentrated. The concentrate was dissolved in EtOAc (40 mL) and washed with water (10 mL) followed by brine. The organic layer was dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain crude product that was purified by HPLC. 1H NMR (DMSO-d6) δ (ppm): 0.64 (bs, 1H), 8.68-8.66 (d, 2H), 7.79-7.77 (d, 2H), 7.6-7.56 (m, 2H),7.2-7.1(d, 1H), 7.0-6.9 (m, 1H), 6.5-6.4 (d, 1H), 5.15-5.03 (m, 2H), 4.64-4.60 (d, 1H), 4.3-4.25 (m, 1H), 3.79-3.76 (m, 1H), 3.52-3.50 (m, 1H), 3.17 (bs, 2H), 2.98 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1[O:44][C:45]([F:48])([F:47])[F:46])[CH2:5][NH:6][C:7]([C@H:9]1[CH2:14][N:13]([C:15]2[S:16][C:17]3[C:22](Cl)=[N:21][C:20]([CH:24]4[CH2:26][CH2:25]4)=[N:19][C:18]=3[N:27]=2)[CH2:12][CH2:11][N:10]1[S:28]([C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=1)(=[O:30])=[O:29])=[O:8].C([O-])=O.[NH4+]>C(O)C.C(OCC)(=O)C.[C].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1[O:44][C:45]([F:48])([F:46])[F:47])[CH2:5][NH:6][C:7]([C@H:9]1[CH2:14][N:13]([C:15]2[S:16][C:17]3[CH:22]=[N:21][C:20]([CH:24]4[CH2:26][CH2:25]4)=[N:19][C:18]=3[N:27]=2)[CH2:12][CH2:11][N:10]1[S:28]([C:31]1[CH:32]=[CH:33][C:34]([C:37]([F:38])([F:40])[F:39])=[CH:35][CH:36]=1)(=[O:30])=[O:29])=[O:8]
Reactant: O=C(NCc1ccc(OC(F)(F)F)c(F)c1)[C@H]1CN(c2nc3nc(C4CC4)nc(Cl)c3s2)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(OC(F)(F)F)c(F)c1)[C@H]1CN(c2nc3nc(C4CC4)ncc3s2)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
To a mixture of the compound (49 mg) obtained in Step 6 and ammonium formate (42 mg) in ethanol (1.0 ml) was added 10% palladium carbon (25 mg) at 80° C. After stirring at 80° C. for 30 min, 10% palladium carbon (25 mg) was added. After stirring at 80° C. for 30 min, ammonium formate (42 mg) and 10% palladium carbon (25 mg) were added. After stirring at 80° C. for 30 min, 10% palladium carbon (25 mg) was added. After stirring at 80° C. for 30 min, the reaction mixture was allowed to return to room temperature, and the reaction mixture was diluted with ethyl acetate. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (methanol:chloroform=1:10) to give the title compound (29 mg).
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[CH2:22]([O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][N:15]1[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12][CH:11]([CH2:10][CH2:9][OH:1])[C:16]1=[O:17])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: OCc1cccc(OCc2ccccc2)c1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Product: O=C1C(CCO)Oc2ccccc2N1Cc1cccc(OCc2ccccc2)c1

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Methods F and G, alkylating with the methanesulfonate ester of 3-benzyloxybenzyl alcohol, in 67% overall yield as a viscous liquid, after flash chromatography eluting with 30-100% EtOAc in hexane, IR (CHCl3) 3434, 2933, 1681, 1500, 1401, 1256, 1054, 751 cm-1 ; 1H NMR (CDCl3) δ1.77 (br s, 1H plus HDO), 2.20-2.34 (m, 2H), 3.91 (t, J=5.5 Hz, 2H), 4.82 (dd, J=7.5, 5.7 Hz, 1H), 5.02 (s, 2H), 5.11 (ABq, JAB =16.0 Hz, 2H), 6.85-7.01 (m, 7H), 7.22-7.41 (m, 6H); MH+ at m/z=390; Anal. Calc'd for C24H23NO4 : C, 74.02; H, 5.95; N, 3.60. Found: C, 73.61; H, 6.03; N, 3.55.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])[CH2:6][CH3:7])[CH3:2].Cl[CH2:19][C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH3:35].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[S:24][C:23]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=3)=[N:22][C:21]=2[CH3:35])=[CH:11][C:10]=1[CH3:16])[CH2:6][CH3:7])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Reactant: CCOC(=O)C(CC)Cc1ccc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCOC(=O)C(CC)Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C

Procedure:
In analogy to the procedure described in example 14 b], [rac]-2-(4-hydroxy-2-methyl-benzyl)-butyric acid ethyl ester was reacted with 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole [PCT Int. Appl. (2002), WO 0292590 A1] in the presence of cesium carbonate and potassium iodide to yield [rac]-2-{2-methyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzyl}-butyric acid ethyl ester as colorless oil.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[N:12]=1)[CH2:2][CH3:3].Br[CH2:14][C:15]1[CH:34]=[CH:33][C:18]2/[C:19](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:20]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=3[O:22][CH2:23][C:17]=2[CH:16]=1>>[F:28][C:25]1[CH:26]=[CH:27][C:20]2=[C:21]([CH:24]=1)[O:22][CH2:23][C:17]1[CH:16]=[C:15]([CH2:14][N:5]3[C:6]4[CH:11]=[CH:10][N:9]=[CH:8][C:7]=4[N:12]=[C:4]3[CH2:1][CH2:2][CH3:3])[CH:34]=[CH:33][C:18]=1/[C:19]/2=[C:29](/[CH3:32])\[C:30]#[N:31]
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: CCCc1nc2cnccc2[nH]1
Product: CCCc1nc2cnccc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 13.6 %

Procedure:
Using 2-propyl-1H-imidazo[4,5-c]pyridine (135 mg, 0.838 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (300 mg, 0.838 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (50 mg, 14%) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([NH:16][NH:17][C:18]([C@H:20]2[CH2:26][CH2:25][C@@H:24]3[CH2:27][N:21]2[C:22](=[O:36])[N:23]3[O:28]CC2C=CC=CC=2)=[O:19])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([NH:16][NH:17][C:18]([C@H:20]2[CH2:26][CH2:25][C@@H:24]3[CH2:27][N:21]2[C:22](=[O:36])[N:23]3[OH:28])=[O:19])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)NNC(=O)[C@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)NNC(=O)[C@H]2CC[C@@H]3CN2C(=O)N3O)C1

Procedure:
By using the procedure described in Step-2 of Example-1 above, and by using trans-3-[N′-(6-benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)-hydrazinocarbonyl]-(R)-piperidin-1-carboxylic acid tert-butyl ester (16.5 gm, 0.033 mol), methanol (170 ml) and 10% palladium on carbon (3.5 gm) to provide the title compound in 13.5 gm quantity as a pale pink solid and it was used for the next reaction immediately.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:3]=1[O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH3:22])=[O:7].N1C=CC=CC=1.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)=[O:36]>ClCCl>[N+:44]([C:41]1[CH:40]=[CH:39][C:38]([O:37][C:35](=[O:36])[NH:1][C:2]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:3]=2[O:4][CH2:5][C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:10][C@H:9]2[CH3:22])=[O:7])=[CH:43][CH:42]=1)([O-:46])=[O:45]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1NC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of 2-(2-amino-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-ethanone (0.14 g, 0.36 mmol) in dichloromethane (5 mL) was added pyridine (0.032 mL, 0.39 mmol) and 4-nitrophenyl chloroformate (0.079 g, 0.39 mmol). The reaction was stirred at ambient temperature for one hour and concentrated in vacuo to give the title compound (0.20 g).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH:7]([C:13]([CH3:15])=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:13]([CH3:15])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)C(Oc1ccc(Cl)cc1)C(C)=O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1oc2ccc(Cl)cc2c1C
Temperature: 0 °C
Yield: 64.7 %

Procedure:
Ethyl 2 (4-chlorophenoxy)acetoacetate (90.3 g, 0.353 mol) was added dropwise to sulfuric acid (240 ml) stirred at 0° C. The resulting suspension was stirred at 0° C. for 3.5 hours, poured onto crushed ice and the mixture stirred for 0.5 hours. The mixture was extracted with toluene and the organic phase was washed with 5% sodium bicarbonate and water. The organic phase was dried with magnesium sulfate, filtered and concentrated. The crude product was recrystallized from cyclohexane to give 54.5 g (65%) of ethyl 5-chloro-3-methyl-2-benzofuran carboxylate: mp 80°-82° C.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]3[CH:12]=[C:11]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])[CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:4]=[C:3]1[CH3:22].[OH-].[K+].CO>O>[CH3:1][N:2]1[C:14]2[C:13]3[CH:12]=[C:11]([O:15][CH2:16][C:17]([OH:19])=[O:18])[CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:4]=[C:3]1[CH3:22]
Reactant: CCOC(=O)COc1ccc2ncc3nc(C)n(C)c3c2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc2cnc3ccc(OCC(=O)O)cc3c2n1C
Yield: 86.1 %

Procedure:
Ethyl 2-[(1,2-dimethyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]acetate (1.6 g, 5.35 mmol) was added to a solution of potassium hydroxide (0.90 g, 0.16 mol) in a 50:50 mixture of methanol:water (30 mL). The solution was stirred under a nitrogen atmosphere until it was complete as evidenced by HPLC analysis. The methanol was removed under reduced pressure, and 6 N aqueous hydrochloric acid was added until the solution exhibited a neutral pH. A precipitate formed and was isolated by filtration to provide 1.25 g of 2-[(1,2-dimethyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]acetic acid as a white solid, mp 290° C. (decomposition).
Reaction SMILES: N12CCCN=C1CCCCC2.[CH2:12]([O:15][C:16](=[O:26])[CH2:17][C:18]1[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:19]=1[F:25])[CH:13]=[CH2:14].C(NC1C=CC(S([N:40]=[N+:41]=[N-])(=O)=O)=CC=1)(=O)C>C1COCC1>[CH2:12]([O:15][C:16](=[O:26])[C:17]([C:18]1[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:19]=1[F:25])=[N+:40]=[N-:41])[CH:13]=[CH2:14]
Reactant: C=CCOC(=O)Cc1cc(Br)ccc1F
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: C=CCOC(=O)C(=[N+]=[N-])c1cc(Br)ccc1F
Temperature: 23 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
To a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (4.2 ml, 28 mmol) in THF (24 ml) at 23° C. was added a solution of (5-bromo-2-fluoro-phenyl)-acetic acid allyl ester (intermediate B3A) (7.29 g, 27 mmol) and commercially available p-acetamidobenzenesulfonyl azide ([CAS No. 2158-14-7], 6.94 g, 28 mmol) in THF (48 ml) over 1 h. The mixture was stirred for 5 h at 23° C. Then it was quenched with sat. aqueous ammonium chloride solution, diluted with ethyl acetate, and the organic layer was washed with brine and dried over sodium sulfate. Removal of the solvent in vacuum left a yellow oil, which was purified by silica gel column chromatography with hexane/ethyl acetate to give the title compound as a yellow solid (7.344 g, 92%). MS (ISP): m/z=316.1 [(M+NH4)+] and 318.0 [(M+2+NH4)+].
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[C:6](F)[N:5]=[C:4]([F:10])[C:3]=1[Cl:11].[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>C(#N)C>[Br:1][C:2]1[C:3]([Cl:11])=[C:4]([F:10])[N:5]=[C:6]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])[C:7]=1[F:8]
Reactant: Fc1nc(F)c(Cl)c(Br)c1F
Reactant: CC(C)(C)N
Solvent: CC#N
Product: CC(C)(C)Nc1nc(F)c(Cl)c(Br)c1F
Yield: 103.2 %

Procedure:
To 40 ml of acetonitrile was dissolved 10.2 g of 4-bromo-3-chloro-2,5,6-trifluoropyridine and 10.5 g of t-butylamine, and the mixture was heated under reflux for 1 hour and the solvent and the like were distilled off under reduced pressure. To the residue was added 80 ml of chloroform and the mixture was washed with 50 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 12.8 g of the title compound as reddish orange oil.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]\[CH2:5]Cl.[O:7]=[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[N:9]1[CH2:18][C:19]1[CH:26]=[C:25]([OH:27])[C:24]([OH:28])=[CH:23][C:20]=1[C:21]#[N:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:17]=[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](=[O:7])[N:9]1[CH2:18][C:19]1[C:20]([C:21]#[N:22])=[CH:23][C:24]2[O:28][CH2:5][CH:4]=[CH:3][CH2:2][O:27][C:25]=2[CH:26]=1
Reactant: N#Cc1cc(O)c(O)cc1CN1C(=O)c2ccccc2C1=O
Reactant: ClC/C=C\CCl
Agent: N#Cc1cc2c(cc1CN1C(=O)c3ccccc3C1=O)OC/C=C\CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc2c(cc1CN1C(=O)c3ccccc3C1=O)OCC=CCO2
Temperature: 50 °C
Reaction time: 8 h

Procedure:
cis-1,4-Dichloro-2-butene (0.200 g, 1.6 mmol), 2((1,3-dioxoisoindolin-2-yl)methyl)-4,5-dihydroxybenzonitrile (0.500 g, 1.7 mmol), and potassium carbonate (0.77 g, 5.6 mmol) were suspended in dry DMF (80 ml) and heated to 50° C. for 5 h. The resulting mixture was cooled to room temperature and stirred overnight, then filtered. The filtrate was diluted with ethyl acetate, washed with water (2×), brine (2×), dried (Na2SO4) and concentrated in vacuo. The resulting residue was chromatographed eluting with ethyl acetate/heptanes (50:50) to yield (Z)-9-((1,3-dioxoisoindolin-2-yl)methyl)-2,5-dihydrobenzo[b][1,4]dioxocine-8-carbonitrile as a residue. 1H NMR (CDCl3): δ 7.94-7.86 (m, 2H), 7.78-7.73 (m, 2H), 7.32 (s, 1H), 6.83 (s, 1H), 5.92-5.85 (m, 2H), 4.98 (s, 4H), 4.80 (s, 2H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([NH:19][C@@H:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH3:21])[C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:29][OH:30]>C(O)C>[NH2:18]/[C:17](=[N:29]\[OH:30])/[C:14]1[CH:13]=[CH:12][C:11]([CH:10]([NH:19][C@@H:20]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH3:21])[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])=[CH:16][CH:15]=1
Reactant: C[C@@H](NC(CO[Si](C)(C)C(C)(C)C)c1ccc(C#N)cc1)C(=O)OC(C)(C)C
Reactant: NO
Solvent: CCO
Product: C[C@@H](NC(CO[Si](C)(C)C(C)(C)C)c1ccc(/C(N)=N/O)cc1)C(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 93.3 %

Procedure:
To a solution of tert-butyl N-[2-{[tert-butyl(dimethyl)silyl]oxy}-1-(4-cyanophenyl)ethyl]-D-alaninate (2 g, 0.0049 mol) in Ethanol (40 ml) was added 50% aqueous Hydroxylamine (1.63 ml, 0.0247 mol) at RT. The reaction mixture was heated at 70° C. for 6 h, cooled to RT and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, brine, dried over Na2SO4 and evaporated to afford (2 g, 90%) of the title compound as brown oil. 1H NMR: (DMSO-d6, 400 MHz) δ 9.57 (s, 1H), 7.61-7.59 (d, J=8.3 Hz, 2H), 7.30-7.28 (d, J=8.3 Hz, 2H), 5.76-5.74 (d, J=5.00 Hz, 2H), 4.77-4.74 (m, 1H), 3.21-3.19 (m, 1H), 2.69-2.59 (m, 1H), 1.95-1.72 (m, 1H), 1.39 (s, 9H), 1.10-1.06 (m, 3H), 0.86-0.82 (m, 9H), 0.03 (s, 3H), −0.12 (s, 3H). LC/MS (Method A): 438.3 (M+H)+. HPLC (Method A) Rt 3.82 min. (Purity: 71.1%).