Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]C.[CH3:3][C:4]([O:8][SiH3])=C(C)C.[CH2:10]([Si:13]1(Cl)[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]1)[CH:11]=[CH2:12]>CCCCC>[CH2:10]([Si:13]1([O:8][CH:4]=[CH2:3])[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]1)[CH:11]=[CH2:12]
Reactant: CC(C)=C(C)O[SiH3]
Reactant: C=CC[Si]1(Cl)OC(C)(C)C(C)(C)O1
Agent: [Li]C
Solvent: CCCCC
Product: C=CC[Si]1(OC=C)OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
To a cooled (0° C.) solution of MeLi (16.2 mL; 23 mmol; 1.4 M in Et20) was added trimethylvinyloxysilane (2.7 g; 23 mmol). The solution was warmed to room temperature and was stirred for 1 hour. The solution was cooled to −78° C., and 2-allyl-2-chloro-4,4,5,5-tetramethyl-[1,3,2]dioxasilolane (5.5 g; 25 mmol) was added. The solution was warmed to room temperature and stirred for 2 hours. The solution was diluted with pentane (20 mL), and the mixture was then filtered through a pad of celite. The filtrate was concentrated, and the residue was distilled under reduced pressure to give 3.8 g (70%) of 2-allyl-4,4,5,5-tetramethyl-2-vinyloxy-[1,3,2]dioxasilolane as a clear, colorless liquid.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].[CH3:12][NH2:13]>>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([S:3](=[N:13][CH3:12])([NH:2][CH3:1])=[O:4])=[CH:6][CH:7]=1
Reactant: CNS(=O)c1ccc(Br)cc1
Reactant: CN
Product: CN=S(=O)(NC)c1ccc(Br)cc1

Procedure:
The title compound is prepared from 4-bromo-benzenesulfinic acid methylamide and methylamine following a procedure analogous to that described for Intermediate 17 (Step 2). LC (method 1): tR=0.70 min; Mass spectrum (ESI+): m/z=263, 265 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[CH:12]([Sn](CCCC)(CCCC)CCCC)=[CH2:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd]>[CH3:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[CH:12]=[CH2:13]
Reactant: Cc1cc([N+](=O)[O-])ccc1Br
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc([N+](=O)[O-])cc1C
Yield: 98 %

Procedure:
2Bromo-5-nitrotoluene (1.0 g, 4.54 mmol) and vinyltributyl tin (1.59 g, 4.99 mmol) were dissolved in toluene (25 mL) under argon. Palladium dibenzylidene acetone (4.15 g, 0.455 mmol) and triphenylphosphine (488 mg, 1.86 mmol) was added and the reaction refluxed overnight. The solvent was evaporated and the residue dissolved in 200 mL of methylene chloride and washed with 10% ammonium hydroxide, water, and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography heptane-methylene chlolride 1:1) to yield 726 mg of 2-methyl-4-nitrostyrene. 2-methyl-4-nitrostyrene (700 mg, 4.5 mmol) was dissolved in methylene chloride (20 mL) and cooled to −78° C., and treated with ozone until a blue color remained, after 5 minutes the excess ozone was removed by passing a stream of oxygen through the solution. Dimethyl sulfide (1 mL) was added and the reaction mixture stirred at room temperature overnight. The solvent was evaporated and the residue purified by flash column chromatography to yield 580 mg of the 2-methyl-4-nitrobenzaldehyde. 2-Methyl-4-nitrobenzaldehyde (570 mg, 3.45 mmol) and potassium carbonate (476 mg, 3.45 mmol) were suspended in methanol. Tosylmethylisocyanide (674 mg, 3.45 mmol) was added and the reaction mixture refluxed for 3 h, cooled to room temperature and concentrated. The residue was dissolved in methylene chloride (200 mL) and the organic layer was washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to yield 710 mg (94%) of 5-(4-nitro-2-methylphenyl)oxazole. 5-(4-Nitro-2-methylphenyl)oxazole was dissolved in methanol (100 mL) and 10% palladium on carbon 200 mg was wetted with water and added. The reaction mixture was hydrogenated at 45 psi overnight. The catalyst was removed by filtration and 560 mg of 5-(4-amino-2-methylphenyl)oxazole was isolated in 92% purity by HPLC method A. Mass spectrum M+H+=175.1, 1H 400 MHz NMR (CDCl3): δ7.88 (s, 1H), 7.45 (m, 1H), 7.08 (s, 1H), 6.60 m(m, 2H), 2.38 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[N:16]3)[O:11][C:10]2=[O:21])[CH:5]=[CH:6][C:7]=1I.C[Sn](C)(C)[C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH2:34][CH:33]([CH2:35][OH:36])[O:32][N:31]=2)=[N:28][CH:29]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[N:16]3)[O:11][C:10]2=[O:21])[CH:5]=[CH:6][C:7]=1[C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH2:34][CH:33]([CH2:35][OH:36])[O:32][N:31]=2)=[N:28][CH:29]=1
Reactant: C[Sn](C)(C)c1ccc(C2=NOC(CO)C2)nc1
Reactant: Cc1cn(C[C@H]2CN(c3ccc(I)c(F)c3)C(=O)O2)nn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: ClC(Cl)Cl
Product: Cc1cn(C[C@H]2CN(c3ccc(-c4ccc(C5=NOC(CO)C5)nc4)c(F)c3)C(=O)O2)nn1
Temperature: 90 °C
Yield: 26.4 %

Procedure:
(5R)-3-(3-Fluoro-4-iodophenyl)-5-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]-1,3-oxazolidin-2-one (236 mg, 0.58 mM), {3-[5-(trimethylstannyl)pyridin-2-yl)-4,5-dihydroisoxazol-5-yl}methanol (200 mg, 0.58 mM), tris(dibenzylideneacetone) dipalladium (0)-chloroform adduct (60 mg, 0.058 mM) and tri-2-furylphosphine (27 mg, 0.116 mM) were placed in a flask. The solids were degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the suspension was heated at 90° C. for 5 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was chromatographed on silica gel eluting with 5% methanol in dichloromethane to give the title compound (70 mg).
Reaction SMILES: C(O[C:4]([C:6]1([OH:14])[CH2:11][CH:10]([CH3:12])[CH2:9][CH:8]([CH3:13])[CH2:7]1)=[O:5])C.Cl.[NH2:16][C:17](N)=[NH:18].[OH-].[K+].C(O)(=O)C>C(O)C.O>[NH2:18][C:17]1[O:14][C:6]2([CH2:7][CH:8]([CH3:13])[CH2:9][CH:10]([CH3:12])[CH2:11]2)[C:4](=[O:5])[N:16]=1
Reactant: CCOC(=O)C1(O)CC(C)CC(C)C1
Reactant: N=C(N)N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC1CC(C)CC2(C1)OC(N)=NC2=O
Reaction time: 3 h
Yield: 35.6 %

Procedure:
A mixture of 9.43 grams of 1-hydroxy-3,5-dimethylcyclohexane carboxylic acid ethyl ester with 4.38 grams of guanidine hydrochloride and 2.59 grams of potassium hydroxide pellets in 52 ml of ethanol is refluxed for 1 hour. The solution is cooled, diluted with 172 ml of water and brought to pH 7 with glacial acetic acid resulting in a white precipitate being formed. After refrigeration at 5° C for 3 hours, the crystals are filtered, washed with water and ether, and dried yielding 3.20 grams of 2-amino-7,9-dimethyl-1-oxa-3-aza-spiro[4,5]dec-2-en-4-one, having a melting point of 276°-81° C.
Reaction SMILES: [CH2:1]([C:10]1[CH:25]=[CH:24][C:13]([C:14]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]C)=[O:21])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[OH-].[Na+]>C(O)C>[CH2:1]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:15])=[CH:24][CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCc1ccc(C(=O)CCCCC(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCc1ccc(C(=O)CCCCC(=O)O)cc1
Yield: 71.5 %

Procedure:
Adipic acid monomethyl ester (50 g; 0.31 mole) is converted to the acid chloride with thionyl chloride (50 g) in the manner described in Example 1. This product is reacted with nonylbenzene (400 ml) and aluminum chloride (80 g; 0.6 mole) and the product purified in a manner analogous to that described in Example 1 to provide methyl 5-(4-n-nonylbenzoyl)pentanoate (35.2 g). This ester (35 g) is hydrolysed with sodium hydroxide in aqueous ethanol as in Example 1 to give, on recrystallization from aqueous ethanol, 5-(4-n-nonylbenzoyl)pentanoic acid (24 g) as colorless crystals, m.p. 29°-31° C.
Reaction SMILES: [CH:1]([C:4]1[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[C:5]=1[N:20]1[CH2:24][CH2:23][N:22]=[C:21]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:3])[CH3:2].[O-][Mn](=O)(=O)=O.[K+].O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>C(#N)C>[CH:1]([C:4]1[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[C:5]=1[N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1cc(C(C)C)c2oc3ccccc3c2c1N1CCN=C1c1ccccc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=[Si]=O
Agent: [Al+3]
Solvent: CC#N
Solvent: O
Product: CC(C)c1cc(C(C)C)c2oc3ccccc3c2c1-n1ccnc1-c1ccccc1
Reaction time: 2 h
Yield: 27.5 %

Procedure:
1-(2,4-diisopropyldibenzo[b,d]furan-1-yl)-2-phenyl-4,5-dihydro-1H-imidazole (4.7 g, 12 mmol) was dissolved in 100 mL acetonitrile. To the stirred solution fine mixture of KMnO4 (3.8 g, 24 mmol) and 4 g montmorillonite K10 clay was added in small portions and the reaction mixture was stirred for 2 h. At the end, reaction was quenched with MeOH and filtered thru a Celite pad. Crude product was purified by flash chromatography over silica gel with 80% DCM/Hexane to 80% DCM/ethylacetate. 3 g light yellow color oil was isolated. This oil was further purified by reverse phase chromatography. Target compound (1.3 g, 28% yield) was isolated as white solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.O[N:40]=[C:41]([C:43]1[C:44]2[CH2:45][CH2:46][CH:47]([OH:52])[C:48]=2[CH:49]=[CH:50][CH:51]=1)[NH2:42].[Na+].[Cl-]>CN(C=O)C>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]2[O:11][N:42]=[C:41]([C:43]3[CH:51]=[CH:50][CH:49]=[C:48]4[C:44]=3[CH2:45][CH2:46][CH:47]4[OH:52])[N:40]=2)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: NC(=NO)c1cccc2c1CCC2O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC4O)no2)cc1C(F)(F)F
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 68 %

Procedure:
In a microwave vial, a stirring solution of 4-isopropoxy-3-(trifluoromethyl)benzoic acid (700 mg, 2.82 mmol) in DMF was treated with HOBt (495 mg, 3.67 mmol) and EDCI (702 mg, 3.67 mmol) at room temperature. The reaction was stirred for 20 min followed by addition, in a single portion, of N′,1-dihydroxy-2,3-dihydro-1H-indene-4-carboximidamide (650 mg, 3.38 mmol). The reaction was stirred for additional 30 min at room temperature and then heated to 130° C. for 35 min in the initiator. The reaction was diluted using a saturated solution of NaCl and extracted with EtOAc (100 ml×3). The organic phase was dried over Na2SO4 anhydrous and concentrated under reduced pressure. The product was purified by column chromatography using CH2Cl2:MeOH (9:1) to offer the product as white solid in 68% yield (780 mg). 1H NMR (300 MHz, CDCl3—CH3OD): δ 8.38 (d, J=1.8 Hz, 1H), 8.28 (dd, J1=2.4 Hz, J2=8.7 Hz, 1H), 8.06 (d, J=7.8 Hz, 1H), 7.55 (d, J=7.5 1H), 7.7.37 (t, J=7.5 Hz, 1H), 7.11 (dd, J1=2.4 Hz, J2=9.0 Hz, 1H), 5.24 (t, J=6.3 Hz, 1H), 4.20 (q, J=6.9 Hz, 1H), 3.48-3.40 (m, 1H), 3.19-3.09 (m, 1H), 2.57-2.46 (m, 1H), 2.04-1.92 (m, 1H), 1.46 (t, J=6.9 Hz, 3H), 1.39 (d, J=6.0 Hz, 3H); 13C NMR (75 MHz, CDCl3—CH3OD): δ 169.05, 158.85, 146.82, 143.33, 133.55, 128.79, 127.41, 127.22, 116.23, 113.38, 104.88, 65.27, 35.55, 31.44, 21.87, 14.55. MS (EI) m/z 405 (M+), HRMS (EI) for C21H19N2O3 (M+): calcd 405.1420. found 405.1424.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@H:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:10]([CH3:12])[CH3:11].Cl.[NH:21]([C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[C@H:22]([C:31](ON1C(=O)CCC1=O)=[O:32])[CH2:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>CN(C)C=O>[NH:21]([C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[C@H:22]([C:31]([NH:8][C@H:9]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:32])[CH2:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
1.68 ml (12.0 mmol) of triethylamine are added to a suspension containing 2.58 g (12.0 mmol) of H-Val-OtBu.HCl and 4.62 g (11.0 mmol) of Z-Asp(OtBu)-OSu in 25 ml of dimethylformamide (DMF). The reaction mixture is left to stand overnight, then evaporated under reduced pressure. The residue is mixed with 50 ml of ethyl acetate and the suspension obtained is successively washed with 25 ml of water, 3 times with 25 ml of 1 mol/liter hydrochloric acid each, 3 times with 25 ml of 5% aqueous sodium hydrogenocarbonate each and finally with 25 ml of water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain 4.3 g (81.7%) of oily Z-Asp(OtBu)-Val-OtBu protected dipeptide, Rf1 =0.85.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[N:32][CH:31]=[CH:30][N:29]=2)=[CH:24][CH:23]=1>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:23]=[CH:24][C:25]([C:28]4[CH:33]=[N:32][CH:31]=[CH:30][N:29]=4)=[CH:26][CH:27]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2cnccn2)cc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4cnccn4)cc3)o2)cc(OC)c1Br

Procedure:
1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(pyrazin-2-yl)phenyl)ethanone was prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan and N,2-dimethoxy-N-methyl-2-(4-(pyrazin-2-yl)phenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (60% EtOAc/hexanes) gave the product as a pale yellow solid (0.060 g, 17% yield). MS: m/z 509.3 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])C)C1C=CC=CC=1>CO.O.[OH-].[OH-].[Pd+2]>[CH3:1][NH:8][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18]
Reactant: CN(CCNC(=O)OC(C)(C)C)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CNCCNC(=O)OC(C)(C)C
Reaction time: 2.5 h
Yield: 93.6 %

Procedure:
To a flask was added 20% Pd(OH)2 on carbon (3.1 g), compound B (3.3 g, 12.5 mmol) in MeOH (200 mL) and water (10 mL), while being exposed to H2 (40 psi). After 2.5 h, the reaction mixture was filtered through celite and concentrated in vacuo. Water was then added (50 mL) and the mixture brought to pH 12 (by addition of 1 N NaOH) and extracted with DCM (3×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give compound C (2.0 g, 11.7 mmol, 94%) as a colorless oil. LC-MS [M+H] 686.5 (C35H51N5O7S+H, calc: 685.9). Compound C was used without further purification.
Reaction SMILES: C(C1COC(=O)N1[C:14](=[O:33])[CH:15]([CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[CH2:16][N:17]([O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[CH:18]=[O:19])C1C=CC=CC=1.C1C[O:37]CC1.O.OO>[Cl-].[Na+].O>[CH:28]1([CH2:27][CH:15]([CH2:16][N:17]([CH:18]=[O:19])[O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[C:14]([OH:33])=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: C1CCOC1
Reactant: O=CN(CC(CC1CCCC1)C(=O)N1C(=O)OCC1Cc1ccccc1)OC1CCCCO1
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=CN(CC(CC1CCCC1)C(=O)O)OC1CCCCO1
Reaction time: 1.5 h
Yield: 50 %

Procedure:
N-[3-(4-Benzyl-2-oxo-oxazolidin-3-yl)-2-cyclopentylmethyl-3-oxo-propyl]-N-(tetrahydro-pyran-2-yloxy)-formamide (3.65 g, 7.96 mmol), THF (125 mL), and water (40 mL) is cooled to 4° C. To this mixture, is added 30% H2O2 (5.2 mL, 50.90 mmole) and LiOH monohydrate (0.40 g, 9.53 mmol), respectively. The reaction mixture is stirred for 1.5 hours. The mixture is slowly quenched with 0.5 M Na2SO3, while maintaining the temperature below 15° C. with an ice bath. The quenched mixture is stirred for an addition 30 minutes, concentrated in vacuo until the THF solvent is removed, and washed with EtOAc. The basic reaction mixture is acidified with Amberlite IR-120 resin (H+) to pH=4.5. Brine is added to the acidic solution, and the combined mixture is extracted with EtOAc. The organic layers from the acidic solution washing are combined, dried over Na2SO4, and concentrated in vacuo. This gave 2-cyclopentylmethyl-3-[formyl-(tetrahydro-pyran-2-yloxy)-amino]-propionic acid (1.20 g, 50% yield) as an oil.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][C:24]([O:26]CC)=[O:25].Cl>[OH-].[Na+].[Cl-].[Na+].O>[F:1][C:2]([F:29])([F:30])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)COCCOCCOCCOCCOCCOCCOCC(F)(F)F
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(O)COCCOCCOCCOCCOCCOCCOCC(F)(F)F
Temperature: 20 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
The product of step (e) (400 mg) was dissolved in an aqueous sodium hydroxide solution (0.1M, 10 mL) and the reaction was stirred at 20° C. for 16 hours. The reaction mixture was acidified to pH 2 by the addition of hydrochloric acid (2M), then this was diluted with brine (200 mL) and extracted with dichloromethane (2×200 mL). The combined organic layers were dried and the solvent was removed in vacuo to give the title compound as a colourless oil (330 mg). LC retention time 2.41 mins. Mass spectrum m/z 440 [MNH4+]
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:29]=1[NH:28][C:27]([C:30]1[S:31][CH:32]=[CH:33][N:34]=1)=[CH:26]2)[S:9]([C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17](OC)=[O:18])(=[O:11])=[O:10].O.[OH-].[Na+]>O1CCCC1>[OH:18][CH2:17][C:13]1[S:14][CH:15]=[CH:16][C:12]=1[S:9]([N:8]([CH3:7])[C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:29]=1[NH:28][C:27]([C:30]1[S:31][CH:32]=[CH:33][N:34]=1)=[CH:26]2)(=[O:11])=[O:10]
Reactant: COC(=O)c1sccc1S(=O)(=O)N(C)c1cccc2cc(-c3nccs3)[nH]c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN(c1cccc2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1ccsc1CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.5 %

Procedure:
To a suspension of lithium aluminum hydride (260 mg) in tetrahydrofuran (10 mL) was added dropwise a solution of methyl 3-({methyl[2-(1,3-thiazol-2-yl)-1H-indol-7-yl]amino}sulfonyl)thiophene-2-carboxylate (1.4 g) in tetrahydrofuran (5 mL) under ice-cooling, and the mixture was stirred at room temperature for 4 hr. To the reaction mixture were added water (260 μL), 15% aqueous sodium hydroxide solution (260 μL) and water (780 μL) in this order and the mixture was stirred at room temperature for 2 hr. The insoluble material was filtered off, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound (701 mg, yield 54%) as pale-yellow crystals. melting point 192° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])([CH3:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:22](N(CC)CC)[CH3:23].ClCC(Cl)=O>ClCCCl>[CH3:16][C:14]1([CH3:15])[N:17]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:23][C:22]2=[N:1][C:2]3[CH:3]=[N:4][C:5]4[C:10]([C:11]=3[N:12]2[CH2:13]1)=[CH:9][CH:8]=[CH:7][CH:6]=4
Reactant: CCN(CC)CC
Reactant: CC(C)(CNc1c(N)cnc2ccccc12)NS(C)(=O)=O
Agent: O=C(Cl)CCl
Solvent: ClCCCl
Product: CC1(C)Cn2c(nc3cnc4ccccc4c32)CN1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
Under a nitrogen atmosphere, a solution of N-{2-[(3-aminoquinolin-4-yl)amino]-1,1-dimethylethyl}methanesulfonamide (2.65 g, 8.59 mmol) in 1,2-dichloroethane (100 mL) was cooled to 0° C. Triethylamine (2.4 mL, 17 mmol) and chloroacetyl chloride (0.82 mL, 10.3 mmol) were sequentially added, and the reaction was allowed to warm to ambient temperature, stirred overnight, and then heated at reflux for 1.5 days. The reaction was washed with saturated aqueous sodium bicarbonate (2×100 mL) and brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 1.92 g of 10,10-dimethyl-9-(methylsulfonyl)-8,9,10,11-tetrahydropyrazino[4′,3′:1,2]imidazo[4,5-c]quinoline as a brown solid, which was used without purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[Cl:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:26][CH:27]=2)[CH:20]=[CH:21][CH:22]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[Cl:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:25]([N:28]3[CH2:29][CH2:30][N:31]([C:8]([NH:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:32][CH2:33]3)[S:26][CH:27]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Clc1cccc(-c2csc(N3CCNCC3)n2)c1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)N1CCN(c2nc(-c3cccc(Cl)c3)cs2)CC1
Temperature: 70 °C
Reaction time: 15 h
Yield: 39.5 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (212 mg, 0.786 mmol), 1-[4-(3-chlorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.715 mmol) and diisopropylethylamine (0.249 ml, 1.43 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 113 mg (39.7%) of the desired product as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[N:6]=[C:5]2[NH:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH2:23])=[O:22].Cl[CH2:29][C:30]([NH:32][CH3:33])=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CN(C=O)C.O>[CH3:33][NH:32][C:30](=[O:31])[CH2:29][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[N:6]=[C:5]2[NH:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH2:23])=[O:22]
Reactant: NC(=O)c1ccccc1Nc1nc(-c2cccnc2)nc2ccc(O)cc12
Reactant: CNC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)COc1ccc2nc(-c3cccnc3)nc(Nc3ccccc3C(N)=O)c2c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 45.8 %

Procedure:
The suspension of 2-(6-hydroxy-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide (synthesized as described in Scheme 24) (0.20 g, 0.56 mmol), 2-chloro-N-methylacetamide (90 mg, 0.80 mmol), cesium carbonate (0.37 g, 112 mmol) and potassium iodide (0.19 g, 1.12 mmol) in DMF (10 mL) was stirred for 4 days at room temperature. Water (20 mL) was added to the mixture. The resultant solid was collected by filtration. The obtained solid was washed with CH2Cl2-THF (1:1) solution and dried to give 0.11 g of 2-(6-(2-(methylamino)-2-oxoethoxy)-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide as pale brown solid (46%), LCMS m/z=429 (M+1) (Method C) (retention time=1.65 min). 1H NMR (300 MHz, DMSO) δ 9.58 (s, 1H), 9.12 (d, J=8.4 Hz, 1H), 8.82-8.64 (m, 2H), 8.48 (s, 1H), 8.32-8.17 (m, 1H), 8.10-7.87 (m, 3H), 7.81-7.49 (m, 4H), 7.21 (t, J=7.5 Hz, 1H), 4.66 (s, 2H), 2.71 (d, J=4.5 Hz, 3H).