Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6](=[O:28])[C:5]2([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:38])[N:29]([CH3:31])[CH3:30].[H-].[Na+].[CH3:41]I.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:15]=[CH:16][C:17]([N:20]([CH3:41])[C:21]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[O:22])=[CH:18][CH:19]=1)(=[O:13])=[O:12])[C:6](=[O:28])[C:5]2([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:38])[N:29]([CH3:30])[CH3:31]
Reactant: CI
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)N2C(=O)C(c3ccccc3Cl)(N(C)C)c3cc(Cl)ccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)C(=O)N(C)c1ccc(S(=O)(=O)N2C(=O)C(c3ccccc3Cl)(N(C)C)c3cc(Cl)ccc32)cc1
Reaction time: 0.5 h

Procedure:
A solution of 0.420 g of the compound obtained in EXAMPLE 30 in 7 ml of DMF is cooled to 0° C. under an argon atmosphere and 0.027 g of sodium hydride as an 80% dispersion in oil is added. After stirring for 30 minutes, 0.05 ml of methyl iodide is added and the reaction mixture is stirred for 10 minutes. It is poured into water, extracted with AcOEt, washed with water, dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on silica using DCM and then a DCM/AcOEt mixture (95/5; v/v) as the eluent to give the expected product after crystallization from a DCM/iso ether mixture. m=0.211 g. M.p.=145°-148° C.
Reaction SMILES: C[C:2]1([CH2:13][OH:14])[C:7]([CH3:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][NH:3]1>C(Cl)Cl.O=[Mn]=O>[CH3:8][C:7]1[C:2]([CH:13]=[O:14])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:10])[F:11])[CH:6]=1
Reactant: CC1=CC(C(F)(F)F)=CNC1(C)CO
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)cnc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
A suspension of (2,3-dimethyl-5-trifluoromethyl-pyridin-2-yl)-methanol (0.300 g, 1.57 mmol)) and activated MnO2 (1.36 g, 15.6 mmol) in CH2Cl2 (10 mL) was stirred at room temperature overnight. After that period of time the suspension was filtered through a celite cake. the solvent was removed from the filtrate, and the residue was purified on silica gel column (CH2Cl2) to afford 3-methyl-5-trifluoromethyl-pyridine-2-carbaldehyde as a pale yellow liquid (0.180 g, 61%). 1H NMR (CD3Cl) δ 2.73 (s, 3H), 7.87 (s, 1H), 8.90 (s, 1H), 10.23 (s, 1H).
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]1([N:13]=[C:14]=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:16]1([N:22]2[C:26]([NH2:27])=[C:25]([C:28]#[N:29])[CH:24]=[N:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[C:16]1([N:22]2[C:26]([NH:27][C:14]([NH:13][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:15])=[C:25]([C:28]#[N:29])[CH:24]=[N:23]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N#Cc1cnn(-c2ccccc2)c1N
Reactant: O=C=Nc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#Cc1cnn(-c2ccccc2)c1NC(=O)Nc1ccccc1
Temperature: 80 °C
Yield: 96 %

Procedure:
9.0 g (80 mmol) of potassium tert-butylate and 8.7 ml (80 mmol) of phenyl isocyanate were added to a solution of 5.52 g (30 mmol) of 1-phenyl-4-cyano-5-aminopyrazole in 100 ml of toluene. The mixture was heated for 15 hours at 80° C. and then cooled, the insoluble constituents were separated off and the resulting solution was acidified with acetic acid, the product crystallizing out. Yield: 96%.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:14][N:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11][C:6]21[CH2:10][CH2:9][CH2:8][CH2:7]2)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[OH:2][CH2:3][CH:5]1[CH2:14][N:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11][C:6]21[CH2:10][CH2:9][CH2:8][CH2:7]2
Reactant: COC(=O)C1CN(Cc2ccccc2)CCC12CCCC2
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCC1CN(Cc2ccccc2)CCC12CCCC2

Procedure:
A solution of 11.4 gm (39.1 mMol) 8-benzyl-8-azaspiro[4,5]decane-6-carboxylic acid methyl ester in 150 mL tetrahydrofuran was treated dropwise with a solution of 58 mL (58 mMol) lithium aluminum hydride (1.0 M in tetrahydrofuran). The reaction mixture was heated at reflux for 4 hours and was then cooled in an ice bath. The mixture was then diluted with ethyl acetate and treated dropwise with 100 mL 1N hydrochloric acid. The pH of the solution was then adjusted to about 8 with 5N sodium hydroxide and the mixture was extracted well with dichloromethane. The organic phases were combined, dried over magnesium sulfate and concentrated under reduced pressure to provide 6-hydroxymethyl-8-benzyl-8-azaspiro[4,5]decane.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(#N)C>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][O:11][C:5]1[CH:4]=[C:3]([O:12][CH3:13])[C:2]([Cl:1])=[CH:7][C:6]=1[C:8](=[O:10])[CH3:9])[CH3:26]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(O)c(C(C)=O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COc1cc(OC)c(Cl)cc1C(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the above prepared 1-(5-chloro-2-hydroxy-4-methoxy-phenyl)-ethanone (4.22 g, 21.0 mmol) in 50 mL of acetonitrile were successively added Cs2CO3 (8.22 g, 1.2 eq.) and ethyl bromoacetate (2.44 mL, 1.05 eq.) and the mixture vigorously stirred at ambient temperature for 2 h. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water, drying over magnesium sulfate, and evaporation of the solvents left 6.05 g of the title compound as off-white solid, used directly for the next step.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=1)[C:2]#[C:3][CH3:4].[CH3:15][C:16]1[C:17]([NH2:31])=[N:18][C:19]2([C:29]3[C:24](=[CH:25][CH:26]=[C:27]([NH2:30])[CH:28]=3)[O:23][CH2:22][CH2:21]2)[N:20]=1>>[NH2:31][C:17]1[C:16]([CH3:15])=[N:20][C:19]2([C:29]3[C:24](=[CH:25][CH:26]=[C:27]([NH:30][C:12](=[O:14])[C:9]4[CH:8]=[CH:7][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:11][N:10]=4)[CH:28]=3)[O:23][CH2:22][CH2:21]2)[N:18]=1
Reactant: CC1=NC2(CCOc3ccc(N)cc32)N=C1N
Reactant: CC#CCOc1ccc(C(=O)O)nc1
Product: CC#CCOc1ccc(C(=O)Nc2ccc3c(c2)C2(CCO3)N=C(C)C(N)=N2)nc1
Yield: 15.5 %

Procedure:
The title compound (15 mg, 16% yield) was prepared as described for Example 13a starting from 5-(but-2-ynyloxy)picolinic acid (Intermediate 19, 45 mg, 0.24 mmol) and 5′-methylspiro[chroman-4,2′-imidazole]-4′,6-diamine (Intermediate 30, 54.7 mg, 0.24 mmol): 1H NMR (500 MHz, CDCl3) δ ppm 1.87 (t, 3H), 2.03 (m, 1H), 2.30 (m, 1H), 2.39 (m, 3H), 4.50 (m, 1H), 4.62 (m, 1H), 4.76 (m, 2H), 6.92 (d, 1H), 6.98 (m, 1H), 7.41 (dd, 1H), 7.49 (m, 1H), 8.18 (d, 1H), 8.28 (d, 1H), 9.61 (s, 1H); MS (ES+) m/z 404 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:12][C:13](=[O:26])[N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[C:39]([O:47][C:48]([F:51])([F:50])[F:49])[CH:38]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:43]([C:40]1[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][C:39]=1[O:47][C:48]([F:49])([F:50])[F:51])(=[O:45])=[O:44])[C:6](=[O:11])[C:5]2([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:12][C:13](=[O:26])[N:14]1[CH2:15][CH2:16][N:17]([C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[CH2:18][CH2:19]1
Reactant: COc1ccccc1C1(CC(=O)N2CCN(c3cnccn3)CC2)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(CC(=O)N3CCN(c4cnccn4)CC3)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 92.3 %

Procedure:
With 300 mg of 5-chloro-3-(2-methoxyphenyl)-3-[2-oxo-2-(4-pyrazine-2-ylpiperazin-1-yl)ethyl]-1,3-dihydro-2H-indol-2-one, which is the compound described in Composes IV.1 of the brochure Publication No. WO03/008407, and 201 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 424 mg of the title compound (pale yellow amorphous) was obtained by a similar method to Example 2.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4](Cl)=[O:5].C[O:14][P:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]2[CH:25]=[CH:26][CH:27]=[CH:28][C:17]=2[O:16]1.CCl>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([P:15]1(=[O:14])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]2[CH:25]=[CH:26][CH:27]=[CH:28][C:17]=2[O:16]1)=[O:5]
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Reactant: COP1Oc2ccccc2-c2ccccc21
Agent: CCl
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(C(=O)P2(=O)Oc3ccccc3-c3ccccc32)c(C)c1
Temperature: 105 °C

Procedure:
18.25 g (0.1 mol) of 2,4,6-trimethylbenzoyl chloride were warmed to 85° C. under a nitrogen atmosphere 23 g (0.1 mol) of 6-methoxy-(6H)-dibenz[c,e][1,2]-oxaphosphorin were added dropwise while stirring. The temperature was slowly increased to 105° C. It was kept at this temperature until evolution of methyl chloride could no longer be detected. When the reaction was complete, toluene was added. After crystallization, 27 g (75% of theory) of the abovementioned compound of melting point 109° C. were obtained.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]=[C:24]([C:26]4[CH:30]=[C:29]([CH3:31])[NH:28][C:27]=4[CH3:32])[CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[CH3:32][C:27]1[NH:28][C:29]([CH3:31])=[CH:30][C:26]=1[C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:15][CH:16]=2)[N:25]=1
Reactant: Cc1cc(-c2cccc(-c3ccc(C4CCN(Cc5ccccc5)CC4)cc3)n2)c(C)[nH]1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1cc(-c2cccc(-c3ccc(C4CCNCC4)cc3)n2)c(C)[nH]1
Yield: 77.2 %

Procedure:
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 1.21 g (2.87 mmol) N-benzyl-4-(4-(2-(2,5-dimethylpyrrolyl)pyrid-6-yl)phenyl)piperidine, 30 mL ethanol, 0.90 g (14.37 mmol) ammonium formate, and 140 mg 10% palladium-on-carbon (Pd-C). The reaction was refluxed 1 hour treated with additional ammonium formate and Pd-C, and refluxed 3 hours. It was then cooled and filtered through Celite with ethanol and methylene chloride. The filtrate was evaporated, taken up in ethyl acetate and aqueous sodium bicarbonate solution, and the organic layer separated, washed with brine, dried over sodium sulfate, and evaporated to afford 734 mg (77%) of an oil.
Reaction SMILES: [Na].[N:2]([C:5](=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)C(OC)=O)=[N+]=[N-].ClC1C=CC(C=O)=CC=1F.N(CC(OC)=O)=[N+]=[N-]>CO>[Cl:17][C:14]1[C:13]([F:18])=[C:12]2[C:11]([CH:10]=[CH:5][NH:2]2)=[CH:16][CH:15]=1
Reactant: COC(=O)C(=Cc1ccc(Cl)c(F)c1)N=[N+]=[N-]
Agent: COC(=O)CN=[N+]=[N-]
Agent: O=Cc1ccc(Cl)c(F)c1
Agent: [Na]
Solvent: CO
Product: Fc1c(Cl)ccc2cc[nH]c12
Temperature: -15 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
Methyl 2-azido-3-(4-chloro-3-fluorophenyl)propenoate Sodium (2.32 g, 100 mmol) was added portionwise to stirred methanol (200 mL) at 0° C. under Ar. The mixture was stirred for 1 h and cooled to −15° C. A solution of 4-chloro-3-fluorobenzaldehyde (4.0 g, 25 mmol), methyl azidoacetate (8.7 g, 75 mmol) in methanol (20 mL) was added. The mixture was stirred for 3 h, warmed to 4° C. and stirred for 16 h and partitioned between water (300 mL) and ether (3×200 mL). The organic extracts were combined and washed with brine (2×), dried (magnesium sulfate) and concentrated in vacuo to give an orange solid. Recrystallisation (methanol) gave the product (5.09 g, 80% yield) as a pale yellow solid: IR νmax (Nujol)/cm−1 2115, 1708, 1616, 1234, 1060, 896, 818 and 616; NMR δH (400 MHz, CDCl3) 3.82 (3H, s) 6.64 (1H, s) 7.35-7.46 (2H, m) 7.74-7.78 (1H, m).
Reaction SMILES: FS(C1C=CC([O:11][CH:12]([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])=CC=1)(=O)=O.[F:21][C:22]([F:40])([F:39])[CH:23]([C:35]([F:38])([F:37])[F:36])[O:24]C1C=CC(S([O-])(=O)=O)=CC=1>>[F:14][C:13]([F:16])([F:15])[CH:12]([OH:11])[C:17]([F:20])([F:19])[F:18].[CH:23]([OH:24])([C:35]([F:38])([F:37])[F:36])[C:22]([F:40])([F:39])[F:21]
Reactant: O=S(=O)(F)c1ccc(OC(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=S(=O)([O-])c1ccc(OC(C(F)(F)F)C(F)(F)F)cc1
Product: OC(C(F)(F)F)C(F)(F)F

Procedure:
Diazonium salt 1 (106.8 mg, 0.3359 mmol) was dissolved in HFIP (7.16 g) and the mixture was heated at 60° C. for 4 h. After cooling, Na2CO3 was added and the mixture was filtered. Most of the solvent was evaporated to give a pale-yellow oil, which was purified by SiO2 column chromatography with hexane/CH2Cl2 (9:1) to afford 1-(pentafluorosulfanyl)-4-[2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]benzene (colorless oil; 2.0 mg, 1.6%), 1-fluoro-4-(fluorosulfonyl)benzene (Ferm & VanderWerf, J. Am. Chem. Soc. 1950, 72, 4809-4810) (colorless oil; 7.7 mg, 13%), and 2,2,2-trifluoro-1-(trifluoromethyl)-ethyl 4-fluorophenylsulfonate (Popov, et al., Ukrainskii Khim. Zh. 1991, 57, 843-849) (colorless oil; 15.7 mg, 14.3%). Elution with hexane/CH2Cl2 (8:2) gave 1-(fluorosulfonyl)-4-[2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]benzene (colorless oil, 6.6 mg, 6.0%), a 2:1 mixture of 1-(fluorosulfonyl)-4-[2,2,2-trifluoro-1-(trifluoromethyl) ethoxy]benzene and 2,2,2-trifluoro-1-(trifluoromethyl)ethyl-4-[2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]phenylsulfonate (colorless oil, 27.2 mg, 19.1%), and 4-[2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]phenylsulfonate (colorless oil, 3.8 mg, 2.4%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[S:11][CH:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=O.S(Cl)(Cl)=O>ClCCl>[Cl:8][C:7]1[C:6]([O:9][CH3:10])=[CH:5][C:4]2[C:13](=[O:15])[CH:12]([CH:16]([CH3:18])[CH3:17])[S:11][C:3]=2[C:2]=1[Cl:1]
Reactant: COc1ccc(SC(C(=O)O)C(C)C)c(Cl)c1Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1cc2c(c(Cl)c1Cl)SC(C(C)C)C2=O
Temperature: 25 °C
Yield: 45 %

Procedure:
To 6.0 g of α-(2,3-dichloro-4-methoxyphenylthio)isovaleric acid in 27 ml of dry dichloromethane is added 5.5 ml of thionyl chloride. The reaction is heated under reflux for 1 hour and excess reagent is removed under aspirator pressure. The residue is diluted with 70 ml of dichloromethane and the resulting slurry is added over less than one minute to a slurry of 2.79 g of aluminum chloride in 8 ml of dichloromethane at -60°. The cooling bath is removed and the reaction allowed to warm to room temperature over one hour. Stirring is continued for an additional hour and reaction is quenched with 250 ml of water. The mixture is extracted with three 125 ml portions of ether and the combined ether extracts are washed with two 150 ml portions and one 60 ml portion of saturated sodium bicarbonate solution, water and brine and dried over anhydrous magnesium sulfate to give 2.54 g of oily 6,7-dichloro-5-methoxy-2-isopropylbenzo[b]thiophen-3(2H)-one.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[C:15]2[N:16]=[C:17]3[CH2:22][O:21][CH2:20][C@H:19]([CH2:23]O)[N:18]3[C:14]=2[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.[OH-].[Na+]>C(#N)C>[Cl:3][CH2:23][C@@H:19]1[N:18]2[C:14]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[N:7]=[C:6]([NH2:5])[C:15]=3[N:16]=[C:17]2[CH2:22][O:21][CH2:20]1
Reactant: O=S(Cl)Cl
Reactant: Nc1nc2ccccc2c2c1nc1n2[C@@H](CO)COC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Nc1nc2ccccc2c2c1nc1n2[C@@H](CCl)COC1
Temperature: 70 °C
Yield: 62.2 %

Procedure:
Thionyl chloride (1.5 mL, 20.7 mmol) was added neat to [(11S)-6-amino-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]methanol (280 mg, 1.03 mmol). The nearly homogeneous yellow reaction mixture was heated to 70° C. for 2 hours and turned dark red. The reaction mixture was cooled to ambient temperature and poured over ice. While maintaining the temperature at 0° C., the pH of the mixture was brought to 14 with 50% aqueous NaOH. The resulting white suspension was extracted with CHCl3. The layers were separated and the organic layer was dried over Na2SO4 and concentrated under reduced pressure to provide a tan foam. The tan foam was slurried with acetonitrile and filtered to give 185 mg of (11R)-11-(chloromethyl)-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine as a white solid.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[C:14]([N+:21]([O-:23])=[O:22])[CH:15]=[CH:16][C:17]=3[O:19][CH3:20])[CH:12]=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>CO.O>[CH3:20][O:19][C:17]1[CH:16]=[CH:15][C:14]([N+:21]([O-:23])=[O:22])=[C:13]2[C:18]=1[NH:10][CH:11]=[CH:12]2
Reactant: COc1ccc([N+](=O)[O-])c2ccn(S(=O)(=O)c3ccccc3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc([N+](=O)[O-])c2cc[nH]c12

Procedure:
To a solution of 1-benzenesulfonyl-7-methoxy-4-nitro-1H-indole (R) (1 eq) in methanol was added a solution of sodium hydroxide (5 eq) in water. The solution was heated to reflux for 3 hrs. Methanol was removed under reduced pressure then water and ethyl acetate were added. The ethyl acetate layer separated and washed repeatedly (3×) with water. The ethyl acetate layer was concentrated and evaporated to dryness to produce the desired product.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:5]2=[N:4][CH:3]=1.C([Mg]Cl)(C)C.Cl[Sn:17]([CH3:20])([CH3:19])[CH3:18]>O1CCCC1>[CH3:18][Sn:17]([CH3:20])([CH3:19])[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: Brc1cnc2ncccn12
Reactant: C[Sn](C)(C)Cl
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1cnc2ncccn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled (−78° C.) solution of 3-bromoimidazo[1,2-a]pyrimidine (1.0 g, 5.1 mmol) in anhydrous tetrahydrofuran (40 mL) under an atmosphere of nitrogen was added isopropylmagnesium chloride (2.0M solution in tetrahydrofuran, 2.8 mL, 5.6 mmol) dropwise over 10 minutes. The reaction was stirred for 2 h then a solution of chlorotrimethylstannane (1.1 g, 5.6 mmol) in tetrahydrofuran (10 mL) was added dropwise over 10 minutes. The reaction mixture was stirred for 30 minutes then allowed to warm to room temperature. The reaction was quenched with water (20 mL) and extracted with DCM (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered, and evaporated in vacuo to afford the title compound as an orange oil which was used without any further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]2[S:23][C:22]([CH3:24])=[N:21][C:4]=2[N:5]([CH3:20])[C:6](=[O:19])[C:7]=1[C:8]([NH:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])=[O:9].C(N(CC)C(C)C)(C)C.OC1C2SC(C)=NC=2N(C)C(=O)C=1C(OCC)=O>O1CCOCC1>[OH:1][C:2]1[C:3]2[S:23][C:22]([CH3:24])=[N:21][C:4]=2[N:5]([CH3:20])[C:6](=[O:19])[C:7]=1[C:8]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[O:9]
Reactant: Cc1nc2c(s1)c(O)c(C(=O)NCC(=O)OC(C)(C)C)c(=O)n2C
Agent: CCOC(=O)c1c(O)c2sc(C)nc2n(C)c1=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2c(s1)c(O)c(C(=O)NCC(=O)O)c(=O)n2C
Temperature: 25 °C

Procedure:
tert-Butyl 2-(7-hydroxy-2,4-dimethyl-5-oxo-4,5-dihydrothiazolo[4,5-b]pyridine-6-carboxamido)acetate. N,N-diisopropylethylamine (0.25 g, 2.0 mmol), tert-butyl glycine ester hydrochloride (0.33 g, 2.0 mmol) and ethyl 7-hydroxy-2,4-dimethyl-5-oxo-4,5-dihydrothiazolo[4,5-b]pyridine-6-carboxylate (0.35 g, 1.31 mmol) were heated at 90° C. for 5 hours in 1,4-dioxane (5 mL). The mixture was cooled to room temperature and concentrated to about ¼ of the original volume. Et2O (5 mL) was added, and the resulting suspension was filtered and washed with Et2O to give a solid. This material was washed with cold MeOH (0.5 mL) to give the title compound. MS (ESI) m/z: Calculated; 353.1: Observed; 298.1 (M-tert-butyl+H+). 1H NMR (400 MHz, CDCl3) δ ppm 10.52-10.83 (1H, m), 4.11 (2H, d, J=5.3 Hz), 3.81 (3H, s), 2.83 (3H, s), 1.52 (9H, s)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([NH2:11])=[S:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:12]([S:14][C:15](=O)[CH2:16]Br)[CH3:13]>C(O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[S:10][CH:13]=[C:12]([S:14][CH2:15][CH3:16])[N:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCSC(=O)CBr
Reactant: CC(C)(C)OC(=O)NC(N)=S
Solvent: CCO
Product: CCSc1csc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
N-tert-butoxycarbonyl-thiourea (0.600 g, 3.40 mmole) was suspended in ethanol (5 mL) and the mixture was cooled in an ice-water bath. To this mixture was added a solution of bromo-thioacetic acid S-ethyl ester (0.880 g [75% pure]; 3.61 mmole) in ethanol (5 mL). Following completion of the addition, the mixture was warmed to room temperature and stirred overnight. After 20 hours, the reaction was concentrated. The residue was partitioned between methylene chloride and water. The organic phase was washed with water and brine. The aqueous phases were then backwashed with methylene chloride. The two organic phases were combined, dried over sodium sulfate and concentrated. The crude material was purified by chromatography over silica gel eluted with 20% v/v ethyl acetate in hexanes, to give (4-ethylsulfanyl-thiazol-2yl)-carbamic acid tert-butyl ester (0.514 g, 58%).
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][C:9]([Sn](C)(C)C)=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].Cl[C:17]1[N:26]=[C:25]([NH:27][CH2:28][C@H:29]2[O:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]2)[C:24]2[C:19](=[N:20][CH:21]=[CH:22][N:23]=2)[CH:18]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[C:6]1[CH:11]=[CH:10][C:9]([C:17]2[N:26]=[C:25]([NH:27][CH2:28][C@H:29]3[O:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]3)[C:24]3[C:19](=[N:20][CH:21]=[CH:22][N:23]=3)[CH:18]=2)=[CH:8][CH:7]=1
Reactant: CN(CCO)c1ccc([Sn](C)(C)C)cc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CNc2nc(Cl)cc3nccnc23)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CN(CCO)c1ccc(-c2cc3nccnc3c(NC[C@@H]3CN(C(=O)OC(C)(C)C)CCO3)n2)cc1

Procedure:
2-(methyl(4-(trimethylstannyl)phenyl)amino)ethanol (223 mg, 0.713 mmol), (R)-tert-butyl 2-((7-chloropyrido[4,3-b]pyrazin-5-ylamino)methyl)morpholine-4-carboxylate (246 mg, 0.648 mmol), tetrakis(triphenylphosphine)palladium (150 mg, 0.13 mmol) was mixed in toluene, reacted at 100° C. overnight. Then it was filtrated and concentrated, purified by flash chromatography (PE: EA=2:1 to 1:1) to give crude product as a reddish-brown oil. And it was used without further purification.