Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH:11](=[O:15])[CH2:12][CH2:13][CH3:14].Cl>CCO>[CH:1](=[C:12]([CH2:13][CH3:14])[CH:11]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CCCC=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCC(C=O)=Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 70 %

Procedure:
30.0 mL Benzaldehyde was dissolved in 150 mL EtOH and cooled with an ice bath. Added was 5.01 mL. 45% KOH (0.2 equiv.), followed by dropwise addition of 16.5 mL butyraldehyde. The mixture was stirred for 3 days at room temperature, acidified with 1M HCl and extracted with ether. The organic layer was dried over Na2SO4, filtrated and concentrated in vacuo. Vacuum destillation yielded 20.4 g of a yellow fluid (78-82° C., 0.6 mbar) containing 70% of the desired product. This material was used in subsequent steps without further purification. Characteristic signals in 1H NMR (400 MHz, CDCl3): δ 1.15 (t, J=7.5 Hz, 3H), 2.57 (q, J=7.5 Hz, 1H), 7.22 (s, 1H), 9.56 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([O:22]C)[CH:21]=1)[C:5]([N:7]([C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)[CH2:8][CH2:9][CH3:10])=[O:6].B(Br)(Br)Br.CO>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([OH:22])[CH:21]=1)[C:5]([N:7]([C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)[CH2:8][CH2:9][CH3:10])=[O:6]
Reactant: CCCN(C(=O)c1cc(Cl)cc(OC)c1)c1cc(F)cc(F)c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CCCN(C(=O)c1cc(O)cc(Cl)c1)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a stirred solution of 3-chloro-N-(3,5-difluoro-phenyl)-5-methoxy-N-propyl-benzamide (0.164 g) in anhydrous dichloromethane (5 ml) at −78° C. was added 1M boron tribromide solution in dichloromethane (3.5 ml). The reaction mixture was stirred at this temperature for 15 min. The reaction was allowed to warm to room temperature, and after 3.5 h the reaction was cooled to −78° C. and methanol (6 ml) added. The reaction was allowed to rewarm to room temperature and the solvent removed in vacuo. The residue was purified by flash column chromatography eluting with cyclohexane:ethyl acetate (3:1 v/v) to give the title compound as a colourless oil (0.110 g).
Reaction SMILES: [F:1][CH2:2][C:3]([N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])([CH2:6][CH2:7][CH2:8]OC)[C:4]#[N:5].C[Si]([I:26])(C)C>C(Cl)(Cl)Cl>[F:1][CH2:2][C:3]([N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])([CH2:6][CH2:7][CH2:8][I:26])[C:4]#[N:5]
Reactant: C[Si](C)(C)I
Reactant: COCCCC(C#N)(CF)N1C(=O)c2ccccc2C1=O
Solvent: ClC(Cl)Cl
Product: N#CC(CF)(CCCI)N1C(=O)c2ccccc2C1=O

Procedure:
2-Fluoromethyl-2-phthalimido-5-methoxy-valeronitrile (1.20 g, 4.14 mmol), trimethylsilyl iodide (3.2 g, 16 mmol) and chloroform (15 ml) are heated to 60° C. under nitrogen for 48 hours. After removal of the solvent, the residue is dissolved in chloroform, washed with water, sodium thiosulfate solution and water again, dried and evaporated to give the crude product as an oil (1.2 g). This is purified by chromatography on silica (ethyl acetate/petroleum ether 1:3) to give pure 2-fluoromethyl-2-phthalimido-5-iodo-valeronitrile.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([O:9]C)=[CH:5][C:4]=1/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14].Cl.N1C=CC=CC=1>O>[OH:9][C:6]1[CH:5]=[C:4]2[C:3](=[CH:8][CH:7]=1)[O:15][C:13](=[O:14])[CH:12]=[CH:11]2
Reactant: COc1ccc(OC)c(/C=C/C(=O)O)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=c1ccc2cc(O)ccc2o1
Yield: 49 %

Procedure:
The carboxylic acid (1.97 g; prepared in reference example 24) and pyridine hydrochloride (12 g) were heated to 180°-190° C. The mixture was reacted for 3.5 hr. The reaction mixture was cooled and then dissolved in water. The solution was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and then evaporated. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1→1:1). The obtained crystals were washed with a mixture of n-hexane and ethyl acetate (3:1→1:1) to give the title compound (751 mg) having the following physical data.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:18]=[C:19]([N:23]3[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([OH:32])C>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:18]=[C:19]([N:23]3[CH:27]=[C:26]([C:28]([NH2:29])=[O:32])[CH:25]=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCO
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)cn4)c3)ncc2c1
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)cn4)c3)ncc2c1
Temperature: 85 °C
Reaction time: 0.75 h
Yield: 54 %

Procedure:
In a 25 mL round-bottomed flask, 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)-1H-pyrazole-4-carbonitrile (87 mg, 225 μmol, Eq: 1.00) and hydrido(dimethylyphosphinous acid-kP) (4.82 mg, 11.2 μmol, Eq: 0.05) were combined with Ethanol (1 ml) and Water (1.00 ml) to give a colorless solution. The reaction mixture was heated to 85° C. and stirred for 45 min. After the required reaction time (conversion checked my LCMS and TLC), the reaction was allowed to come to room temperature and the solvent was removed under vacuum. The mixture was then filtered through the HPLC teflon filter and passed through reverphase HPLC and lyophilized overnight to give 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-phenyl]-1H-pyrazole-4-carboxylic acid amide (49 mg, 54%, [M+H]+ 406)
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]([CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]/[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:6]([O:8][CH2:9][CH:10]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7].C(O)(C(F)(F)F)=O>O>[C:6]([N:5]([CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]/[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:4][CH:3]=[O:2])([O:8][CH2:9][CH:10]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7]
Reactant: CCCCC/C=C/CCCN(CC(OC)OC)C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCCCC/C=C/CCCN(CC=O)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 115 %

Procedure:
N-Fmoc-2-(trans-Dec-4-en-1-ylamino)acetaldehyde dimethyl acetal (5 g, 10.7 mmol) was mixed with 30 mL of TFA and stirred at room temperature for 30 minutes. The reaction was poured into water (140 mL) and centrifuged to obtain a clear oil. The supernatant was decanted and the oil was mixed with 40 mL of water and centrifuged again. The supernatant was again decanted and the oil was dissolved in dichloromethane (100 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to obtain 5.2 g (12.3 mmol) of N-Fmoc-2-(trans-Dec-4-en-1-ylamino)acetaldehyde as a clear oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH2:15][CH2:16][C:17](=[O:26])[CH2:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH:9]=[CH:8]2.[BH4-].[Na+]>CO>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH2:15][CH2:16][CH:17]([OH:26])[CH2:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH:9]=[CH:8]2
Reactant: COCOc1ccc2cc(CCC(=O)CCc3cccnc3)ccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCOc1ccc2cc(CCC(O)CCc3cccnc3)ccc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 49.2 %

Procedure:
1-{6-(Methoxymethoxy)-2-naphthyl}-5-(3-pyridyl)-3-pentanone (1.9 g; from Example 31 above) was immediately dissolved in methanol (100 ml) and cooled to 0° C. Solid sodium borohydride (0.284 g) was added and the reaction mixture stirred at 25° C. for 2 hours. The mixture was concentrated under reduced pressure and water was added to the residue. The aqueous mixture was extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane:methanol (95:5) to give an oil (0.94 g).
Reaction SMILES: C(N1CCN(C2C=[C:11]([NH:15][C:16]([C:18]3[C:19]4[N:20]=[CH:21][CH:22]=[N:23][C:24]=4[C:25]([C:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH:31]=[N:30][CH:29]=4)=[CH:26][CH:27]=3)=[O:17])C=CC=2)CC1)C>C(Cl)Cl.CO>[NH:20]1[CH:19]=[CH:24][N:23]=[C:11]1[NH:15][C:16]([C:18]1[C:19]2[N:20]=[CH:21][CH:22]=[N:23][C:24]=2[C:25]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[N:30][CH:29]=2)=[CH:26][CH:27]=1)=[O:17]
Reactant: CCN1CCN(c2cccc(NC(=O)c3ccc(-c4cncc5ccccc45)c4nccnc34)c2)CC1
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1ncc[nH]1)c1ccc(-c2cncc3ccccc23)c2nccnc12

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but using 8-isoquinolin-4-yl-quinoxaline-5-carboxylic acid (Example 52) in Step 14.1. Title compound: ESI-MS: 367.0 [M+H]+; TLC: Rf=0.17 (DCM/MeOH, 95:5).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[C:17]3[O:16][CH:15]=[CH:14][C:13]=3[CH:12]=[C:11]([N+:18]([O-])=O)[CH:10]=2)[C@H:5]([CH3:21])[CH2:4][N:3]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].O.NN>C1COCC1.CCO.[Ni]>[NH2:18][C:11]1[CH:10]=[C:9]([CH2:8][N:6]2[C@H:5]([CH3:21])[CH2:4][N:3]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C@@H:2]([CH3:1])[CH2:7]2)[C:17]2[O:16][CH:15]=[CH:14][C:13]=2[CH:12]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1Cc1cc([N+](=O)[O-])cc2ccoc12
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1Cc1cc(N)cc2ccoc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
tert-Butyl trans-2,5-dimethyl-4-[(5-nitro-1-benzofuran-7-yl)methyl]piperazine-1-carboxylate (0.14 g, 0.35 mmol; obtained in Step 2) was dissolved in THF/EtOH (4:1; 5 mL). Excess Raney-Ni (slurry in EtOH) was added followed by hydrazine hydrate (0.07 g, 1.39 mmol). The reaction mixture was stirred overnight at ambient temperature. After filtration and evaporation of solvent, a crude oil (0.11 g, 87%) was obtained that was used in the next step without further purification. HPLC 86% RT=1.15 min (System B; 10-97% MeCN over 3 min). MS (ESI+) m/z 360.2 (M+H)+.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][S:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.[N:35]1([C:41]2[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][N:42]=2)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(#N)CC>[O:17]=[C:7]1[NH:6][C:5]2[CH:4]=[C:3]([CH2:2][N:38]3[CH2:39][CH2:40][N:35]([C:41]4[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][N:42]=4)[CH2:36][CH2:37]3)[CH:12]=[N:11][C:10]=2[N:9]2[CH2:13][CH2:14][S:15][CH2:16][C@@H:8]12
Reactant: N#Cc1ccc(N2CCNCC2)nc1
Reactant: O=C1Nc2cc(CO)cnc2N2CCSC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: N#Cc1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)nc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 40.2 %

Procedure:
(R)-3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one (80.0 mg, 0.318 mmol) was suspended in propionitrile (0.8 mL) and (cyanomethyl)trimethylphosphonium iodide (93.0 mg, 0.382 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (167 ul, 0.955 mmol). To the stirred mixture was then added 6-(piperazin-1-yl)nicotinonitrile (59.9 mg, 0.318 mmol). The reaction was heated to 90° C. with stirring for 16 h. The reaction was cooled to room temperature and left to sit 48 h. The precipitate was filtered off, washed with ethanol (5 mL) and dried in vacuum to afford the title compound (53.9 mg, 40.2%) as a white solid. 1H NMR (CHLOROFORM-d) δ (ppm): 8.41 (d, J=1.8 Hz, 1H), 7.78 (d, J=1.8 Hz, 2H), 7.62 (dd, J=8.8, 2.3 Hz, 1H), 6.95 (br. s., 1H), 6.60 (d, J=8.8 Hz, 1H), 5.06 (dt, J=13.6, 2.8 Hz, 1H), 4.43 (dd, J=10.4, 3.3 Hz, 1H), 3.70 (br. s., 4H), 3.45 (br. s., 2H), 3.15 (td, J=12.9, 2.3 Hz, 1H), 3.00 (td, J=12.8, 2.8 Hz, 1H), 2.78-2.94 (m, 2H), 2.54 (br. s., 4H), 2.40 (dd, J=13.6, 1.5 Hz, 1H). [M+H] calc'd for C21H23N7OS, 422; found, 422.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[NH:6][CH:7]=[C:8]([I:10])[CH:9]=1)=[O:4].[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][C:3]([C:5]1[NH:6][CH:7]=[C:8]([I:10])[CH:9]=1)=[O:4]
Reactant: O=C(c1cc(I)c[nH]1)C(Cl)(Cl)Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(I)c[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
2,2,2-Trichloro-1-(4-iodo-1H-pyrrol-2-yl)-ethanone 57c (47 g, 136 mmol) was dissolved in 265 mL of methanol followed by dropwise addition of a solution of sodium methoxide (17.23 g, 163 mmol) in 200 mL of methanol. The reaction mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure. The residue was diluted with 20 mL of water and then extracted with ethyl acetate (30 mL×3). The combined organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain the title compound 4-iodo-1H-pyrrole-2-carboxylic acid methyl ester 57d (32.2 g, yield 92.5%) as a grey solid.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=O)[N:9]3CC[C@H:10]3[C:11]3[N:12](C=NC=3/C=C\Cl)[C:6]=2[CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[OH2:33]>CN(C)C=O>[N:12]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]2[C:6]=1[C:5](=[O:33])[CH:4]=[CH:3][CH:2]=2
Reactant: O
Reactant: O=C1c2c(Cl)cccc2-n2cnc(/C=C\Cl)c2[C@@H]2CCN12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=c1cccc2cnccnc1-2

Procedure:
2.21 g (6.9 mmol) of (S)-8-chloro-1-[(Z)-2-chlorovinyl]-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one was heated to boiling under reflux for 4 hours together with 1.23 ml (8.3 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 30 ml of N,N-dimethylformamide. The reaction mixture was subsequently poured into 300 ml of water and extracted five times with methylene chloride. The organic extracts were washed four times with water, dried over magnesium sulphate and evaporated. After chromatography on silica gel while eluting with ethyl acetate and subsequent recrystallization from ethyl acetate there was obtained (S)-8-chloro-1-ethynyl-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4benzodiazepin-9-one of melting point 249°-250°.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2)(=[O:4])=[O:3].[C:19](=O)([O-])[O-].[K+].[K+].IC>C1COCC1>[CH3:19][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[C:6]1[CH:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2
Reactant: COC(=O)c1cc(NS(C)(=O)=O)c2cc[nH]c2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)c1cc(N(C)S(C)(=O)=O)c2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.2 %

Procedure:
To a mixture of Methyl 4-[(methylsulfonyl)amino]-1H -indole-6-carboxylate (0.6 g) in THF (10 mL) was added potassium carbonate (0.309 g) and iodomethane (0.63 mL). The mixture was stirred at room temperature for 4 h then heated to 40° C. overnight. Iodomethane (0.3 mL) was added and the mixture heated an additional 3 h. The mixture was cooled to room temperature, partitioned between water and diethyl ether, dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in ether and decolorizing carbon (2 g) was added and the mixture refluxed for 5 minutes then filtered through celite while hot. The ether was removed under reduced pressure to give 0.437 g of the title compound: MS (ESI+) for C12 H14 N2 O4 Si m/z 321.1 (M+K).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[C:24]([O:25][CH3:26])=[CH:23][C:22]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([CH3:34])[CH:28]=3)=[C:21]([F:35])[CH:20]=1)[C:14](=[O:36])[CH2:13][NH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CN(C=O)C.[O-2].[O-2].[Mn+4]>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[C:24]([O:25][CH3:26])=[CH:23][C:22]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([CH3:34])[CH:28]=3)=[C:21]([F:35])[CH:20]=1)[C:14](=[O:36])[CH:13]=[N:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2ccc(Cl)c(C)c2)c(F)cc1N1C(=O)CNc2cc(SCc3ccccc3)ccc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: CN(C)C=O
Product: COc1cc(-c2ccc(Cl)c(C)c2)c(F)cc1-n1c(=O)cnc2cc(SCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.9 %

Procedure:
A mixture of 6-(benzylthio)-1-(4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)-3,4-dihydroquinoxalin-2(1H)-one (1.43 g, 2.76 mmol), and manganese dioxide (0.095 ml, 5.51 mmol) in DMF (13.78 ml) was stirred at room temperature for 4 hour. The reaction mixture was filtered through Celite, washed with methanol and the solvent was removed. The residue was purified using Biotage, eluting with a 0-50% ethyl acetate in hexane gradient, to afford 6-(benzylthio)-1-(4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)quinoxalin-2(1H)-one (0.897 g, 1.735 mmol, 63.0% yield). m/z (ESI) 518.2 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:2]#[C:1][C:3]2[N:4]=[CH:5][N:6]3[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:28]=1
Reactant: Brc1cccnc1
Reactant: C#Cc1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3cnc(C#Cc4cccnc4)c3n2)cc1

Procedure:
The title compound was prepared from 8-ethynyl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (example C.18) (130 mg, 0.37 mmol) and commercially available 3-bromo-pyridine (58 mg, 0.37 mmol) according to general procedure II. Obtained as a dark red solid (54 mg, 34%). MS (ISP) 433.0 [(M+H)+]; mp 199° C.
Reaction SMILES: CC1C=C(C)C=C(C)C=1O.[H-].[Na+].[Cl:13][C:14]1[C:19](C)=[C:18]([Cl:21])[CH:17]=[C:16]([CH3:22])[N+:15]=1[O-:23]>C1COCC1>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:21])[CH:17]=[C:16]([CH3:22])[N+:15]=1[O-:23]
Reactant: Cc1c(Cl)cc(C)[n+]([O-])c1Cl
Agent: Cc1cc(C)c(O)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(Cl)[n+]1[O-]
Yield: 147.7 %

Procedure:
To a solution of 2,4,6-trimethylphenol (415 mg, 3.05 mmol) in dry THF (20 ml) was treated with 60% sodium hydride in oil (122 mg, 3.05 mmol) at room temperature. After all H2 was evolved, 2,4-dichloro-3,6-dimethyl-pyridine 1-oxide (585.4 mg, 3.05 mmol) was added and the resulting mixture was heated at reflux for 2 hours. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried and concentrated to dryness to give solid. The solid was recrystallized from pet ether to give 802 mg (90%) of the title compound as white crystals. mp 106107° C. 1H NMR (CDCl3) δ 7.04 (s, 1H), 6.78 (s, 2H), 2.41 (s. 3H). 2.36 (s, 3H), 2.22 (s. 3H), 2.06 (s, 6H) ppm.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[S:8]/[C:9]/1=[N:10]\C(=O)OCC)[CH2:2][CH2:3][CH3:4].I[Si](C)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:16]([N:7]1[CH:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:9](=[NH:10])[S:8]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)OCC
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCc1cn(C(C)(C)C)sc1=N
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a 250-mL, round-bottomed flask containing a magnetic stir bar were added the product from Example 92A (7.11 g, 25.0 mmol) and chloroform (100 mL). Neat iodotrimethylsilane (Aldrich, 6.25 g, 31.1 mmol) was added. A reflux condenser with nitrogen inlet was attached and a heating mantle was applied. The yellow reaction mixture was heated to 60° C. and stirred overnight. After cooling to room temperature, saturated aqueous sodium bicarbonate solution was added. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated by rotary evaporator to give a yellow semi-solid. The product was purified by flash chromatography (silica get: 30-90% ethyl acetate in hexanes) to afford the title compound. LC-MS (ESI+) m/z 213 (M+H)+
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:16][C:15](=[O:17])[C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCC)C>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH:12][C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:17])=[O:16])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2nc3ccccc3c(=O)o2)cc1
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccccc2)cc1
Yield: 8.9 %

Procedure:
To a stirred solution of 2-(4-tert-butylphenyl)-4H-3,1-benzoxazin-4-one (1.0 g, 3.6 mmol) in toluene (15 mL) was added aniline (0.33 g, 3.6 mmol). After refluxing for 8 h, the solution was allowed to cool, diethyl ether was added, and the precipitate was filtered and dried In vacuo to give 120 mg (9%) of the title compound as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C(S[C:15](=[O:28])[CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:17](=[O:19])[CH3:18])(C)(C)C>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][CH:16]([C:17](=[O:19])[CH3:18])[C:15]([NH:1][C:2]2[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=2[Cl:8])=[O:28])=[CH:26][CH:25]=1
Reactant: Nc1cc(O)ccc1Cl
Reactant: CC(=O)C(Cc1ccc(Cl)cc1)C(=O)SC(C)(C)C
Product: CC(=O)C(Cc1ccc(Cl)cc1)C(=O)Nc1cc(O)ccc1Cl

Procedure:
The title compound was prepared by the method of Preparation 34b using 3-amino-4-chlorophenol and 2-(4-chlorobenzyl)-3-oxothiobutyric acid S-tert-butyl ester.
Reaction SMILES: [CH2:1]([NH2:17])[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].Cl[CH2:19][CH2:20][O:21][CH2:22][CH2:23][OH:24].[OH-].[K+].C(O)C>C(O)C>[OH:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][NH:17][CH2:1][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: CCCCCCCCCCCCCCCCN
Reactant: OCCOCCCl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCNCCOCCO
Temperature: 25 °C
Yield: 70 %

Procedure:
Into a 1 l rounded-flask, were introduced 48.2 g of hexadecyl amine and 700 ml of ethanol. The mixture was heated to reflux, and then was gradually added 11 ml of 2-(2-chloroethoxy)ethanol. The mixture was refluxed for 3 hours and cooled to a room temperature. Thereto was added solution of KOH/ethanol to produce precipitates, which were removed by filtration. The filtrate was concentrated under reduced pressure, and then was recrystallized from ethanol, and dried to give 24.1 g of the title compound(Yield: 70%) as white powder, which was identified by IR and NMR. The results are shown in Table 1.