Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([Cl:11])[N:3]=1.FC(F)(F)C(O)=O.[NH2:19][CH2:20][CH2:21][NH:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][N:24]=1.CCN(C(C)C)C(C)C.O>CC(O)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:19][CH2:20][CH2:21][NH:22][C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][N:24]=2)[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[CH:5]=1
Reactant: N#Cc1ccc(NCCN)nc1
Reactant: Clc1cc2ncnn2c(Cl)n1
Solvent: O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(NCCNc2nc(Cl)cc3ncnn23)nc1
Temperature: 80 °C

Procedure:
707 mg (3.20 mmol) of 5,7-dichloroimidazo[1,2-c]pyrimidine (Example 53A) are suspended in 25 ml of 2-propanol, and 1.35 g (3.52 mmol) of 6-[(2-aminoethyl)amino]nicotinonitrile trifluoroacetate (Example 13A) and 1.03 g (7.99 mmol) of DIPEA are added. The mixture is heated at 80° C. for 16 h. After this time, water is added and the precipitate which separates out is filtered off with suction. It is washed with a little 2-propanol/water, and the resulting solid is dried under high vacuum. 523 mg (50% of theory) of the product is obtained as a solid.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH:16]([O:18][CH2:19][CH3:20])[C:15]2[C:10](=[CH:11][C:12]([O:29][CH3:30])=[C:13]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.CO.C(Cl)(=O)C.C(Cl)Cl>C1COCC1.C(OCC)(=O)C.CO>[CH2:22]([O:21][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[O:29][CH3:30])[CH2:9][NH:8][CH2:17][CH:16]2[O:18][CH2:19][CH3:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC1CN(C(=O)OC(C)(C)C)Cc2cc(OC)c(OCc3ccccc3)cc21
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC(=O)Cl
Product: CCOC1CNCc2cc(OC)c(OCc3ccccc3)cc21
Temperature: 25 °C
Yield: 42 %

Procedure:
6-Benzyloxy-4-ethoxy-7-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (4.7 g, 11.4 mmol) was stirred in THF (50 mL) and methanol (5 mL) and cooled to 0° C. before acetyl chloride (2 mL, 28 mmol) was added drop wise. The solution was stirred at rt for an o/n. After addition of DCM (100 mL) the organic layer was washed with a solution of saturated aqueous NaHCO3, water, brine, dried (MgSO4), filtered and concentrated to afford 3.6 g of crude product. Column chromatography (petroleum ether/ethyl acetate 9/1 to 0/1 then ethyl acetate/methanol 1/0 to 10/1) afford 1.5 g (42%) of 6-Benzyloxy-4-ethoxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline F15 and 6-benzyloxy-7-methoxyisoquinoline F16 (0.7 g, 23%). F15 white powder, m.p. 55-56° C., 1H NMR (270 MHz, CDCl3) δ 1.16 (3H, t, J=6.9 Hz), 2.10 (1H, br), 2.91 (1H, dd, J=13.8 and 2.8 Hz), 3.29 (1H, dd, J=13.8 and 2.5 Hz), 3.37-3.61 (2H, m), 3.84 (3H, s), 3.87-3.95 (2H, m), 4.00-4.06 (1H, m), 5.14 (2H, s), 6.53 (1H, s), 6.78 (1H, s), 7.26-7.44 (5H, m). HRMS (ES) calcd. for C19H24NO3 (MH+), 314.1751 found 314.1744. HPLC: tr=4.16 (95.8%) CH3CN/H2O 90/10.
Reaction SMILES: C1C2C(=CC=CC=2)CC1C(O)=O.[CH3:13][C@@H:14]1[NH:19][CH2:18][CH2:17][N:16]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)[CH2:15]1.C[O:32][C:33]([CH:35]1[CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][C:41]=2[S:44](Cl)(=[O:46])=[O:45])[CH2:36]1)=[O:34]>>[CH3:13][C@H:14]1[CH2:15][N:16]([C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]([F:30])([F:28])[F:29])=[CH:24][CH:25]=2)[CH2:17][CH2:18][N:19]1[S:44]([C:41]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:42]=1[CH2:43][CH:35]([C:33]([OH:34])=[O:32])[CH2:36]2)(=[O:46])=[O:45]
Reactant: C[C@H]1CN(c2ccc(OC(F)(F)F)cc2)CCN1
Reactant: COC(=O)C1Cc2cccc(S(=O)(=O)Cl)c2C1
Agent: O=C(O)C1Cc2ccccc2C1
Product: C[C@H]1CN(c2ccc(OC(F)(F)F)cc2)CCN1S(=O)(=O)c1cccc2c1CC(C(=O)O)C2

Procedure:
4-|2-(S)-Methyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl|-indan-2-carboxylic acid. The compound 4-[2-(S)-Methyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid was prepared from 3-(S)-methyl-1-(4-trifluoromethoxy-phenyl)-piperazine and 4-chlorosulfonyl-indan-2-carboxylic acid methyl ester following the procedure outlined in Example 79. 1H NMR (400 MHz, DMSO-d6): δ 7.65 (d, 1H), 7.53 (d, 1H), 7.38 (t, 1H), 7.18 (d, 2H), 6.98-6.92 (m, 2H), 4.15-4.00 (m, 1H), 3.60-3.12 (m, 9H), 2.83-2.75 (m, 1H), 2.64-2.50 (m, 1H), 1.18 (d, 3H); MS (ESI): 485.3 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C@H:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16][CH2:15]3)=[C:5]([O:29][CH3:30])[CH:4]=1)#[N:2].[SH2:31].C(NCC)C>CN(C=O)C>[NH2:2][C:1]([C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C@H:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16][CH2:15]3)=[C:5]([O:29][CH3:30])[CH:4]=1)=[S:31]
Reactant: S
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C#N)cc3OC)ccc21
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C(N)=S)cc3OC)ccc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
Into a solution of ethyl {(1S-5-[3-(4-cyano-2-methoxyphenoxy)propoxy]-2,3-dihydro-1H-inden-1-yl}acetate (2.2 g, 5.4 mmol) (Example 145) in DMF (anhydrous, 20 mL) under argon at rt was passed H2S gas at a moderate rate for 30 min. A solution of diethylamine (0.8 g, 8.1 mmol) in DMF (5 mL) was added in one portion, and the reaction was stirred at 60° C. for 3 h. Then the reaction was cooled to rt and argon was passed through the reaction mixture for 1 h to remove residual H2S. The reaction mixture was then concentrated under reduced pressure and the residue purified by silica gel flash chromatography (EtOAc/Hexane (v/v)=1:1) to afford 1.9 g (81%) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 1.21 (t, 3H), 1.60-1.68 (m, 1H), 2.15-2.22 (m, 2H), 2.23-2.34 (m, 1H), 2.38 (q, 1H), 2.70-2.86 (m, 3H), 3.38-3.44 (m, 1H), 3.80 (s, 3H), 4.05-4.16 (m, 4H), 4.19 (t, 2H), 6.70 (d, 1H), 6.80 (s, 1H), 6.97 (d, 1H), 7.06 (d, 1H), 7.56-7.64 (m, 2H), 9.33-9.40 (s, 1H), 9.65 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH:5](Br)[CH3:6])[CH3:2].[N:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:8])[CH:5]([O:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:9]=[CH:10][CH:11]=[CH:12]2)[CH3:6])[CH3:2]
Reactant: Oc1ccc2ncccc2c1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc2ncccc2c1
Temperature: 90 °C
Yield: 80.1 %

Procedure:
A mixture of 2-bromo-propionic acid ethyl ester (14.6 mL, 0.112 mol), quinolin-6-ol (16.3 g, 0.112 mol) and Cs2CO3 (44 g, 0.135 mol) in 500 mL of DMF was heated to 90° C. for overnight. The mixture was filtered and diluted with Et2O (500 mL). Organic layer was washed with water and brine. The combined aqueous layer was then extracted with EtOAc. Combined organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated. Crude material was purified by chromatography (Rf=0.3 in hexanes/acetone=1:1) to give 22 g of title compound as light yellow oil. 1H NMR (400 MHz, CDCl3) δδ8.78 (dd, 1H, J=4.0, 0.8 Hz), 8.02 (d, 1H, J=8.8 Hz), 8.01 (d, 1H, J=8.0 Hz), 7.42 (dd, 1H, J=9.4, 3.0 Hz), 7.35 (dd, 1H, J=8.6, 4.2 Hz), 7.26 (d, 1H, J=1.2 Hz), 6.99 (d, 1H, J=2.8 Hz), 4.89 (q, 1H, J=6.8 Hz), 4.27-4.20 (m, 2H), 1.69 (d, 3H, J=6.8 Hz), 1.24 (t, 3H, J=6.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=1)[C:8]([C@@H:19]([NH2:21])[CH3:20])=[CH:7]2.C(O)CCC.Br[C:28]1[N:36]=[CH:35][N:34]=[C:33]2[C:29]=1[NH:30][CH:31]=[N:32]2.C(N(CC)C(C)C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=1)[C:8]([C@@H:19]([NH:21][C:28]1[N:36]=[CH:35][N:34]=[C:33]3[C:29]=1[N:30]=[CH:31][NH:32]3)[CH3:20])=[CH:7]2
Reactant: Brc1ncnc2nc[nH]c12
Reactant: Cc1cccc(-c2nc3c(Cl)cccc3cc2[C@H](C)N)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cccc(-c2nc3c(Cl)cccc3cc2[C@H](C)Nc2ncnc3[nH]cnc23)n1
Temperature: 110 °C

Procedure:
To a stirred solution of (1S)-1-(8-chloro-2-(6-methylpyridin-2-yl)quinolin-3-yl)-ethanamine (146 mg, 0.49 mmol) in 1-butanol (5.4 mL, 59 mmol) was added 6-bromopurine (0.107 g, 0.54 mmol) and N,N-diisopropylethylamine (0.17 mL, 0.98 mmol) with heating (110° C.) overnight. solvents were removed and the residue subjected to chromatography, gradient, 89:9:1(DCM:MeOH:NH4OH).
Reaction SMILES: [C:1]1(=[C:8]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]C(C)(C)C)=[O:18])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1(=[C:8]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C/c1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 57.9 %

Procedure:
To an ice-water cooled mixture of 1,1-dimethylethyl (2E)-3-{4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoate (10) (4.42 g, 10.9 mmol) and CH2Cl2 (20 mL) was slowly added trifluoroacetic acid (10 mL) with stirring under a nitrogen atmosphere. After 3 h, the reaction mixture was filtered. The filtered solid was washed with CH2Cl2 and dried to give 2.2 g of compound 11 as a white solid. The filtrate was concentrated and the impure product was partially purified by flash chromatography on silica gel with CH2Cl2:MeOH (100:0 to 9:1) to give a yellow solid. The solid was triturated with Et2O and the suspension was filtered. The filtered solid was dried to give a second crop of compound 11 (354 mg) as a pale tan solid. The Et2O filtrate noted above was concentrated in vacuo and the impure product was crystallized from hexanes and EtOAc. The solid was dried to give a third crop of compound 11 (185 mg) as a pale tan solid. The total yield of 11 was 2.74 g (72%). Analytical data for all three batches were comparable. The analytical data is herein presented for the first batch. 1H NMR (400 MHz, DMSO-d6): δ 1.50 (m, 8H), 2.21 (m, 4H), 6.43 (d, J=15.9 Hz, 1H), 6.65 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.5 Hz, 2H), 7.11 (d, J=8.0 Hz, 2H), 7.52 (d, J=16.1 Hz, 1H), 7.57 (d, J=8.0 Hz, 2H), 9.28 (s, 1H), 12.21 (br s, 1H). LRMS (ESI): m/z 347 (M−H)−. Anal. Calcd for C23H24O3: C, 79.28; H, 6.94. Found: C, 79.16; H, 6.97.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[Br-].[Li+].[CH3:17][N:18]1CCCC1=O>>[C:17]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])#[N:18]
Reactant: CN1CCCC1=O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: [Br-]
Agent: [Li+]
Product: N#Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 175 °C
Reaction time: 24 h

Procedure:
In a flask were placed 1.13 grams (g) (5.0 mmol) 4-chloro-3-nitrobenzotrifluoride, 0.4478 g (5.0 mmol) cuprous cyanide, 0.4342 g (5.0 mmol) lithium bromide and 10 milliliters (ml) N-methyl-2-pyrrolidinone, under a nitrogen blanket. The reaction mixture was then heated to a temperature of 175° C. and reaction was continued at a range of 172°-178° C. over a period of 24 hours. At the end of that run, the heat source was removed and the reaction mixture cooled. Product was recovered by washing with water, 3M HCl, diethyl ether, again with 3M HCl, and again with ether. The ether extract was dried over magnesium sulfate, filtered and the solvent stripped, yielding 0.875 g (81% of theoretical yield) of an amber, somewhat tarry looking oil, which was identified by gas chromatographic analysis as the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C@H:9]([NH:20]C(=O)OC(C)(C)C)[C:10]([N:12]2[CH2:16][C@@H:15]([F:17])[CH2:14][C@H:13]2[C:18]#[N:19])=[O:11])=[CH:4][CH:3]=1.[C:35]1([CH3:45])[CH:40]=[CH:39][C:38]([S:41]([OH:44])(=[O:43])=[O:42])=[CH:37][CH:36]=1>C(O)C>[C:35]1([CH3:45])[CH:36]=[CH:37][C:38]([S:41]([OH:44])(=[O:42])=[O:43])=[CH:39][CH:40]=1.[F:17][C@@H:15]1[CH2:16][N:12]([C:10](=[O:11])[C@H:9]([CH:8]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[NH2:20])[C@H:13]([C:18]#[N:19])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1C[C@@H](F)C[C@H]1C#N)C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)[C@@H](N)C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 60 °C
Yield: 70 %

Procedure:
A 10L reactor equipped with overhead stirring was charged with a slurry of tert-Butyl {(1S)-1-[bis(4-fluorophenyl)methyl]-2-[(2S,4S)-2-cyano-4-fluoro-1-pyrrolidinyl]-2-oxoethyl}carbamate (500 g, 1 wt, 1 eq) in ethanol (3.5L, 7 vol). To this solution was added para-toluenesulfonic acid (403g, 0.806 wt, 2 eq). This solution was heated to 60° C., and was allowed to stir at this temperature for 12 hours. The reaction mixture was cooled to 5° C. and was stirred at this temperature for 30 minutes. The solids were collected by filtration, washed with ethanol (2×1 L), and dried to constant weight in a 50° C. vacuum oven. Yield: 70-80% over 2 steps.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:29]([C:28]3[CH:31]=[CH:32][C:25]([Cl:24])=[CH:26][CH:27]=3)=[N:15][C:14]=2[CH:16]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Reactant: O=Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc(-c2nc3cc(-c4nc5ccccc5o4)ccc3n2C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (150 mg, 0.485 mmol) in dimethylformamide (3 mL) was added p-chlorobenzaldehyde (81.8 mg, 0.582 mmol) and oxone (179 mg, 0.291 mmol), and this was stirred at room temperature for 2 hours. After the reaction was complete, aqueous potassium carbonate solution was added, and after this was filtered and washed with water, drying yielded the title compound (188 mg, 90% yield) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(COc2ccc(CN3CCNCC3)cc2)cc1

Procedure:
Synthesized according to General Procedure A: 4-benzyloxybenzyl chloride (4{18}, 3.7 g, 15.9 mmol, 1 equiv.), piperazine (8.22 g, 95.4 mmol, 6 equiv.), THF (55 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{18} (3.84 g, 86%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 7.43 (d, 2H, J=7.0 Hz), 7.38 (t, 2H, J=7.5 Hz), 7.32 (t, 1H, J=7.5 Hz), 7.23 (d, 2H, J=8.5 Hz), 6.93 (d, 2H, J=8.5 Hz), 5.04 (s, 2H), 3.43 (s, 2H), 2.87 (t, 4H, J=5.0 Hz), 2.39 (br s, 4H), 1.59 (br s, 1H). 13C-NMR (125 MHz, CDCl3): δ 157.8, 137.0, 130.3, 128.4, 127.8, 127.3, 114.4, 69.9, 63.0, 54.3, 46.0.
Reaction SMILES: C1(COC2C=CC(S(C)(=O)=O)=CC=2[C:16]2[C:17]3[O:26][C:25]([CH3:27])=[N:24][C:18]=3[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=2)CC1.[F:28][C:29]1[CH:56]=[C:55]([F:57])[CH:54]=[CH:53][C:30]=1[O:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH2:42][CH3:43])(=[O:41])=[O:40])=[CH:34][C:33]=1B1OC(C)(C)C(C)(C)O1>>[F:28][C:29]1[CH:56]=[C:55]([F:57])[CH:54]=[CH:53][C:30]=1[O:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH2:42][CH3:43])(=[O:40])=[O:41])=[CH:34][C:33]=1[C:16]1[C:17]2[O:26][C:25]([CH3:27])=[N:24][C:18]=2[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1
Reactant: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1nc2c(=O)n(C)cc(-c3cc(S(C)(=O)=O)ccc3OCC3CC3)c2o1
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3nc(C)oc23)c1

Procedure:
7-bromo-2,5-dimethyl-[1,3]oxazolo[4,5-c]pyridin-4-one prepared in Example 238 and N-[4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanesulfonamide prepared in Example 240 were reacted in a manner similar to Example 237, step 6 to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (t, J=6.95 Hz, 3H) 2.45 (s, 3H) 3.13 (d, J=7.83 Hz, 2H) 3.58 (s, 3H) 6.95 (d, J=8.59 Hz, 1H) 7.03-7.30 (m, 3H) 7.30-7.48 (m, 2H) 7.91 (s, 1H) 9.86 (s, 1H). LCMS: 476 (M+H)+
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([OH:18])(=[O:17])[CH:14]([CH3:16])[CH3:15].CN(P(N(C)C)(N(C)C)=O)C.[CH2:30]([O:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH2:41]Cl)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>C1COCC1.O>[CH3:15][C:14]([CH3:16])([CH2:41][C:40]1[CH:43]=[CH:44][CH:45]=[C:38]([O:37][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:39]=1)[C:13]([OH:18])=[O:17]
Reactant: ClCc1cccc(OCc2ccccc2)c1
Reactant: CC(C)C(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: CC(C)(Cc1cccc(OCc2ccccc2)c1)C(=O)O
Reaction time: 0.17 h
Yield: 85 %

Procedure:
A solution of diisopropylamine (1.55 mL, 11.9 mmole) in 20 mL of THF was cooled to −78° and treated with n-BuLi (6.5 mL 1.6N solution in hexane, 10.4 mmole). After 10 minutes, a solution of isobutyric acid (436 mg, 4.96 mmole) in 3 mL of THF was added, followed by HMPA (1.74 mL, 10 mmole). The reaction was allowed to warm to 23°, then heated at 55° for 30 minutes. The reaction was cooled to −78° and a solution of 3-benzyloxybenzyl chloride (1.15 g, 4.96 mmole) in 6 mL of THF was added. The reaction was warmed to 23° for 30 minutes, then heated at 55° for 30 minutes. The reaction was cooled, diluted with H2O, acidified with 3N HCl, and extracted with Et2O. The extracts were washed three times with H2O, dried and the solvent removed, and gave the titled compound as a white powder, 1.2 g (85% yield). MS (ESI) 285 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:23]([Cl:24])=[CH:22][C:21]2[C:4](=[CH:5][C:6]3[C:7](=[O:28])[C:8]4[C:17]([C:18](=[O:25])[C:19]=3[CH:20]=2)=[CH:16][C:15]2[C:10](=[CH:11][C:12]([Cl:27])=[C:13]([Cl:26])[CH:14]=2)[CH:9]=4)[CH:3]=1.[BH4-].[Na+]>CO>[OH:28][C@H:7]1[C:8]2[C:17](=[CH:16][C:15]3[C:10]([CH:9]=2)=[CH:11][C:12]([Cl:27])=[C:13]([Cl:26])[CH:14]=3)[C@H:18]([OH:25])[C:19]2[CH:20]=[C:21]3[C:4]([CH:3]=[C:2]([Cl:1])[C:23]([Cl:24])=[CH:22]3)=[CH:5][C:6]1=2
Reactant: O=C1c2cc3cc(Cl)c(Cl)cc3cc2C(=O)c2cc3cc(Cl)c(Cl)cc3cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O[C@H]1c2cc3cc(Cl)c(Cl)cc3cc2[C@H](O)c2cc3cc(Cl)c(Cl)cc3cc21
Temperature: 0 °C
Reaction time: 16 h
Yield: 91.2 %

Procedure:
To a suspension of 2,3,9,10-tetrachloro-6,13-pentacenequinone (1.0 g, 2.24 mmol) in dry MeOH (40 mL) at 0° C. under an argon atmosphere was slowly added NaBH4 (0.85 g, 22.47 mmol). The reaction mixture was stirred at 0° C. for 0.5 h and at RT for 16 h, and then quenched with H2O at 0° C. The resulting mixture was filtered and washed with H2O and dried in vacuo to give product as a brown solids (0.92 g, 90%) which was identified as mixture of two isomers. 1H NMR (500 MHz, DMSO-d6): δ 8.36 (s, 4H), 8.16 (s, 4H), 6.82 (d, 2H), 5.82 (d, 2H). 1H NMR (500 MHz, DMSO-d6): δ 8.35 (s, 4H), 8.13 (s, 4H), 6.30 (d, 2H), 5.99 (d, 2H). LDI-MS m/z: 449.96[M+], 431[M+-OH], 415.97 [M+-2(OH)].
Reaction SMILES: ClC(SS[C:7]([O:28][CH2:29][C:30]([F:37])([N+:34]([O-:36])=[O:35])[N+:31]([O-:33])=[O:32])([O:18][CH2:19][C:20]([N+:25]([O-:27])=[O:26])([N+:22]([O-:24])=[O:23])[F:21])[O:8][CH2:9][C:10]([N+:15]([O-:17])=[O:16])([N+:12]([O-:14])=[O:13])[F:11])(Cl)Cl.ClCl.[NH:40]1[CH2:44][CH2:43][NH:42][C:41]1=[O:45].ClC(Cl)C.[K+].[Br-]>ClCCCl.O.C(Cl)(Cl)Cl>[F:11][C:10]([N+:15]([O-:17])=[O:16])([N+:12]([O-:14])=[O:13])[CH2:9][O:8][C:7]([O:28][CH2:29][C:30]([N+:34]([O-:36])=[O:35])([N+:31]([O-:33])=[O:32])[F:37])([O:18][CH2:19][C:20]([N+:25]([O-:27])=[O:26])([N+:22]([O-:24])=[O:23])[F:21])[N:40]1[CH2:44][CH2:43][NH:42][C:41]1=[O:45]
Reactant: O=C1NCCN1
Reactant: O=[N+]([O-])C(F)(COC(OCC(F)([N+](=O)[O-])[N+](=O)[O-])(OCC(F)([N+](=O)[O-])[N+](=O)[O-])SSC(Cl)(Cl)Cl)[N+](=O)[O-]
Agent: ClCl
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Solvent: O
Product: O=C1NCCN1C(OCC(F)([N+](=O)[O-])[N+](=O)[O-])(OCC(F)([N+](=O)[O-])[N+](=O)[O-])OCC(F)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 19.6 g (0.03 mol) of tris(2-fluoro-2,2-dinitroethoxy)methyl trichloromethyl disulfide in 55 ml of dry 1,2-dichloroethane at 55°-60° C. was treated with chlorine gas for 2 hours, then held at 55°-60° C. for 2 hours before the solvent was removed with a stream of nitrogen. The residue was washed three times with hexane to give a white solid which was dissolved in 60 ml of dry 1,2-dichloroethane. 2-Imidazolidone (6.0 g, 0.069 mol) was added and the mixture was stirred at ambient temperature for 24 hours before the insoluble solid was removed by filtration and stirred with water to give 11.63 g, mp 154°-156° C. Removal of the solvent from the dichloroethane mother liquor (reaction solution) gave a residue which was stirred with chloroform and water to yield an additional 1.12 g, mp 152°-155° C. [total yield=12.75 g (76%)]. The analytical sample from dichloroethane had mp 155°-156° C.; H--NMR(C6D6): δ 4.46 (d, 6H); 4.00 (s, 1H), 2.66 (t, 2H), 2.20 (t, 2H); IR (KBr): 3480 (NH), 1725 (C=O), 1605 (NO2) cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.C([Li])CCC.[O:16]1[CH2:20][CH2:19]OS1(=O)=O.C(=O)=O.Cl.CC1CCCO1>C1COCC1>[Cl:1][C:2]1[C:7]([CH2:19][CH2:20][OH:16])=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: O=S1(=O)OCCO1
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC1CCCO1
Solvent: C1CCOC1
Product: CSc1nc(Cl)c(CCO)c(Cl)n1
Reaction time: 0.5 h
Yield: 758.5 %

Procedure:
To a vial containing 4,6-dichloro-2-(methylsulfanyl)pyrimidine (200 mg, 0.102 mmol) in THF (10 mL) was added n-butyllithium (0.554 mL, 1.38 mmol, 2.5 M in hexane) at −78° C. and the resulting mixture was stirred for 30 min. 1,3,2-dioxathiolane 2,2-dioxide (172 mg, 1.39 mmol) was added at −78° C. and stirring was continued for 2 h. The reaction vial was removed from the dry ice bath, 6 N HCl (3.5 mL, 21 mmol) was added, and the mixture was stirred at room temperature for 18 h. 2-Methyltetrahydrofuran (20 mL) was added and the solution was washed with a 1:1 mixture of brine/water and then with saturated aqueous NaHCO3. The organic layer was dried over Na2SO4, filtered, concentrated and purified via silica gel chromatography using a gradient of EtOAC/heptane (30-50%) to give the title compound (185 mg, 76% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 4.84 (t, J=5.4 Hz, 1 H), 3.61 (q, J=6.3 Hz, 2 H), 2.93 (t, J=6.8 Hz, 2 H), 2.52 (s, 3 H). m/z (APCI+) for C7H8Cl2N2OS 239.0 (M+H)+.