Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1)=[O:6].C[O:23][C:24](=[O:39])[C:25]([CH3:38])([CH3:37])[CH2:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([CH:34]=O)=[C:29]([CH3:36])[CH:28]=1>>[CH3:36][C:29]1[CH:28]=[C:27]([CH2:26][C:25]([CH3:38])([CH3:37])[C:24]([OH:39])=[O:23])[CH:32]=[C:31]([CH3:33])[C:30]=1[C:34]1[NH:21][C:20]2[CH:19]=[CH:18][C:4]([C:5](=[O:6])[NH:7][C:8]3[CH:9]=[N:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=3)=[CH:3][C:2]=2[N:1]=1
Reactant: COC(=O)C(C)(C)Cc1cc(C)c(C=O)c(C)c1
Reactant: Nc1ccc(C(=O)Nc2ccc(C(F)(F)F)nc2)cc1N
Product: Cc1cc(CC(C)(C)C(=O)O)cc(C)c1-c1nc2cc(C(=O)Nc3ccc(C(F)(F)F)nc3)ccc2[nH]1

Procedure:
The title compound was prepared from 3,4-diamino-N-(6-trifluoromethylpyridin-3-yl)-benzamide (from Example 6-36) and 3-(4-formyl-3,5-dimethylphenyl)-2,2-dimethylpropionic acid methyl ester analogous to Example 6-29. 1N NMR (400 MHz, MeOD): δ 9.20 (s, 1H), 8.68 (d, 1H), 8.43 (s, 1H), 8.10 (d, 1H), 7.98 (d, 1H), 7.85 (d, 1H), 7.19 (s, 2H), 3.00 (s, 2H), 2.27 (s, 6H), 1.29 (s, 6H). MS (m/z) 511.2 (M+1); Retention time: 1.20 min (Method 10).
Reaction SMILES: C1([C@@H](C)C([NH:10][C@@H:11]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@H:12]2[OH:21])=O)C=CC=CC=1.[ClH:23]>>[ClH:23].[NH2:10][C@@H:11]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][C@H:12]1[OH:21]
Reactant: C[C@@H](C(=O)N[C@@H]1Cc2ccccc2C[C@H]1O)c1ccccc1
Agent: Cl
Product: N[C@@H]1Cc2ccccc2C[C@H]1O

Procedure:
Trans-N-[(2R)-2-phenylpropanoyl]-3-amino-1,2,3,4-tetrahydro-2-naphthalenol, diastereoisomer A (183 mg) was refluxed in 6N aqueous hydrochloric acid (20 ml) for 4 hours. The reaction mixture was evaporated in vacuo and the residue taken up in water. The aqueous solution was washed with ethyl acetate and evaporated to give a white solid which was recrystallized from a methanol/ethyl acetate mixture to yield the title compound (99 mg).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:15][CH2:16][O:17]C)=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7](O)=[O:8])[CH:2]=[CH2:3].[C:19](N1C=CN=C1)([N:21]1C=CN=C1)=O.CN.Cl>O1CCCC1>[CH2:1]([C:4]1[C:5]2[O:15][C:16](=[O:17])[N:21]([CH3:19])[C:7](=[O:8])[C:6]=2[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:2]=[CH2:3]
Reactant: C=CCc1c(OC)ccc(C(=O)O)c1OCOC
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Product: C=CCc1c(OC)ccc2c(=O)n(C)c(=O)oc12
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 82.5 %

Procedure:
1.20 g of 3-allyl-4-methoxy-2-(methoxymethoxy)benzoic acid was dissolved in 15 ml of anhydrous tetrahydrofuran, and 0.84 g of 1,1′-carbonyldiimidazole was then added thereto. The obtained mixture was stirred at room temperature under nitrogen atmosphere for 25 minutes. Thereafter, 11.8 ml of methylamine (a 2.0 M tetrahydrofuran solution) was added to the reaction solution, and the obtained mixture was then stirred at room temperature for approximately 5 hours. Thereafter, the reaction mixture was cooled on ice, and 2.5 ml of concentrated hydrochloric acid was added thereto. The obtained mixture was stirred at room temperature for 15 minutes. The reaction solution was extracted with ethyl acetate. The organic layer was washed with water 3 times and then washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride solution. The resultant product was then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. 20 ml of anhydrous tetrahydrofuran was added to the obtained residue, and then, 1.53 g of 1,1′-carbonyldiimidazole was added thereto. The reaction mixture was heated to reflux under nitrogen atmosphere for approximately 2 hours. The reaction solution was cooled to a room temperature, and the solvent was then removed under a reduced pressure. Ethyl acetate and water were added to the residue, so as to separate an organic layer. The obtained organic layer was washed with water twice and then with a saturated sodium chloride solution. The resultant product was then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was reprecipitated from ethyl acetate-n-hexane, so as to obtain 0.97 g of the subject compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)[NH:48]C1(C2C=CC(C3C(=O)C4C(=C(Br)C=CC=4)OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C.O=C1CNCCN1>>[C:1]([O:5][C:6](=[O:41])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([N:29]5[CH2:30][CH2:31][NH:48][C:33](=[O:32])[CH2:34]5)[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Br)cccc4c3=O)cc2)CCC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(N5CCOCC5)cccc4c3=O)cc2)CCC1
Agent: O=C1CNCCN1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(N5CCNC(=O)C5)cccc4c3=O)cc2)CCC1
Yield: 64 %

Procedure:
Following the procedure of {1-[4-(8-morpholin-4-yl-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, {1-[4-(8-bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted with 2-oxopiperazine to give the title compound as a white solid (35 mg, 64%). LCMS (Method G): RT=3.45 min, [M+H]+=566.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:8]
Reactant: Nc1ccccc1
Reactant: COc1cc(C(=O)O)ccn1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cc(C(=O)Nc2ccccc2)ccn1
Temperature: 0 °C
Reaction time: 6 h
Yield: 83.9 %

Procedure:
To a solution of 2-methoxyisonicotinic acid (2.00 g, 13.06 mmol) in anhydrous tetrahydrofuran (80 mL) was added 4-methyl morpholine (1.84 g, 18.28 mmol). After cooling to 0° C., isobutyl chloroformate (2.31 g, 16.98 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 6 hours, followed by the addition of aniline (1.70 g, 18.28 mmol). The resulting mixture was stirred at ambient temperature for 16 hours. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (150 mL) and washed with saturated aqueous sodium bicarbonate (2×50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo to afford 2-methoxy-N-phenylisonicotinamide (2.50 g, 86%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 11.85 (s, 1H), 10.31 (s, 1H), 7.75-7.60 (m, 2H), 7.47 (d, J=4.6 Hz, 1H), 7.35-7.20 (m, 2H), 7.12-7.04 (m, 1H), 6.83-6.80 (m, 1H), 6.54-6.42 (m, 1H); MS (ES+) m/z 229.2 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[NH2:16][C:17]1[CH:38]=[CH:37][C:20]([CH2:21][O:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[CH2:29][CH:28]([CH2:33][N:34]([CH3:36])[CH3:35])[CH2:27][CH2:26]3)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[C:1]([NH:16][C:17]1[CH:38]=[CH:37][C:20]([CH2:21][O:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[CH2:29][CH:28]([CH2:33][N:34]([CH3:35])[CH3:36])[CH2:27][CH2:26]3)=[CH:19][CH:18]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CC1CCc2cc(OCc3ccc(N)cc3)ccc2C1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CN(C)CC1CCc2cc(OCc3ccc(NC(=O)c4ccccc4)cc3)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Benzoyl chloride (0.14 ml) was added dropwise to pyridine solution (6 ml) of 6-[(4-aminobenzyl)oxy]-2-[(N,N-dimethylamino)methyl]tetralin (300 mg) under ice-cooling, which was stirred at room temperature for 30 minutes. 10% aqueous potassium carbonate solution was added to the reaction mixture, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was purified using alumina column chromatography (development solvent; ethyl acetate), and recrystallized (THF-IPE) to give the titled compound (240 mg).
Reaction SMILES: C([O:5][CH2:6][C@H:7]1[CH2:11][O:10][C:9](=[N:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][N:17]=[C:16]3[NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][O:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[C:26]([Cl:39])[CH:25]=2)[N:8]1[CH3:40])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.ClCCCl>[Cl:39][C:26]1[CH:25]=[C:24]([NH:23][C:16]2[C:15]3[C:20](=[CH:21][CH:22]=[C:13]([N:12]=[C:9]4[N:8]([CH3:40])[C@@H:7]([CH2:6][OH:5])[CH2:11][O:10]4)[CH:14]=3)[N:19]=[CH:18][N:17]=2)[CH:29]=[CH:28][C:27]=1[CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1
Reactant: CN1C(=Nc2ccc3ncnc(Nc4ccc(COc5cccc(F)c5)c(Cl)c4)c3c2)OC[C@@H]1COC(C)(C)C
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=Nc2ccc3ncnc(Nc4ccc(COc5cccc(F)c5)c(Cl)c4)c3c2)OC[C@@H]1CO
Temperature: 0 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
(S)-(2-{4-[3-Chloro-4-(3-fluoro-phenoxymethyl)-phenylamino]-quinazolin-6-ylimino}-3-methyl-oxazolidin-4-yl)-methanol is prepared from (S)—N6-(4-tert-butoxymethyl-3-methyl-oxazolidin-2-ylidene)-N4-[3-chloro-4-(3-fluoro-phenoxymethyl)-phenyl]-quinazoline-4,6-diamine. TFA (1 ml) is added to (S)—N6-(4-tert-butoxymethyl-3-methyl-oxazolidin-2-ylidene)-N4-[3-chloro-4-(3-fluoro-phenoxymethyl)-phenyl]-quinazoline-4,6-diamine (0.104 g, 0.184 mmol) in 1 ml methylene chloride at 0° C. After stirring for 2 hours at 0° C. and 3 hours at room temperature, the reaction mixture is diluted with 1,2-dichloroethane and concentrated. The residue is diluted with methylene chloride and washed with 10% Na2CO3. The aqueous layer is extracted with methylene chloride, and the combined organic extracts dried (Na2SO4) and concentrated to give 60 mg (64%) pure desired product. MS ESI (+) m/z 508, 510 (M+1, Cl pattern) detected; 1H NMR (400 MHz, CDCl3) δ 8.7 (s, 1H), 8.1 (s, 1H), 7.8-7.4 (m, 6H), 7.2 (m, 1H), 6.8-6.7 (m, 3H), 5.1 (s, 2H), 4.5 (m, 2H), 4.0 (dd, 1H, J=13, 3.9 Hz), 3.9 (m, 1H), 3.8 (br d, 1H, J=13.0 Hz), 3.1 (s, 3H).
Reaction SMILES: B.CSC.[Cl:5][C:6]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12]>O1CCCC1>[Cl:5][C:6]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[OH:12]
Reactant: CCOC(=O)C1(Cl)CCCCC1=O
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cl)CCCCC1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
First, ethyl 1-chloro-2-oxocyclohexanecarboxylate was prepared from ethyl 2-oxocyclohexanecarboxylate referring to the process described in Organic Synthesis volume 4, page 162. 17 g (0.1 mol) of ethyl 2-oxocyclohexanecarboxylate was dissolved in 50 ml of carbon tetrachloride, and to the solution was added dropwise 14.8 g (0.11 mol) of sulfuryl chloride dissolved in 15 ml of carbon tetrachloride at 0° C. After stirring at room temperature for 2 hours, the reaction solution was poured into 100 ml of ice water, the mixture was extracted three times with 50 ml each of carbon tetrachloride, and the extract was washed twice with 75 ml each of saturated aqueous sodium bicarbonate and once with 75 ml of saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled away to obtain 18 g (yield: 88%) of ethyl 1-chloro-2-oxocyclohexanecarboxylate. 1.22 ml (2 mmol) of dimethyl sulfide borane was dissolved in 40 ml of tetrahydrofuran, and 2.5 g (12 mmol) of ethyl 1-chloro-2-oxocyclohexanecarboxylate was added dropwise at -5° C. to 0° C. After stirring at 0° C. for 1 hour, the solvent was distilled away under reduced pressure and the reaction solution was poured into 50 ml of ice water. The mixture was extracted three times with 50 ml each of ethyl acetate, and the resulting organic layer was washed once with 75 ml of saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled away to obtain 2.2 g of a stereoisomer mixture of ethyl 1-chloro-2-hydroxy-1-cyclohexanecarboxylate.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:24])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>[C].[Pd]>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:24])=[CH:17][CH:18]=1
Reactant: COc1ccc(NC(=O)N2CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Product: COc1ccc(NC(=O)N2CCNCC2)cc1
Yield: 81.7 %

Procedure:
Suspension of 3.25 g. (10 mmole) of N-benzyl-N'-(4-methoxyphenylcarbamoyl)piperazine and 0.10 g. of 5%-palladium-carbon was stirred under hydrogen at 60° C. for 7 hours. After the catalyst was filtered off, ethanol was evaporated under reduced pressure to give 1.92 g. of the desired product as oily substance.
Reaction SMILES: [NH3:1].Cl[C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:5]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:4]=1>C(O)C>[NH2:1][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:5]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:4]=1
Reactant: N#Cc1cc(-c2ccncc2)c(-c2ccco2)nc1Cl
Reactant: N
Solvent: CCO
Product: N#Cc1cc(-c2ccncc2)c(-c2ccco2)nc1N
Temperature: 100 °C
Reaction time: 24 h
Yield: 27 %

Procedure:
A solution of ammonia in ethanol, 30 ml, (ethanol saturated at 0° C. with an ammonia gas) was added to 2-chloro-6-(2-furyl)-5-(4-pyridyl)-3-pyridinecarbonitrile (200 mg, 0.710 mmol). Then, it was sealed in a stainless steel autoclave, and heated under stirring at 100° C. After 24 hours, the reaction solution was cooled as it was and concentrated. The residue was subjected to silica gel column chromatography (elution solvent; hexane, hexane:ethyl acetate=2:1, 1:1, 1:2), and then suspended in diethyl ether. The resulting precipitates were collected by filtration and washed with diethyl ether, to give the title compound (50 mg, 27%) as a pale orange solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[S:13][C:14]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[F:21][C:18]1[CH:19]=[CH:20][C:14]2[S:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][C:15]=2[CH:17]=1
Reactant: C#CCCc1nc2cc(F)ccc2s1
Reactant: Brc1ccccn1
Product: Fc1ccc2sc(CCC#Cc3ccccn3)nc2c1
Yield: 9.4 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (220 mg, 1.39 mmol) and 2-but-3-ynyl-5-fluoro-benzo[d]thiazole (286 mg, 1.39 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 38 mg (0.13 mmol, 10%) of 5-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as an orange solid.
Reaction SMILES: C([O:4][C:5]([CH3:28])([CH3:27])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][CH2:16][C:17]1[C:25]([Cl:26])=[CH:24][C:20]2[O:21][CH2:22][O:23][C:19]=2[CH:18]=1)=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:26][C:25]1[C:17]([CH2:16][S:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:6](=[O:7])[C:5]([OH:4])([CH3:27])[CH3:28])=[CH:18][C:19]2[O:23][CH2:22][O:21][C:20]=2[CH:24]=1
Reactant: CC(=O)OC(C)(C)C(=O)Nc1ccccc1SCc1cc2c(cc1Cl)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(O)C(=O)Nc1ccccc1SCc1cc2c(cc1Cl)OCO2

Procedure:
The material from Example 20 was treated with potassium carbonate in methanol overnight. The solvent was evaporated under a stream of nitrogen and the residue chromatographed on silica to give the title product. MS (ESI+) for C18H18ClNO4S m/z 380 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([F:7])([CH3:6])[C:3](=[O:5])[CH3:4].[Br-:8].[Br-:9].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Br:8][CH:4]([Br:9])[C:3](=[O:5])[C:2]([F:7])([CH3:6])[CH3:1]
Reactant: [Br-]
Reactant: CC(=O)C(C)(C)F
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(F)C(=O)C(Br)Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.1 %

Procedure:
To a stirred solution of 3-methyl-3-fluoro-2-butanone (0.1031 g, 0.990 mmol) in anhydrous dichloromethane (5 ml) under nitrogen was added solid pyridinium tribromide (0.7035 g, 1.98 mmol) and the mixture was stirred at room temperature for 18 h. The mixture was then diluted with dichloromethane (5 ml), washed with dilute aqueous sodium hydrogensulfite (10 ml), then saturated aqueous NaCl (10 ml), dried (Na2SO4) and evaporated under low vacuum with no heat. The residue was purified by flash chromatography [silica gel, 5% Et2O/petroleum ether (40-60° C.)] to afford 0.1869 g (72%) of the title compound as a colourless oil: 1H NMR (360 MHz, CDCl3) δ1.65 (6H, d, J 21.5 Hz), 6.51 (1H, d, J 1.5 Hz).
Reaction SMILES: [N+:1]([CH:4]([CH3:15])[CH:5]([OH:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(Cl)Cl>[N+:1]([CH:4]([CH3:15])[CH:5]([O:14][C:21](=[O:23])[CH3:22])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C(O)CCc1ccccc1)[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(=O)OC(CCc1ccccc1)C(C)[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Crude 4-Nitro-1-phenyl-pentan-3-ol (179) from above was dissolved in CH2Cl2 (60 mL) and cooled in an ice bath under nitrogen. Concentrated sulfuric acid (0.76 mL, 14.2 mmol) then acetic anhydride (13.83 mL, 146.2 mmol) were added slowly, and the reaction was allowed to warm to room temperature, and was stirred until judged complete by HPLC (3 h, 40 min). (Note: The reaction turned black soon after the addition of the acetic anhydride.) The reaction was quenched by pouring slowly into water, then the organic layer was removed, washed with aq. NaHCO3, dried, filtered, and concentrated. The crude product was purified by purified by silica gel chromatography (Combiflash column, 95:5 Hexanes:EtOAc) to achieve pure 180 (21.4447 g, 65.5%, 2 steps). HPLC: 10.45 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1)[CH3:2].C([Li])(C)(C)C.[CH3:15][C:16]1([CH3:47])[CH:25]=[C:24](OS(C(F)(F)F)(=O)=O)[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:34]#[C:35][C:36]3[CH:46]=[CH:45][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][N:37]=3)[CH:22]=2)[S:17]1>C1COCC1.CCCCC.[Cl-].[Cl-].[Zn+2].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>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:34]#[C:35][C:36]4[CH:46]=[CH:45][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][N:37]=4)[CH:22]=3)[S:17][C:16]([CH3:15])([CH3:47])[CH:25]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Br)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CC(C)(C)S3)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(CC)cc2)=CC(C)(C)S3)nc1
Temperature: 25 °C

Procedure:
A solution of 4-ethylbromobenzene (300.0 mg, 1.62 mmol) in 2.0 mL of THF was cooled to -78° C. and tert-butyllithium (207.6 mg, 3.24 mmol, 1.9 mL of a 1.7M solution in pentane) was added to give a yellow solution. After 30 minutes a solution of ZnCl2 (408.0 mg, 3.0 mmol) in 4.0 mL THF was slowly added via cannula. The resulting solution was warmed to room temperature and transferred via cannula to a solution of ethyl 6-(2,2-dimethyl-4-trifluoromethanesulfonyloxy-(2H)-thiochromen-6-ylethynyl) nicotinate (Compound 239, 178.0 mg, 0.36 mmol) and tetrakis(triphenylphosphine)palladium(0) (24 mg, 0.02 mmol) in 2.0 mL THF. This solution was heated to 50° C. for 1 hour, cooled to room temperature, and the reaction quenched by the addition of saturated aqueous NH4Cl. This solution was extracted with EtOAc and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound was isolated by column chromatography (10 to 15% EtOAc/hexanes) and recrystalization from CH3CN to give 136.0 mg (83%) of pale yellow crystals. 1H NMR (300 MHz, CDCl3) δ: 9.15 (1H, s), 8.23 (1H, dd, J=2.2, 8.2 Hz), 7.51 (1H, d, J=8.1 Hz), 7.49-7.34 (3H, m), 7.24-7.17 (4H, m), 5.83 (1H, s), 4.40 (2H, q, J=7.1 Hz), 2.70 (2H, q, J=7.6 Hz), 1.47 (6H, s), 1.40 (3H, t, J=7.1 Hz), 1.29 (3H, t, J=7.1 Hz).
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[CH2:11][C@@H:10]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C[C:29]([N:31](C)C)=O>CCOCC.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.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].[C-]#N.[C-]#N.[Zn+2].[Zn]>[CH2:24]([C:21]1[CH:20]=[N:19][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([C@H:10]3[CH2:11][C@H:9]3[CH2:8][O:7][CH2:6][C:5]3[CH:26]=[CH:27][C:2]([C:29]#[N:31])=[CH:3][CH:4]=3)[CH2:13][CH2:14]2)=[N:23][CH:22]=1)[CH3:25]
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(Br)cc3)CC2)nc1
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(C#N)cc3)CC2)nc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
The product of example 54 (step A) (500 mg, 1.17 mmol), Pd2(dba)3 (43 mg, 0.046 mmol), dppf (51.5 mg, 0.093 mmol), Zn(CN)2 (89 mg, 0.755 mmol) and zinc dust (18 mg, 0.278 mmol) in DMA (1 mL) was evacuated and back-filled with argon (×3). The mixture was stirred at 100° C. for 4 h. The reaction was cooled to room temperature, diluted with Et2O and filtered through a pad of silica. The filtrate was concentrated under vacuum to leave a residue which was purified by silica gel column chromatography (elution with 5:1 hexane:ethyl acetate) to yield the title compound as a colorless gum. MS (ESI) m/z 377 [M+H]+.
Reaction SMILES: S1(CCCC1)(=O)=O.P(Cl)(Cl)(Cl)=O.O=[C:14]1[C:19]2[C:20]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][C:21]=3[S:34][C:18]=2[N:17]=[CH:16][NH:15]1.[Cl-:35].[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[Cl:35][C:14]1[C:19]2[C:20]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][C:21]=3[S:34][C:18]=2[N:17]=[CH:16][N:15]=1
Reactant: CC(C)(C)OC(=O)N1CCCc2c(sc3nc[nH]c(=O)c23)C1
Reactant: [Cl-]
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCCc2c(sc3ncnc(Cl)c23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To sulfolane (20 mL) was added phosphoryl chloride (7.40 g, 48.3 mmol). Triethylamine (4.88 g, 48.3 mmol) was added dropwise, and the mixture was stirred for 30 min at rt. Subsequently, tert-butyl 4-oxo-3,4,5,6,7,9-hexahydro-8H-pyrimido[5′,4′:4,5]thieno[2,3-c]azepine-8-carboxylate from Example 78A (5.17 g, 16.1 mmol) was added, and the reaction mixture was heated for 2 h to 65° C. The mixture was then cooled to rt, and triethylamine (7.0 mL) was added. It was diluted with toluene and cooled to 0° C. Half-saturated aqueous sodium chloride solution was added, and the mixture was stirred for 20 min. The organic layer was separated, washed with water and dried over sodium sulfate, and the solvent was removed in vacuo. The residue was triturated with tert-butyl methyl ether, and the precipitate was collected by suction filtration to yield 4.40 g (80%) of the title compound.