Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[CH:17][CH:16]=2)[CH:11]=[C:12]([F:14])[CH:13]=1>O1CCCC1>[F:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:19][CH:20]=2)[CH:11]=[C:12]([F:14])[CH:13]=1
Reactant: COC(=O)CCc1ccc(-c2cc(F)cc(F)c2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(-c2cc(F)cc(F)c2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred solution of lithium aluminum hydride (0.2 g) in tetrahydrofuran (15 mL), the compound obtained from step c above (0.77 g) in tetrahydrofuran (50 mL) was added at 0° C. The reaction mixture was stirred at 0° C. for 3 hours. The reaction mixture was quenched carefully with saturated ammonium chloride solution, filtered through a celite pad, and washed with ethyl acetate. The organic layers were separated, washed with brine, and dried over anhydrous sodium sulfate, and solvents were evaporated under reduced pressure. The crude product was purified by silica gel flash column chromatography using 20% to 30% ethyl acetate in hexane to get the title compound as a white crystalline solid (0.70 g).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([N:18]1[CH2:23][CH2:22][N:21]([N:24]2[CH2:29][CH2:28][CH2:27][NH:26][C:25]2=[O:30])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:31]I>C1COCC1>[CH2:11]([N:18]1[CH2:23][CH2:22][N:21]([N:24]2[CH2:29][CH2:28][CH2:27][N:26]([CH3:31])[C:25]2=[O:30])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1NCCCN1N1CCN(Cc2ccccc2)CC1
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCCN(N2CCN(Cc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Lithium bis(trimethylsilyl)amide (1M THF solution; 1.5 mL) was added to a solution of 1-(4-benzylpiperazin-1-yl)tetrahydropyrimidin-2(1H)-one (0.27 g) obtained in Example 25a} in THF (10 mL) at 0° C., and the mixture was stirred at room temperature for one hour. Methyl iodide (0.09 mL) was added thereto, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with an aqueous sodium bicarbonate solution, and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (0.30 g, quantitative) as a brown oil.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=O)[C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1CCCCC1>N1C=CC=CC=1>[S:1]1[C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4](/[CH:6]=[CH:13]\[C:14]([OH:16])=[O:15])=[CH:5]1
Reactant: O=Cc1csc2ccccc12
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)/C=C\c1csc2ccccc12
Temperature: 110 °C
Yield: 44.9 %

Procedure:
A suspension of benzo[b]thiophene-3-carbaldehyde (4.9 g, 30 mol), malonic acid (6.6 g, 60 mmol) and piperidine (1 mL) in 100 mL anhydrous pyridine was heated at 110° C. for overnight. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was taken up in 100 mL of water and 1 N hydrochloric acid was added to adjust the pH of this solution to ca. 3. The resulting suspension was filtered and the yellow solid was collected, washed with water (3×30 mL) dried in vacuo to give 329a as a yellow solid (5.5 g, 89%). MS: [M+H]+ 205.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([C:6]1[C:7](I)=[CH:8][C:9]([O:17][CH2:18][CH3:19])=[C:10]([CH:16]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:5])=[O:4].[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[CH3:1][N:2]([CH3:21])[S:3]([C:6]1[C:7]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])=[CH:8][C:9]([O:17][CH2:18][CH3:19])=[C:10]([CH:16]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:5])=[O:4]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1cc(S(=O)(=O)N(C)C)c(I)cc1OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(S(=O)(=O)N(C)C)c(C#C[Si](C)(C)C)cc1OCC
Temperature: 50 °C
Yield: 84.1 %

Procedure:
Ethyl 5-dimethylsulfamoyl-2-ethoxy-4-iodobenzoate (0.142 g, 0.332 mmol; prepared as described in example 14), dichlorobis(triphenylphosphine)palladium(II) (0.023 g, 0.032 mmol), copper(II) iodide (3.2 mg, 0.017 mmol) dimethylformamide (0.5 mL), triethylamine (0.5 mL) and (trimethylsilyl)acetylene (0.066 mL, 0.47 mmol) were added sequentially to a flame-dried Schienk tube. The reaction mixture was heated at 50° C. oil bath for 2 h, allowed to cool to room temperature overnight and then partitioned between water (20 mL) and diethyl ether (3×20 mL), dried over magnesium sulfate and evaporated. The residue was purified by flash column chromatography (eluting with 20% ethyl acetate in hexanes) to give ethyl 5-dimethylsulfamoyl-2-ethoxy-4-trimethylsilanylethynylbenzoate as an off-white glass (0.111 g, 84%). LC-MS: 398.3 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]([OH:5])([CH3:4])[CH3:3].[Li]CCCC.C(Cl)C=CC.[CH2:16]1[CH2:20][O:19][CH2:18][CH2:17]1>>[C:18]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])(=[O:19])/[CH:17]=[CH:16]/[CH3:20]
Reactant: C1CCOC1
Reactant: CC(C)(C)O
Agent: CC=CCCl
Agent: [Li]CCCC
Product: C/C=C/C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of t-BuOH (0.50 mol, 37.1 g, 47.8 mls) in THF (500 mls) is cooled to 5° C.; then over a 30 minute period n-BuLi (0.56 mol., 350 ml, 1.6 M) is added to the solution. The resulting mixture is stirred for 40 minutes at room temperature. Crotyl chloride (0.50 mol., 52.3 g, 47.9 mls) in THF (250 mls) is added to the reaction mixture at room temperature over a 15 minute period. The resulting mixture is heated under reflux for 50 minutes. The reaction mixture is cooled to 0° C. and ice-water (800 mls) is added. The layers are separated and the aqueous layer is extracted with Et2O (3×600 mls). The organic phases are combined, dried over Na2SO4, filtered and concentrated by rotary evaporation to give a red oil. Distillation (55° C., 22 mm) yields t-butyl crotonate: 1H NMR (300 MHz, CDCl3) δ 1.46 (s, 9H), 1.83 (dd, J is 6.9, 1.7 Hz, 3H), 5.74 (dq, J is 15.5, 1.7 Hz, 1H), 6.85 (dq, J is 15.5, 6.9 Hz, 1H).
Reaction SMILES: [CH2:1]([C:3]([NH:8][C:9]([NH:11]C(=O)C1C=CC=CC=1)=[S:10])([CH2:6][OH:7])[CH2:4][CH3:5])[CH3:2].[Li+].[OH-]>O1CCCC1.CO.O>[CH2:1]([C:3]([NH:8][C:9]([NH2:11])=[S:10])([CH2:6][OH:7])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(CO)NC(=S)NC(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCC(CC)(CO)NC(N)=S
Temperature: 25 °C
Reaction time: 21 h
Yield: 67.7 %

Procedure:
A solution of N-({[1-ethyl-1-(hydroxymethyl)propyl]amino}carbonothioyl)benzamide (6.8779 g, 24.5 mmol), prepared in the previous step, and 1 M LiOH (29.4 mL, 29.4 mmol) in 200 mL of tetrahydrofuran plus 200 mL of methanol plus 100 mL of water was stirred under nitrogen at room temperature for 21 h. The reaction was concentrated under reduced pressure to remove most of the tetrahydrofuran and methanol. The solid present was collected by filtration and dried under reduced pressure to give N-[1-ethyl-1-(hydroxymethyl)propyl]thiourea (2.9228 g, 68%) as a white solid, mp 148-151° C.; MS (ESI) m/z 177 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]1)=[CH:8]2.Br>>[OH:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH2:13][N:14]1[CH2:15][CH2:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:18][CH2:19]1)=[CH:8]2
Reactant: COc1cccc2cc(CN3CCN(c4ccccn4)CC3)ccc12
Agent: Br
Product: Oc1cccc2cc(CN3CCN(c4ccccn4)CC3)ccc12

Procedure:
A solution of 3.4 g. of 1-(5-methoxy-β-naphthylmethyl)-4-(2-pyridyl)piperazine in 100 ml. of 48% hydrogen bromide is refluxed for 3 hours. The mixture is cooled, concentrated and treated with sodium carbonate. The mixture is extracted with chloroform and the chloroform extractions are dried to yield 1-(5-hydroxy-β-naphtylmethyl)-4-(2-pyridyl)piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4](I)[CH:3]=1.[CH3:10][N:11]1[C:15](B2OC(C)(C)C(C)(C)O2)=[CH:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>CCCCCCC>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:15]2[N:11]([CH3:10])[N:12]=[CH:13][CH:14]=2)[CH:3]=1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: Nc1ccc(Cl)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Product: Cn1nccc1-c1cc(Cl)ccc1N
Temperature: 70 °C
Yield: 73.6 %

Procedure:
A 250-mL round-bottomed flask was charged with 4-chloro-2-iodoaniline (6.189 g, 24.42 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.62 g, 36.6 mmol), potassium carbonate (13.50 g, 98 mmol), and Pd(dppf) Cl2CH2Cl2 (0.997 g, 1.221 mmol). The flask was flushed with Ar, then 1,4-dioxane (61.0 mL) and water (20.35 mL) were added in sequence. A reflux condenser was attached, and the flask was heated to 70° C. for 4 h. After being cooled to room temperature, the mixture was diluted with water and EtOAc, which resulted in an emulsion (a small amount of brine was added to clear the emulsion). The layers were separated, and the aq. layer was extracted with EtOAc (twice). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was partially purified by chromatography on silica gel (30 to 80% EtOAc/Heptane). The partially purified product was taken up in a boiling mixture of heptane (100 mL) and EtOAc (5 mL) to give a murky solution. A 250 mL flask containing the solid was charged with heptane (100 mL). The mixture was cooled to room temperature after 3 h, then the solid was collected by filtration, washed with heptane (3×50 mL), and dried under a stream of N2 for 20 min to give 4-chloro-2-(1-methyl-1H-pyrazol-5-yl)aniline (3.732 g, 17.97 mmol) as a light purple solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=7.50 (d, J=1.9 Hz, 1H), 7.16 (dd, J=2.6, 8.7 Hz, 1H), 7.02 (d, J=2.5 Hz, 1H), 6.78 (d, J=8.7 Hz, 1H), 6.29 (d, J=1.8 Hz, 1H), 5.07 (s, 2H), 3.65 (s, 3H). m/z (ESI) 208.2 (M+H)+.
Reaction SMILES: C(NC1CCCCC1)(C)C.C([Li])CCC.[CH3:16][O:17][C:18](=[O:28])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.[Cl:29][C:30]1[N:35]=[C:34]([Cl:36])[C:33]([CH2:37]I)=[CH:32][N:31]=1>O1CCCC1.C(OCC)(=O)C>[CH3:16][O:17][C:18](=[O:28])[CH:19]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH2:37][C:33]1[C:34]([Cl:36])=[N:35][C:30]([Cl:29])=[N:31][CH:32]=1
Reactant: Clc1ncc(CI)c(Cl)n1
Reactant: COC(=O)Cc1ccc(OC)cc1
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(Cc1cnc(Cl)nc1Cl)c1ccc(OC)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-isopropylcyclohexylamine (720 mg, 5.0 mmol) (Aldrich) in dry tetrahydrofuran (10 mL) was added n-butyllithium (2.5 M in hexanes, 2.0 mL, 5.0 mmol) (Aldrich) at −78° C. under argon. After 30 minutes, a solution of 4-methoxyphenylacetic acid methyl ester (900 mg, 5.0 mmol) (Aldrich) in tetrahydrofuran (3 mL) was added by injection via a syringe and the reaction mixture was stirred at −78° C. for another 30 minutes. To this reaction mixture was added a solution of 2,4-dichloro-5-iodomethyl-pyrimidine (722. 5 mg, 2.5 mmol) (from Example 1c supra) in tetrahydrofuran (3 mL) at −78° C. and the reaction mixture was stirred at the same temperature for 1 hour, then slowly allowed to warm up to −30° C. and stirred for 10 minutes. The reaction mixture was diluted with ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (50 mL), water (30 mL), and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to give 3-(2,4-dichloro-pyrimidin-5-yl)-2-(4-methoxy-phenyl)-propionic acid methyl ester as a yellow oil. (Yield 620 mg, 72.7%).
Reaction SMILES: FC(F)(F)C([O:5][CH2:6][CH2:7][CH2:8][N:9]1[C:14](=[O:15])[C:13]2[C:16]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[C:17]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[S:18][C:12]=2[N:11]([CH3:35])[C:10]1=[O:36])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][C:16]2[C:13]3[C:14](=[O:15])[N:9]([CH2:8][CH2:7][CH2:6][OH:5])[C:10](=[O:36])[N:11]([CH3:35])[C:12]=3[S:18][C:17]=2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)=[CH:33][CH:32]=1
Reactant: Cn1c(=O)n(CCCOC(=O)C(F)(F)F)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cccc(Cl)c3)sc21
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cccc(Cl)c3)sc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.9 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-6-(3-chlorophenoxy)-1-methyl-2,4-dioxo-1,2-dihydro thieno[2,3-d]pyrimidin-3(4H)-yl)propyl 2,2,2-trifluoroacetate (40 mg, 0.068 mmol) in THF (3 mL) and water (3 mL) was added LiOH.H2O (8.6 mg, 0.20 mmol). The reaction was stirred at RT for 15 min then diluted with EA (20 mL) and water (20 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-6-(3-chlorophenoxy)-3-(3-hydroxypropyl)-1-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (13 mg, 38.9% yield) as a white solid. 1H NMR (CDCl3) δ: 7.26-7.24 (m, 2H), 7.23 (d, J=6.0 Hz, 2H), 7.20 (s, 3H), 7.16 (d, J=8.5 Hz, 4H), 7.11 (d, J=8.0 Hz, 2H), 6.93 (dd, J=19.3, 5.2 Hz, 4H), 4.18 (dd, J=14.0, 8.0 Hz, 9H), 3.60-3.44 (m, 1H), 3.23 (t, J=7.1 Hz, 2H), 1.96-1.85 (m, 4H). LCMS: MH+ 491 and TR=3.276 min.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](I)[CH:15]=2)[N:10]=[C:9]([O:18][CH3:19])[C:8]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1.[CH3:28][C:29]1[C:34]([C:35]([C:37]2[N:41]([CH3:42])[N:40]=[N:39][CH:38]=2)=[O:36])=[CH:33][CH:32]=[C:31]([CH3:43])[N:30]=1.[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C.O>[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:35]([C:34]3[C:29]([CH3:28])=[N:30][C:31]([CH3:43])=[CH:32][CH:33]=3)([C:37]3[N:41]([CH3:42])[N:40]=[N:39][CH:38]=3)[OH:36])[CH:15]=2)[N:10]=[C:9]([O:18][CH3:19])[C:8]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1
Reactant: Cc1ccc(C(=O)c2cnnn2C)c(C)n1
Reactant: COc1nc2ccc(I)cc2c(Cl)c1Cc1ccc(C)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C)cc1
Reaction time: 0.03 h

Procedure:
A solution of n-butyllithium in hexanes (2.5 M, 0.47 mL, 1.2 mmol) was added dropwise to a stirring solution of 4-chloro-6-iodo-2-methoxy-3-(4-methylbenzyl)quinoline (500 mg, 1.2 mmol, Intermediate 22: step c) in tetrahydrofuran (9 mL) at −78° C. After 2 minutes, a solution of (2,6-dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanone (255 mg, 1.2 mmol, Intermediate 19: step b) in tetrahydrofuran (2 mL) was added dropwise. After 5 minutes, the flask was placed into an ice-water bath. After 15 minutes, water (5 mL) and ethyl acetate (50 mL) were added and the biphasic mixture was poured into saturated aqueous sodium chloride solution (15 mL). The layers were separated. The organic layer was dried with sodium sulfate and the dried solution was filtered. Silica gel (6 g) was added to the filtrate and the mixture was concentrated by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a silica gel column for flash column chromatography purification. Elution with 100% hexanes initially, grading to 100% ethyl acetate provided the title compound as a white foam. MS (ESI): mass calcd. for C29H28ClN5O2, 513.2. m/z found, 514.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7]2.Cl.O.[C:28](OCC)(=O)C>CO>[CH3:28][O:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7]2
Reactant: CCOC(C)=O
Reactant: COC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)nc3)cc(O)c2[nH]1
Agent: Cl
Solvent: O
Solvent: CO
Product: COC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)nc3)cc(OC)c2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
Methyl 7-hydroxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (1.1 g) was dissolved in a mixture of ethyl acetate (20 mL) and methanol (5 mL). The mixture was cooled to 0° C., and 2M trimethylsilyldiazomethane diethyl ether solution (2 mL) was added dropwise to the mixture. The mixture was stirred at 0° C. for 30 min, and then 2M trimethylsilyldiazomethane diethyl ether solution (0.5 mL) was added dropwise to the mixture again. After stirring at 0° C. for 30 min, 1M hydrochloric acid (1 mL) was added to the mixture to quench the reaction. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual oil was solidified with diethyl ether to give the title compound (0.99 g, 88%) as a pale orange solid. MS 377 (MH+).
Reaction SMILES: [Br:1]Br.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:28][C:29]1[S:33][C:32]([C:34]([O:36][CH3:37])=[O:35])=[CH:31][CH:30]=1>C(Cl)Cl>[Br:1][CH2:28][C:29]1[S:33][C:32]([C:34]([O:36][CH3:37])=[O:35])=[CH:31][CH:30]=1
Reactant: BrBr
Reactant: COC(=O)c1ccc(CO)s1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CBr)s1
Reaction time: 0.17 h
Yield: 95 %

Procedure:
Bromine (0.47 mL, 9.12 mmol) was added to a solution of imidazole (617 mg, 9.06 mmol) and triphenylphosphine (2.40 g, 9.15 mmol) in CH2Cl2 (30 mL) at room temperature. A solution of methyl 5-hydroxymethyl-thiophene-2-carboxylate (prepared according to the procedures described in WO2004/037808; 1.30 g, 7.59 mmol) in CH2Cl2 (10 mL) was then added. After 10 min at room temperature, the reaction mixture was concentrated in vacuo. Purification of the crude residue by flash column chromatography on 80 g of silica gel (hexane→EtOAc, gradient) afforded 1.70 g (95%) of the title compound (B).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H][H]>O=[Pt]=O.C(O)C>[C:8]1([CH2:7][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [H][H]
Reactant: O=Cc1ccccc1
Reactant: NCCCCO
Agent: O=[Pt]=O
Solvent: CCO
Product: OCCCCNCc1ccccc1
Yield: 98.7 %

Procedure:
Dissolve diaminooctane (10.8 g, 0.075) in methylene chloride (200 mL), methanol (100 mL) with di-t-butyldicarbonate (32.7 g, 0.156 mol). Stir the reaction overnight. Concentrate the reaction under vacuum and crystallize the residue from hexane to provide N, N'-bis(t-butoxycarbonyl)-1,8-octanediamine (20.2 g), mp 96-97° C. Combine 4-amino-butan-1-ol (8.9 g, 0.1 mol), benzaldehyde (10.6 g, 0.1 mol), ethanol (100 mL) and PtO2 (0.3 g) and hydrogenate at 45 lbs./sq. in. until hydrogen is no longer taken up. Filter the reaction and concentrate the filtrate under vacuum to provide 4-[[(phenyl)methyl]amino]-butan-1-ol (17.7 g), Rf =0.70 eluting with 10% conc. NH3 /methanol.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:11](Cl)(Cl)[CH:12]=[O:13].Cl.ON.S([O-])([O-])(=O)=[O:20].[Na+].[Na+].Cl>O>[F:9][C:8]1[C:2]([F:1])=[C:3]2[C:5]([C:12](=[O:13])[C:11](=[O:20])[NH:4]2)=[CH:6][CH:7]=1
Reactant: O=S(=O)([O-])[O-]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: Nc1cccc(F)c1F
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: O
Product: O=C1Nc2c(ccc(F)c2F)C1=O
Temperature: 50 °C
Reaction time: 10 h
Yield: 116.8 %

Procedure:
15.7 g of 2,3-difluoroaniline were added to 825 ml of water followed by adding 24.2 g of trichloroacetaldehyde, 30.8 g of hydroxyamine hydrochloride and 138.6 g of anhydrous sodium sulfate and stirring the mixture for 10 hours at 50° C. After allowing to cool to room temperature, 44 mL of 2N hydrochloric acid were added thereto, followed by stirring the mixture for 30 minutes. Subsequently, crystals were removed by filtration. The resulting crystals were dried, and then added to hot concentrated sulfuric acid at 70° C., followed by stirring the mixture for 1 hour at 80° C. to 90° C. The reaction solution was then poured over ice and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried with magnesium sulfate followed by distilling off the solvent under reduced pressure to obtain 26 g of a crude product of 6,7-difluoroisatin.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][NH:7][C:6]2=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>N1C=CC=CC=1>[Br:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][NH:7][C:6]2=[S:19]
Reactant: O=c1[nH]ncc2c(Br)nc(-c3ccccc3)n12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: S=c1[nH]ncc2c(Br)nc(-c3ccccc3)n12
Temperature: 100 °C

Procedure:
To a solution of 8-bromo-6-phenyl-imidazo[1,5-d]-as-triazin-4(3H)-one (5 gm.) in pyridine (100 ml.) is added phosphorus pentasulfide (5 gm.). The mixture is heated at 100° C. for 6 hours, cooled, and the product isolated by filtration and then washed with dilute hydrochloric acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]2=3)(=[O:10])=[O:9])=[CH:4][C:3]=1[NH2:22].[C:23](OC(C)(C)C)(=[O:28])[CH2:24][C:25]([CH3:27])=[O:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]2=3)(=[O:9])=[O:10])=[CH:4][C:3]=1[NH:22][C:23](=[O:28])[CH2:24][C:25](=[O:26])[CH3:27]
Reactant: Nc1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Reactant: CC(=O)CC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)Nc1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Yield: 79.2 %

Procedure:
To 2-chloro-5-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenylamine (1.0 g, 3 mmol, step 4B) in dry toluene (60 mL) was added tert-butyl acetoacetate (0.75 mL, 4.5 mmol) and 4-dimethyl-aminopyridine (0.37 g, 3 mmol). The mixture was refluxed under N2 for 16 hrs. After the removal of toluene, the reaction residue was repartitioned with ethyl acetate (100 mL) and water (50 mL). The organic layer was washed with sat. NH4Cl (2×50 mL) and brine (2×50 mL) and was dried over MgSO4. Concentration and purification by silica gel column chromatography eluting with hexane/ethyl acetate (3/1 to 1/1) yielded N-[2-chloro-5-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenyl]-3-oxo-butyramide as yellowish solid (1.0 g). MS: 421.0 (M+H)+; tR=2.74 min (method 1).