Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[C:15]=1Br)[CH3:5])=[N+:2]=[N-:3].[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.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>[N:1]([CH:4]([C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[C:15]=1[C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([F:17])[CH:23]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: Cc1nc2c(Br)c(C(C)N=[N+]=[N-])ccc2s1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2c(-c3cccc(F)c3)c(C(C)N=[N+]=[N-])ccc2s1
Temperature: 100 °C
Yield: 83.8 %

Procedure:
To a mixture of 5-(1-azidoethyl)-4-bromo-2-methyl-1,3-benzothiazole (0.100 g, 0.336 mmol) and (3-fluorophenyl)boronic acid (56.5 mg, 0.404 mmol) in 1,4-dioxane (2 mL) was added a 1 M solution of sodium carbonate in water (0.40 mL, 22 mmol) and tetrakis(triphenylphosphine)palladium(0) (19.4 mg, 0.0168 mmol). The reaction mixture was heated at 100° C. overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, and then concentrated. The crude mixture was purified on silica gel, eluting with 0 to 40% EtOAc in hexane, to give the desired product (88 mg, 83%). LCMS calculated for C16H14FN4S(M+H)+: m/z=313.1; found: 313.0.
Reaction SMILES: Cl[C:2]1[C:9]([C:10]#[N:11])=[CH:8][CH:7]=[CH:6][C:3]=1C=O.[H-].[Na+].[SH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].[CH3:20]S(Cl)(=O)=O>C(OCC)(=O)C>[C:10]([C:9]1[CH:8]=[CH:7][C:6]2[CH:20]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[S:14][C:3]=2[CH:2]=1)#[N:11]
Reactant: N#Cc1cccc(C=O)c1Cl
Reactant: COC(=O)CS
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2ccc(C#N)cc2s1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2.5 g (15.1 mmol) of 2-chloro-3-cyanobenzaldehyde are reacted according to the general procedure with 0.90 g (22.7 mmol) of sodium hydride (60% pure) and 1.76 g (16.6 mmol) of methyl mercaptoacetate. The resulting reaction product is initially purified by silica gel column chromatography (mobile phase: dichloromethane/methanol 100:1) and then dissolved in 30 ml of pyridine, and 650 μl (8.4 mmol) of methanesulfonyl chloride are added. The mixture is stirred at 80° C. for 2 h. After cooling, ethyl acetate is added and the mixture is washed twice with 1N hydrochloric acid and once with saturated sodium chloride solution, dried over sodium sulfate, concentrated and dried under high vacuum. This gives 1.63 g (49.9% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[C:18](Cl)[N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C(Cl)Cl>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:18]2[CH:19]=[CH:20][C:21]([C:22]([F:24])([F:25])[F:23])=[C:16]([Cl:15])[N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1ccc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(C(F)(F)F)c(Cl)n2)CC1
Temperature: 25 °C

Procedure:
A stirred mixture of D7 (5.0 g, 25 mmol), 2,6-dichloro-3-trifluoromethyl-pyridine (5.4 g, 25 mmol) and cesium carbonate (12.22 g, 37.5 mmol) in 1,4-dioxane (75 mL) was heated at reflux under argon for 64 h. To the mixture, which was cooled to ambient temperature, was added water (250 mL) and DCM (250 mL) with shaking and the layers were separated. The aqueous phase was further extracted with DCM (250 mL) and the combined organic extracts were dried (MgSO4) and evaporated in vacuo to an oil. This material was purified by chromatography over silica gel eluting with a gradient of ethyl acetate/hexane to afford the title compounds
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][N:15]=2)[CH:10]=[CH:9][C:8]1=[O:17].FC(F)(F)C(O)=O>O>[O:17]=[C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[N:15][CH:14]=[CH:13][CH:12]=2)[N:7]1[CH2:6][CH:2]=[O:1]
Reactant: O=c1ccc2cccnc2n1CC1OCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=CCn1c(=O)ccc2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To 1.1 g of 1-(1,3-dioxolan-2-ylmethyl)-1,8-naphthyridin-2(1H)-one, 11 mL of a 90% aqueous trifluoroacetic acid solution was added, and the mixture was stirred at room temperature for 2 hours. Then, 1.1 mL of water was added thereto and the mixture was stirred for 13 hours, and thereto was further added 1.1 mL of water and the mixture was stirred for 3 hours 30 minutes, and stirred at 50 to 70° C. for 1 hour 30 minutes. The solvent was distilled off under reduced pressure, and to the resultant residue, a saturated aqueous sodium hydrogen carbonate solution, water and chloroform were added. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.75 g of (2-oxo-1,8-naphthyridin-1(2H)-yl)acetaldehyde as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)([OH:7])[CH2:4][CH2:5][CH3:6].CN(C)[CH:20]=[O:21].C(C1NC=CN=1)(C1NC=CN=1)=O>O1CCCC1>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([C:3]2([CH2:4][CH2:5][CH3:6])[O:7][C:20](=[O:21])[NH:1][CH2:2]2)[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: CN(C)C=O
Reactant: CCCC(O)(CN)c1ccc(OC)c(OC)c1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CCCC1(c2ccc(OC)c(OC)c2)CNC(=O)O1

Procedure:
17.35 mmol of 5-amino-4-(3,4-dimethoxyphenyl)-4-pentanol is dissolved in 10 ml. of absolute dimethylformamide and reacted with 18.3 mmol of 98% strength carbonyl diimidazole in 100 ml. of absolute tetrahydrofuran for 4 days at room temperature under the exclusion of moisture. After the solvent has been distilled off, the residue is taken up in ethyl acetate, extracted twice with 1 N hydrochloric acid, and washed neutral with saturated sodium chloride solution. The thus-obtained oil is purified by way of a silica gel column (350 g.) in a chloroform/methanol system 30:1. The product is 5-(3,4-dimethoxyphenyl)-5-propyl-2-oxazolidinone in an 81.7% yield in the form of an oil.
Reaction SMILES: [C:1]([P:5](Cl)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].[C:11](Cl)([CH3:14])([CH3:13])[CH3:12].[Mg].S(=O)(=O)(O)O>O1CCCC1.[Cu]Cl.C1(C)C=CC=CC=1>[C:1]([P:5]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Reactant: CC(C)(C)Cl
Agent: Cl[Cu]
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Reaction time: 3 h
Yield: 90.9 %

Procedure:
In a 200 ml four-necked flask thoroughly purged with nitrogen, 9.0 g (0.05 mol) of di-tert-butylphosphinous chloride, 0.05 g (0.0005 mol (corresponding to 1% by mol)) of copper(I) chloride and 20 ml of tetrahydrofuran were placed. To the contents of the flask, a Grignard reagent solution previously prepared from 6.0 g (0.065. mol) of tert-butyl chloride and 1.9 g (0.078 mol) of metallic magnesium in 50 ml of tetrahydrofuran was dropwise added over a period of 1 hour with maintaining the temperature at 20° C. to 25° C. After the dropwise addition was completed, stirring was conducted at a temperature of 35° C. to 40° C. for 3 hours. Then, disappearance of di-tert-butylphosphinous chloride was confirmed by gas chromatography. Thereafter, 20 ml of toluene and 20 ml of a 5% sulfuric acid aqueous solution were added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, followed by further distillation. Then, fractions given by distillation at 111° C. to 113° C. under reduced pressure of 15 Torr were collected. As a result, 9.2 g (purity: 99.0%) of the aimed tri-tert-butylphosphine was obtained as an oily substance. The yield was 90.2%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:4][C:5]([N:15]2[C:19]3[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=3[N:17]=[CH:16]2)=[N:6][C:7]=1[NH:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[C:30](C1NC=CN=1)(C1NC=CN=1)=[O:31]>C1COCC1>[F:24][C:21]1[CH:22]=[CH:23][C:18]2[N:17]=[CH:16][N:15]([C:5]3[N:6]=[C:7]4[C:2]([NH:1][C:30](=[O:31])[N:8]4[CH:9]4[CH2:10][CH2:11][O:12][CH2:13][CH2:14]4)=[C:3]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:4]=3)[C:19]=2[CH:20]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CCOC(=O)c1nc(-n2cnc3ccc(F)cc32)nc(NC2CCOCC2)c1N
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(-n2cnc3ccc(F)cc32)nc2c1[nH]c(=O)n2C1CCOCC1
Temperature: 60 °C
Reaction time: 48 h
Yield: 70.4 %

Procedure:
To a solution of ethyl 5-amino-2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidine-4-carboxylate (800 mg, 2.0 mmol) in dry THF (10 mL) was added carbonyl diimidazole (2.0 g) and the mixture was stirred at 60° C. for 48 h in a sealed tube. The solvent was evaporated and water (25 mL) was added to the residue. Filtration and drying of the white solid gave 600 mg (51% yield) of desired product. 1H NMR (400 MHz, DMSO-d6) δ, ppm: 11.89 (s, 1H), 9.09 (s, 1H), 8.84 (dd, J=2.8, 2.4 Hz, 1H), 7.78 (dd, J=5.2, 5.2 Hz, 1H), 7.23 (m, 1H), 4.63 (m, 1H), 4.49 (q, J=6.8 Hz, 2H), 4.40 (dd, J=4.0, 3.0 Hz, 2H), 3.51 (t, J=11.6 Hz, 2H), 2.52 (m, 2H), 1.80 (d, J=2 Hz, 2H), 1.41 (t, J=7.1 Hz, 3H); LCMS (EI) m/z 427 (MH)+.
Reaction SMILES: S([O:11][CH2:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(C1C=CC(C)=CC=1)(=O)=O.C1(O)C=CC=CC=1.[OH:32][C@@H:33]([C:44]1[CH:49]=[CH:48][CH:47]=[C:46](O)[CH:45]=1)[CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40].C([O-])(C)(C)C.[K+]>CN(C=O)C>[C:39]([O:38][C:37]([NH:36][CH2:35][CH2:34][C@H:33]([C:44]1[CH:49]=[C:48]([CH:47]=[CH:46][CH:45]=1)[O:11][CH2:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[OH:32])=[O:43])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c1

Procedure:
A mixture of (S)-tert-butyl 2-((tosyloxy)methyl)pyrrolidine-1-carboxylate (1.6 g, 5.4 mmol), phenol (7, Intermediate I) (0.8 g, 2.9 mmol), t-BuO−K+ (0.5 g, 4.5 mmol) in anhydrous DMF (5 mL) was heated at +45° C. for 16 hrs. The reaction mixture was concentrated under reduced pressure, partitioned between EtOAc and 5% NaOH, organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure. Purification by column chromatography gave (S)-tert-butyl 2-((3-((R)-3-((tert-butoxycarbonyl)amino)-1-hydroxypropyl)phenoxy)methyl)pyrrolidine-1-carboxylate as a light yellow oil. Yield (0.8 g, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:21](O)=[O:22])=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[C:28]#[N:29].CCN=C=NCCCN(C)C.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:21]([NH:24][C:25]5[CH:32]=[CH:31][CH:30]=[C:27]([C:28]#[N:29])[CH:26]=5)=[O:22])=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(Cl)cc21
Reactant: N#Cc1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)Nc4cccc(C#N)c4)c3n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.3 %

Procedure:
A mixture of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (70 mg, 0.23 mmol), 3-aminobenzonitrile (41 mg, 0.344 mmol), EDCI (88 mg, 0.46 mmol) and DMAP (56 mg, 0.46 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. Then the mixture was poured into water (5 mL) and filtered to give a crude product. The crude product was triturated with DMSO and MeOH, then decanted and dried to give 2-(6-chloro-1-methyl-1H-indazol-3-yl)-N-(3-cyanophenyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (20 mg, 20%) as a white solid. MS: (M+H)+=428; 1H NMR (300 MHz, DMSO): δ 10.55 (s, 1H), 8.81 (s, 1H), 8.55-8.50 (m, 2H), 8.15 (brs, 1H), 8.03-8.00 (m, 1H), 7.92 (s, 1H), 7.59 (d, 1H, J=8.1 Hz), 7.48 (d, 1H, J=7.8 Hz), 7.26 (d, 1H, J=7.5 Hz), 4.14 (s, 3H).
Reaction SMILES: [CH2:1]=[CH:2]C(=C)C.[CH2:6]([O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[C:7]#[CH:8].C(Br)C>CCCCCC>[CH2:6]([O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[C:7]#[C:8][CH2:1][CH3:2]
Reactant: C#CCOC1CCCCO1
Reactant: C=CC(=C)C
Solvent: CCBr
Solvent: CCCCCC
Product: CCC#CCOC1CCCCO1
Reaction time: 0.25 h
Yield: 105.3 %

Procedure:
0.89 g (127 mmol) of granulated lithium were added within 5 minutes to 100 ml (4 mol) of liquid ammonia at −38° C. The mixture was stirred until no more lithium floated (after approximately 10 minutes). A dark blue solution of lithium in liquid ammonia was obtained. Isoprene (5.94 g, 86 mmol) was added portion wise within 20 minutes. The reaction mixture was held at −38° C. for about 15 minutes. The end of the formation of Li-amide could be recognized by the de-coloration of the reaction mixture. 11.33 g (70 mmol) of 2-prop-2-ynyloxy-tetrahydropyran were added via a dropping funnel to the reaction mixture at −38° C. within 20 minutes. The reaction mixture was held at −38° C. for about 1 hour. Ethyl bromide 14.0 g (126 mmol) was added via a dropping funnel to the reaction mixture within 20 minutes. The reaction mixture was subsequently stirred for 1 hour. 100 ml n-hexane was added to the reaction mixture and the liquid ammonia was evaporated under normal pressure within 1.5 hours. 50 ml of water was added to the reaction mixture at 22° C., and the mixture was stirred until all salt was dissolved. The water layer was extracted twice with 50 ml n-hexane. The organic layer was dried over 5 g of anhydrous sodium sulfate. The solution was concentrated under reduced pressure (40° C., 60 mbar) and the crude product was analyzed by GC. Crude 2-pent-2-ynyloxy-tetrahydro-pyran (12.4 g) was obtained with a purity of 90.1% (94.3% yield based on 2-prop-2-ynyloxy-tetrahydropyran).
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)[CH:9]=[C:8]([CH3:18])[N:7]=1)=[O:5])C.[NH2:19][C:20]1[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=1>>[CH3:25][N:22]1[CH:23]=[CH:24][C:20]([NH:19][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][CH:15]=[N:14][CH:13]=3)[CH:9]=[C:8]([CH3:18])[N:7]=2)=[O:5])=[N:21]1
Reactant: CCOC(=O)c1cc(-c2cncnc2)cc(C)n1
Reactant: Cn1ccc(N)n1
Product: Cc1cc(-c2cncnc2)cc(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 6-Methyl-4-pyrimidin-5-yl-pyridine-2-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 3-Amino-1-methylpyrazole instead of 3-chloroaniline to yield the final compound as a gray crystalline, MS (ISP): m/e=295.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])=[CH:28][CH:27]=[C:26]([F:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14](I)[N:13]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:10]2=[N:11][CH:12]=1)=[O:5].[CH3:38][N:39]([CH3:43])[CH2:40][C:41]#[CH:42]>[Cu]I.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>[CH3:38][N:39]([CH3:43])[CH2:40][C:41]#[C:42][C:14]1[N:13]([S:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[C:10]2=[N:11][CH:12]=[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:26]([F:37])=[CH:27][CH:28]=[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:32])=[O:33])[C:2]=3[F:1])[CH:8]=[C:9]2[CH:15]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)cc(I)n3S(=O)(=O)c2ccccc2)c1F
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)cc(C#CCN(C)C)n3S(=O)(=O)c2ccccc2)c1F
Temperature: 60 °C
Yield: 64 %

Procedure:
A solution of 2,6-difluoro-N-(2-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (91 mg, 0.14 mmol, 1.0 eq.), N,N-dimethylprop-2-yn-1-amine (2.7 eq.), CuI (0.2 eq.) and PdCl2(PPh3)2 (0.2 eq.) in 1:1 TEA/THF (8 mL) was degassed under argon for 10 minutes. The mixture was heated to 60° C. for 16 hours, and the volatiles were removed under reduced pressure. The resulting residue was diluted with EtOAc and water and filtered through GF/F paper. The layers were separated. The organic layer was dried (MgSO4) and purified by silica gel chromatography (eluting with 100% EtOAc) to afford N-(2-(3-(dimethylamino)prop-1-ynyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide as an oil (54 mg, 64%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[Br:9][C:10]1[CH:11]=[C:12]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:13]=[N:14][C:15]=1Cl.[F:21]C1C=CC(S(N)(=O)=O)=CC=1[N+]([O-])=O>>[Br:9][C:10]1[CH:11]=[C:12]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:13]=[N:14][C:15]=1[O:8][CH2:7][C:4]1([F:21])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: OCC1CCOCC1
Reactant: NS(=O)(=O)c1cnc(Cl)c(Br)c1
Product: NS(=O)(=O)c1cnc(OCC2(F)CCOCC2)c(Br)c1

Procedure:
The title compound was prepared by substituting (4-fluorotetrahydro-2H-pyran-4-yl)methanol for (tetrahydro-2H-pyran-4-yl)methanol and 5-bromo-6-chloropyridine-3-sulfonamide for 4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 24A.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[S:16])[NH:11][CH2:12][C:13](N)=[O:14].[CH2:17](I)[CH3:18]>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][N:11]=[C:10]1[S:16][CH2:17][CH3:18]
Reactant: CCI
Reactant: Cc1cccc(Cl)c1NC(=S)NCC(N)=O
Agent: Cl
Product: CCSC1=NCC(=O)N1c1c(C)cccc1Cl

Procedure:
The title compound was prepared by the procedure described in Example 6 using 12.9 g of 2-[3-(2-chloro-6-methylphenyl)-thioureido]-acetamide, and 18.0 g of ethyl iodide. The hydrochloride salt was prepared in ethereal hydrogen chloride. Crystallization from ethyl acetate afforded the title compound as the mono-hydrochloride as a light yellow solid (4.9 g), m.p. 152°-154° C. (dec.). Anal. Calcd. for. C12H13Cl N2O S . HCl: C, 47.22; H, 4.62; N, 9.18. Found: C, 46.99; H, 4.60; N, 9.16. Mass spectrum (+FAB, [M+H]+) m/z 269/271. 1H-NMR (DMSO-d6 ; 400 MHz) δ8.28 (broad s, 2 H), 7.51 (m, 1 H), 7.44 (t, 1 H), 7.39 (m, 1 H), 4.51 (q, 2 H), 3.12 (q, 2 H), 2.17 (s, 3 H), and 1.27 ppm (t, 3 H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](O)=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18].C1C=CN2CC3C=CC=CC=3NCC=12.C(N(CC)C(C)C)(C)C>S(Cl)(Cl)=O.ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:18])([F:19])[F:20]
Reactant: Cc1cc(C(=O)O)ccc1-c1ccccc1C(F)(F)F
Agent: c1ccc2c(c1)Cn1cccc1CN2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: Cc1cc(C=O)ccc1-c1ccccc1C(F)(F)F
Reaction time: 2 h
Yield: 116.9 %

Procedure:
A suspension of (2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carboxylic acid of Step C (0.50 g, 1.78 mmol) in thionyl chloride (3 mL) was heated at reflux for 90 minutes. After cooling, the thionyl chloride was removed in vacuo and the residue dissolved in toluene. The solution was concentrated in vacuo to yield the crude acid chloride as a brown oil. The acid chloride was dissolved in dichloromethane (5 mL) and slowly added to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.49 g, 2.66 mmol) and N,N-diisopropylethyl amine (0.68 mL, 3.90 mmol) in dichloromethane (15 mL). After stirring for 2 hours, the reaction was quenched with water. The organic layer was sequentially washed with 1 N hydrochloric acid, 1 N sodium hydroxide and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow foam. Purification by flash chromatography on silica gel using a solvent gradient of 15 to 25% ethyl acetate in hexane gave a white foam which was crystallized upon sonication in ethanol/hexane to provide the title compound (0.55 g) as a white solid, m.p. 127–130° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([OH:11])=[N:5][NH:6]2.C(=O)([O-])[O-].[K+].[K+].[C:18]([O:24][C@@H:25]1[C@@H:30]([O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[C@H:29]([O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C@@H:28]([CH2:45][O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[O:27][C@@H:26]1Br)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].O>C(#N)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([O:11][C@@H:26]1[O:27][C@H:28]([CH2:45][O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[C@@H:29]([O:38][C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])[C@H:30]([O:31][C:32](=[O:37])[C:33]([CH3:34])([CH3:35])[CH3:36])[C@H:25]1[O:24][C:18](=[O:23])[C:19]([CH3:22])([CH3:20])[CH3:21])=[N:5][NH:6]2
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@H](Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: Oc1n[nH]c2cccc(Br)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3cccc(Br)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C

Procedure:
A mixture of 4-bromo-1H-indazol-3-ol (1.27 g), potassium carbonate (1.65 g) and 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (which can be prepared in a manner described in literature, for example, Liebigs Ann. Chem. 1982, pp. 41-48; J. Org. Chem. 1996, vol. 61, pp. 9541-9545) (4.15 g) in acetonitrile (20 mL) was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethylether. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1-2/1) to give the title compound (2.04 g).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]([C:5](F)=[O:6])[C:3]=1[C:14](F)=[O:15].FC1(F)C2C(=C(F)C(F)=C(F)C=2F)C(=O)[O:19]1>>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]2[C:5](=[O:19])[O:6][C:14](=[O:15])[C:3]=12
Reactant: O=C1OC(F)(F)c2c(F)c(F)c(F)c(F)c21
Reactant: O=C(F)c1c(F)c(F)c(F)c(F)c1C(=O)F
Product: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21

Procedure:
A process for producing tetrafluorophthalic anhydride, which comprises reacting 3,4,5,6-tetrafluorophthaloyldifluoride and/or 3,3,4,5,6,7-hexafluoro-1-[3H]-isobenzofuranone with an Inorganic base or an organic acid to obtain tetrafluorophthalic anhydride.