Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH2:2](O)[CH3:3].[C:5]([CH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])([O:7][CH2:8][CH3:9])=[O:6].C(I)C>[Cl-].[Na+].O.O>[CH2:2]([C:10]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])[CH3:3]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CCO
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCI
Product: CCOC(=O)C1(CC)CCCC1=O
Yield: 99 %

Procedure:
In a three-necked flask 5.0 g. of sodium metal was dissolved in 250 ml. of dry ethanol and 31.24 g. (0.20 mole) 2-carboethoxycyclopentanone added. To the resulting yellow solution 18.4 ml. (0.23 mole) ethyl iodide was added dropwise and the mixture heated at reflux for two hours. After cooling, 250 ml. of brine and 50 ml. of water were added and the mixture extracted with ethyl ether (2×100 ml.). After drying (MgSO4) and evaporation of solvent 36.5 g. (99%) of 2-ethyl-2-carboethoxycyclopentanone was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:41](=[O:47])[O:42][C:43](Cl)(Cl)Cl)Cl.[Cl:49][C:50]1[CH:60]=[CH:59][CH:58]=[CH:57][C:51]=1[O:52][CH2:53][CH2:54]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:42][CH2:43][CH2:54][CH2:53][O:52][C:51]2[CH:57]=[CH:58][CH:59]=[CH:60][C:50]=2[Cl:49])=[CH:18][CH:17]=1
Reactant: OCCCOc1ccccc1Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCCCOc4ccccc4Cl)cc3)c2cc1OC
Temperature: 25 °C
Yield: 46.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (77 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (115 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(2-chlorophenoxy)-1-propanol (72 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (62 mg, yield 44%).
Reaction SMILES: O.Cl.[NH2:3][C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6].[OH-].[Na+].Br[CH2:13][C:14]#[N:15]>O1CCOCC1>[C:14]([CH2:13][S:6][CH2:5][C@@H:4]([C:7]([OH:9])=[O:8])[NH2:3])#[N:15]
Reactant: N#CCBr
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: N#CCSC[C@H](N)C(=O)O
Reaction time: 18 h

Procedure:
A 360 mL aqueous solution of commercially available (Aldrich) L-cysteine hydrochloride monohydrate (60.0 g, 341.7 mmole) and sodium hydroxide (27.33 g, 683.4 mmole), at room temperature, is treated with a solution of bromoacetonitrile (44.5 g, 370.6 mmole) in 130 mL of dioxane over 30 minutes. The reaction is stirred for 18 hours, during which time a thick precipitate will form. The solid is filtered off, washed with diethyl ether (100 mL) and dried under high vacuum at 40° C. to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1I.[F:12][C:13]1[CH:14]=[CH:15][C:16]2=[C:17]([CH:33]=1)[O:18][CH2:19][C:20]1[CH:30]=[C:29]([CH:31]=[O:32])[CH:28]=[CH:27][C:21]=1/[C:22]/2=[C:23](/[CH3:26])\[C:24]#[N:25]>>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[CH:31]([OH:32])[C:29]1[CH:28]=[CH:27][C:21]2/[C:22](=[C:23](/[CH3:26])\[C:24]#[N:25])/[C:16]3[CH:15]=[CH:14][C:13]([F:12])=[CH:33][C:17]=3[O:18][CH2:19][C:20]=2[CH:30]=1
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Reactant: Clc1nc2ccccn2c1I
Product: C/C(C#N)=C1/c2ccc(C(O)c3c(Cl)nc4ccccn34)cc2COc2cc(F)ccc21
Yield: 44.6 %

Procedure:
[step 2] Using 2-chloro-3-iodoimidazo[1,2-a]pyridine (500 mg, 1.80 mmol) obtained in step 1 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (263 mg, 0.90 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8F, step 4, (E)-2-{8-[(2-chloroimidazo[1,2-a]pyridin-3-yl)(hydroxy)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (179 mg, 45%) was obtained.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[C:4](Cl)[CH:3]=1.[CH3:15][OH:16].[OH-:17].[Na+].Cl>O>[CH3:15][O:16][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[C:4]([OH:17])[CH:3]=1
Reactant: CO
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)cc1Cl
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1cc(O)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 65 °C
Yield: 95 %

Procedure:
A 1-liter (L), round-bottom flask equipped with a mechanical stirrer and a reflux condenser is charged with 23.7 grams (g) of 1,3-dichloro-4,6-dinitrobenzene, 100 milliliters (mL) of methanol, 200 mL of water and 15 grams of sodium hydroxide and heated to approximately 65° C. for 8 hours. The reaction mixture is then poured into 0° C. aqueous hydrochloric acid, isolated by filtration and air-dried. The theoretical of 5-methoxy-2,4-dinitrophenol yield is 21.4 g, and the dry weight yield is 20.5 g which gives an overall 95% yield.
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Br:20][C:21]1[C:26]([C:27](Cl)=[O:28])=[C:25]([Br:30])[C:24]([Br:31])=[C:23]([Br:32])[C:22]=1[Br:33]>C1C=CC=CC=1>[Br:20][C:21]1[C:26]([C:27]([N:7]2[C:8](=[O:9])[CH:3]3[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]3[C:5]2=[O:6])=[O:28])=[C:25]([Br:30])[C:24]([Br:31])=[C:23]([Br:32])[C:22]=1[Br:33]
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Reactant: O=C(Cl)c1c(Br)c(Br)c(Br)c(Br)c1Br
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(c1c(Br)c(Br)c(Br)c(Br)c1Br)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Pentabromobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(pentabromobenzoyl)-3,4-dibromohexahydrophthalimide.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][NH:5][C:4](=[O:9])[N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][CH2:19][CH2:20][Cl:21].O>CS(C)=O>[Cl:21][CH2:20][CH2:19][CH2:18][CH2:17][N:5]1[CH:6]=[C:7]([CH3:8])[C:2](=[O:1])[NH:3][C:4]1=[O:9]
Reactant: Cc1c[nH]c(=O)nc1O
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cn(CCCCCl)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 41 %

Procedure:
10.1 g (80.0 mmol) of 4-hydroxy-5-methylpyrimidin-2(1H)-one (thymine) in 300 ml of dimethyl sulfoxide (DMSO) and 11.1 g (80.0 mmol) of K2CO3 were stirred at room temperature for 1 hour. Then 13.7 g (80.0 mmol) of 1-bromo-4-chlorobutane were added dropwise to the mixture, and the reaction mixture was then stirred at room temperature for 5 hours. Water was added to the reaction mixture, and it was then extracted with ethyl acetate. The aqueous phase was then neutralized and extracted with methylene chloride. Drying of the organic phase, removal of the desiccant by filtration and evaporation of the solvent to dryness in vacuo resulted in 7.1 g of the title compound
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[NH2:10][CH2:11][CH2:12][CH2:13][C@:14]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:18]([C:19](=[O:24])[C@@H:20]([O:22]C)[CH3:21])[N:17]=[C:16]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[S:15]1>>[NH2:10][CH2:11][CH2:12][CH2:13][C@:14]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:18]([C:19](=[O:24])[C@@H:20]([O:22][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH3:21])[N:17]=[C:16]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[S:15]1
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CCCN)c1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Product: C[C@H](OCC(=O)OC(C)(C)C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CCCN)c1ccccc1

Procedure:
Prepared as previously described in Example 71 using tert-butyl 2-bromoacetate in place of methyl iodide. MS ESI (+) m/z 520 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.50 (m, 1H), 7.46 (d, 2H, J=8 Hz), 7.34 (m, 2H), 7.27 (m, 1H), 7.13 (m, 2H), 4.93 (q, 1H, J=6 Hz), 4.18 (d, 1H, J=16 Hz), 3.96 (d, 1H, J=16 Hz), 3.30 (m, 1H), 2.96 (m, 2H), 2.45 (m, 1H), 2.01 (m, 1H), 1.63 (m, 1H), 1.50 (d, 3H, J=6 Hz), 1.46 (s, 9H). Stereochemistry was assigned by inference from (S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[C:4]([OH:6])=[O:5].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[C:14]([O:1][N:2]=[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[C:4]([OH:6])=[O:5])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(O)C(=NO)c1cccc(O)c1
Solvent: C1CCOC1
Product: O=C(O)C(=NOC(=O)c1ccccc1)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.9 %

Procedure:
A mixture of 2-hydroxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (9.06 g.), benzoyl chloride (32.25 g.) and tetrahydrofuran (50 ml.) was stirred for 6 hours at ambient temperature. To the reaction mixture was added petroleum ether under 5° C. Precipitates were collected by filtration, washed with petroleum ether and dried to give 2-benzoyloxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (11.12 g.), mp 140° to 142° C. (dec.).
Reaction SMILES: [N:1]1[C:9]([CH:10]([OH:12])[CH3:11])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C)C=O>[O:12]([CH:10]([C:9]1[N:1]=[CH:2][N:3]=[C:4]2[C:8]=1[NH:7][CH:6]=[N:5]2)[CH3:11])[Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)c1ncnc2nc[nH]c12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(O[Si](C)(C)C(C)(C)C)c1ncnc2nc[nH]c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.1 %

Procedure:
To a solution of 0.543 g of 1-(purin-6-yl)ethanol in N,N-dimethylformamide (10 ml) were added 0.27 g of imidazole and 0.598 g of tert-butyldimethylsilyl chloride and the resulting mixture was stirred at room temperature for 15 hours. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 0.793 g of the title compound as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][NH:10][C:9]2=O.S(Cl)([Cl:21])=O>CN(C=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][N:10]=[C:9]2[Cl:21]
Reactant: O=S(Cl)Cl
Reactant: COc1cc2nc[nH]c(=O)c2cc1OCCCCl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Cl)c2cc1OCCCCl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
6-(3-chloropropoxy)-7-methoxyquinazoline-4-one (400 gm), thionyl chloride (3.2 lt) and DMF (100 ml) were refluxed for 7-8 hours. Thionyl chloride was distilled off completely under reduced pressure below 45° C. Methylene chloride (2.5 lt) and water (1.5 lt) were charged, stirred for 30 minutes at room temperature and the layers separated. The aqueous layer was extracted twice with methylene chloride (500 ml), the combined methylene chloride layer was washed with 1% sodium bicarbonate solution (1 lt), dried over sodium sulphate (20 gm) and concentrated under reduced pressure at 35-40° C. The residue was stirred with isopropyl alcohol (400 ml) at 40-45° C. for 1 hour, cooled to 0-5° C., the solids filtered, washed with chilled isopropyl alcohol (200 ml) and dried under vacuum at 45° C. to yield the title compound (406 gm, 95% yield).
Reaction SMILES: C([O:4][C@H:5]1[C@@H:10]([CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:9][C@H:8]([O:20][CH2:21][C@H:22]2[O:29][C@H:26]([O:27][CH3:28])[C@H:25]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:24]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:23]2[O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@H:7]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C@H:6]1[O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)(=O)C.CO.C[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:31]([O:30][C@@H:25]1[C@@H:24]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@H:23]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:22]([CH2:21][O:20][C@H:8]2[O:9][C@H:10]([CH2:11][O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C@H:5]([OH:4])[C@H:6]([O:62][CH2:63][C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)[C@H:7]2[O:54][CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[O:29][C@@H:26]1[O:27][CH3:28])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CO[C@H]1O[C@H](CO[C@H]2O[C@H](COCc3ccccc3)[C@H](OC(C)=O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CO[C@H]1O[C@H](CO[C@H]2O[C@H](COCc3ccccc3)[C@H](O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
Methyl 6-O-(4-O-acetyl-2,3,6-tri-O-benzyl-α-D-galactopyranosyl)-2,3,4-tri-O-benzyl -α-D-glucopyranoside (2.314 g, 2.46 mmol) was dissolved in hot toluene (20 mL) and methanol (80 mL) was added, followed by a few drops of 1M. methanolic sodium methoxide. The mixture was stirred at room temperature during 2 h. The reaction mixture was made neutral with Amberlite IR 120 (H+) resin, filtered and concentrated under reduced pressure to afford methyl 2,3,4-tri-O-benzyl-6-O-(2,3,6-tri-O-benzyl-α-D-galactopyranosyl) -α-D-glucopyranoside (2.21 g, 100%) as an amorphous solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[Cl:19][CH2:20][CH2:21][CH2:22][N:23]1[C:28](=[O:29])[C:27]([CH3:30])=[CH:26][N:25]([CH3:31])[C:24]1=[O:32]>>[ClH:19].[F:18][C:2]([F:1])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:20][CH2:21][CH2:22][N:23]2[C:28](=[O:29])[C:27]([CH3:30])=[CH:26][N:25]([CH3:31])[C:24]2=[O:32])[CH2:13][CH2:12]1
Reactant: FC(F)(F)COc1ccccc1N1CCNCC1
Reactant: Cc1cn(C)c(=O)n(CCCCl)c1=O
Product: Cc1cn(C)c(=O)n(CCCN2CCN(c3ccccc3OCC(F)(F)F)CC2)c1=O
Product: Cl

Procedure:
substituting 1-[2-(2,2,2-trifluoroethoxy)phenyl]piperazine and 3-(3-chloropropyl)-1,5-dimethyl-2,4(1H,3H)-pyrimidinedione gave 3-(3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propyl)-1,5-dimethyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 212°14 213° C.; Anal.: Calcd. for C21H27F3N4O3.(HCl)2 : C, 49.12; H, 5.69; N, 10.91%; Found: C, 48.97; H, 5.68; N, 10.77%;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:10].[O:17]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:20][N:19]=[CH:18]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:28]([C:25]2[CH:26]=[CH:27][C:22]([C:21]3[O:17][CH:18]=[N:19][CH:20]=3)=[CH:23][CH:24]=2)(=[O:29])=[O:30])=[C:3]([C:9]([C:11]2[N:12]=[CH:13][CH:14]=[CH:15][N:16]=2)=[O:10])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ncccn1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Product: O=C(c1ncccn1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(-c2cnco2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-Amino-5-chloro-phenyl)-pyrimidin-2-yl-methanone and 122 mg of 4-oxazol-5-yl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 7.43 (s, 1H), 7.45 (m, 1H), 7.50 (m, 1H), 7.55 (m, 1H), 7.64 (m, 2H), 7.66 (d, 1H, J=8.8 Hz), 7.86 (m, 2H), 7.97 (s, 1H), 8.86 (d, 2H), 10.63 (s, 1H). MS: m/z 441.9 (M++1).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[F:40][C:41]1[CH:42]=[C:43]([CH:60]=[CH:61][CH:62]=1)[CH2:44][N:45]1[CH:49]=[C:48](C2OC(C)(C)C(C)(C)O2)[C:47](C)=[N:46]1.[C:63](=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1.C(O)C.O>[F:40][C:41]1[CH:42]=[C:43]([CH:60]=[CH:61][CH:62]=1)[CH2:44][N:45]1[C:49]([CH3:63])=[C:48]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)[CH:47]=[N:46]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Reactant: O=C([O-])[O-]
Reactant: Cc1nn(Cc2cccc(F)c2)cc1C1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 76.2 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (intermediate 41) (300 mg, 0.455 mmol) was coupled with 1-(3-fluorobenzyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 12) (187 mg, 0.592 mmol) in sodium carbonate (145 mg, 1.365 mmol), Pd(PPh3)2Cl2 (16 mg, 0.0227 mmol), Toluene/ethanol/water (5/10/1 ml) to give 250 mg (76.2% yield) of titled compound after purification by column (SiO2) using 20% ethyl acetate in hexane as eluent. 1H NMR (CDCl3, 300 MHz): δ 8.64 (s, 1H), 8.12-8.09 (d, 2H), 7.87 (s, 1H), 7.70 (s, 1H), 7.56 (s, 1H), 7.49-7.44 (m, 2H), 7.34-7.25 (m, 2H), 7.01-6.99 (m, 3H), 5.31 (s, 2H), 3.62-3.60 (t, 4H), 3.25-3.19 (t, 4H), 2.39 (s, 3H), 2.37 (s, 3H), 1.49 (s, 9H). MS: m/z=721.1 (M+1).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])#[CH:19]>C(#N)C.O1CCOCC1.[Cu]I>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:3][C:2]=1[C:19]#[C:18][Si:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: COc1ccc(NC2CCN(C)CC2)cc1I
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CC#N
Solvent: C1COCCO1
Product: COc1ccc(NC2CCN(C)CC2)cc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
Into a flask maintained under argon atmosphere N-(3-iodo-4-methoxyphenyl)-1-methylpiperidin-4-amine (180 mg, 0.52 mmol), CuI (9.9 mg, 0.052 mmol) and Pd(Ph3P)Cl2 (36.5 mg, 0.052 mmol) were added and dissolved in acetonitrile (5 mL) and dioxane (5 mL). The solution was degassed and backfilled with argon for three times. TEA (0.725 mL, 526 mg, 5.2 mmol) and (ethynyl)trimethylsilane (0.147 mL, 0.102 mg, 1.04 mmol) were added with a syringe and the solution was stirred at room temperature for 75 min. The volatiles were evaporated and the residue was taken up with EtOAc (30 mL), washed with water (3×5 mL), dried over sodium sulfate and the solvent was removed under vacuum.
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:24])[C:5]1[CH:10]=[C:9]([C:11]2[C:15]([F:16])=[C:14]([O:17][CH:18]([F:20])[F:19])[N:13]([CH3:21])[N:12]=2)[C:8]([Cl:22])=[CH:7][C:6]=1[Cl:23].[C:25](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>>[CH3:1][O:2][N:3]=[C:4]([O:24][CH3:25])[C:5]1[CH:10]=[C:9]([C:11]2[C:15]([F:16])=[C:14]([O:17][CH:18]([F:20])[F:19])[N:13]([CH3:21])[N:12]=2)[C:8]([Cl:22])=[CH:7][C:6]=1[Cl:23]
Reactant: O=C([O-])[O-]
Reactant: CONC(=O)c1cc(-c2nn(C)c(OC(F)F)c2F)c(Cl)cc1Cl
Agent: [K+]
Solvent: COS(=O)(=O)OC
Product: CON=C(OC)c1cc(-c2nn(C)c(OC(F)F)c2F)c(Cl)cc1Cl

Procedure:
Using 0.5 g (1.3 mmol) of N-methoxy-2,4-dichloro-5-(5-difluoromethoxy-4-fluoro-1-methyl-1H-pyrazol-3-yl)benzamide, 0.21 g (1.6 mmol) of potassium carbonate and 0.20 g (1.6 mmol) of dimethyl sulfate and following the procedure described in Example 1, 0.17 g of the desired produce of value was obtained.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[Br:16]Br.[CH2:18]([OH:20])[CH3:19]>>[Br:16][C:4]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2][O:1][CH:5]1[O:20][CH2:18][CH3:19]
Reactant: BrBr
Reactant: CCOC(=O)C1=COCC1
Reactant: CCO
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)C1(Br)CCOC1OCC
Temperature: 0 °C
Yield: 95.8 %

Procedure:
To a nitrogen-purged, 1000-mL, four-neck, round-bottom flask equipped with a thermocouple/thermowell, Dry Ice/acetone bath, addition funnel, condenser, and magnetic stirrer was charged 200 mL of ethanol, 142.12 g (1.00 mole) of ethyl 2,3-dihydro-4-furoate, and 93.0 g (1.11 mole) of sodium bicarbonate. The slurry was cooled to about 0° C. then 159.1 g (0.995 mole) of bromine was added dropwise from the addition funnel over 75 minutes at a temperature of -3 to 30° C. After 15 minutes the bath was removed and the light yellow slurry allowed to warm to room temperature over about two hours. The mixture was filtered and the solids rinsed with ethanol. Solvent was stripped from the filtrate by rotary evaporation at up to 45° C. (70 mm). To the concentrated product was added 100 mL of water. The layers were separated and the aqueous layer extracted with 50 mL of dichloromethane. The organic layers were combined and washed with 100 mL of water containing 0.23 g of sodium thiosulfate then with 100 mL of 5% aqueous sodium bicarbonate. The organic layer was dried with anhydrous magnesium sulfate, then filtered and concentrated by rotary evaporation at up to 45° C. (70 mm). The resulting crude product weighed 270.5 g and contained 5.4 weight percent dichloromethane by NMR (theory 267.12 g, 95.8% yield). A portion of this crude product (71.01 g) was distilled using a 10-inch Vigreux column at 3 mm. The product fraction was collected at 101 to 102° C. The yield of distilled ethyl 3-bromo-2-ethoxytetrahydro-3-furoate was 56.63 g (80.8%). The identity of the product was confirmed NMR and mass spectrometry.