Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH2:11][CH2:12]O)[C:3]=1[OH:14].CS(Cl)(=O)=O.C(=O)([O-])O.[Na+].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]2[O:14][CH2:12][CH2:11][C:4]=2[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(O)c(CCO)c1
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(Cl)c2c(c1)CCO2
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
A mixture of 2-chloro-6-(2-hydroxyethyl)-4-nitrophenol (11.3 g) and pyridine (41.8 mL) was cooled to −15° C. To this mixture was added dropwise methanesulfonyl chloride (4.04 mL), followed by stirring at −10° C. for 30 minutes. To this reaction mixture was added methanesulfonyl chloride (2.02 mL), followed by stirring at −10° C. for 20 minutes. To the mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by stirring for 2 hours, the pH was adjusted to 1 with 6 M hydrochloric acid, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The insoluble materials were separated by filtration, the filtrate was concentrated under reduced pressure, and then the obtained residue was dissolved in ethyl acetate. To this mixture was added triethylamine (18.1 mL), followed by stirring at 78° C. overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 70:30) to obtain 7-chloro-5-nitro-2,3-dihydro-1-benzofuran (7.75 g) as a yellow solid.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[C:17]([CH3:25])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:15]3[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[C:17]([CH3:25])[CH:16]=3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Cl
Reactant: Oc1ccc(C2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(C)cc1Oc1ccc(C2CCCCC2)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 88.9 %

Procedure:
5.81 g (33.0 mmol) of 4-cyclohexylphenol, 5.57 g (30.0 mmol) of 4-chloro-2,5-dimethyl-nitrobenzene and 6.22 g (45.0 mmol) of potassium carbonate are suspended in 30 ml of N,N-dimethylformamide and the suspension is stirred at 150° C. for 12 h. It is then poured into ice-water and the precipitate is isolated by filtration, washed repeatedly with hexane and dried under reduced pressure (12.1 g, purity 71.9%, yield 88.9%, log P (pH 2.3)=6.69).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=O)[NH:8][C:4]=2[CH:3]=1.P(Br)(Br)([Br:14])=O>>[Br:14][C:7]1[NH:6][C:5]2[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][C:4]=2[N:8]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=c1[nH]c2ccc(Br)cc2[nH]1
Product: Brc1ccc2[nH]c(Br)nc2c1
Temperature: 110 °C
Reaction time: 5 h

Procedure:
4.5 g (21.12 mmol) of 5-bromo-1,3-dihydrobenzimidazol-2-one is added batchwise at 60° C. to a melt of 30.27 g (105.6 mmol) of phosphorus oxybromide and the reaction mixture is stirred for 5 hours at 110° C. Then the reaction mixture is poured onto water and the precipitate formed is filtered off. The precipitate is stirred with DIPE/acetone (4:1) and the solid is filtered off. The solid is dried in the circulating air dryer at 50° C. Yield: 3.4 g (58% of theoretical); C7H4Br2N2 (M=275.92); calc.: molpeak (M+H)+: 275/277/279; found: molpeak (M+H)+: 275/277/279; Rf value: 0.6 (silica gel, DCM/MeOH 10:1).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[C:9]([F:15])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O.B.O1CCCC1.Cl.C(OCC)C>O>[ClH:1].[Cl:1][C:2]1[C:10]([C:11]([F:13])([F:14])[F:12])=[C:9]([F:15])[CH:8]=[CH:7][C:3]=1[CH2:4][NH2:6]
Reactant: NC(=O)c1ccc(F)c(C(F)(F)F)c1Cl
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: NCc1ccc(F)c(C(F)(F)F)c1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
2-Chloro-4-fluoro-3-(trifluoromethyl)benzamide (0.490 g, 2.03 mmol) was treated with 1M borane in tetrahydrofuran (20.33 ml, 20.33 mmol) and stirred at 60° C. overnight. The mixture was then treated with 2N aqueous hydrogen chloride until gas evolution ceased and then stirred at 100° C. for 2 hrs. The mixture was reduced in vacuo and the residue was taken up in a minimum of water and washed with dichloromethane (30 ml). The pH of the aqueous layer was adjusted to pH11 by the addition of 2N aqueous sodium hydroxide solution and then extracted with dichloromethane (2×25 ml). The dichloromethane layers were separated using a hydrophobic frit, combined and evaporated in vacuo to leave a pale yellow oil. A 1M solution of hydrogen chloride in diethyl ether (3 ml, 3 mmol) was added and the resulting white solid was filtered off to give pure {[2-Chloro-4-fluoro-3-(trifluoromethyl)phenyl]methyl}amine hydrochloride (0.210 g) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][NH:21][CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:23]([O:25][P:26]([CH2:31][C:32](O)=[O:33])([O:28][CH2:29][CH3:30])=[O:27])[CH3:24].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:29]([O:28][P:26]([CH2:31][C:32]([N:21]1[CH2:20][CH2:19][C:18]2[C:11]3[C:10]([NH:9][C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=4)=[N:15][CH:14]=[N:13][C:12]=3[S:16][C:17]=2[CH2:22]1)=[O:33])(=[O:27])[O:25][CH2:23][CH3:24])[CH3:30]
Reactant: CCOP(=O)(CC(=O)O)OCC
Reactant: Fc1ccc(Nc2ncnc3sc4c(c23)CCNC4)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(CC(=O)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
N-(3-Chloro-4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-amine from Example 12A (3.00 g, 8.96 mmol) and (diethoxyphosphoryl)acetic acid (2.46 g, 12.5 mmol) were dissolved in DMF (60 mL). DIPEA (3.47 g, 26.9 mmol) and TBTU (4.32 g, 13.4 mmol) were added, and the reaction was stirred overnight at rt. Subsequently, the mixture was concentrated in vacuo, and the residue was dissolved in ethyl acetate. The solution was extracted with 1 M aqueous sodium hydroxide solution, dried over sodium sulfate, and the solvent was removed in vacuo. The residue was triturated with tert-butyl methyl ether. The precipitate was collected by suction filtration to yield 4.31 g (94%) of the title compound as white crystals.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[O:14][CH3:15])=[O:4].Cl[CH2:17][O:18][CH3:19].[OH-].[Na+]>[Br-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[Cl:1][CH2:2][C:3]([N:5]([CH2:17][O:18][CH3:19])[C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[O:14][CH3:15])=[O:4]
Reactant: COc1cccc(OC)c1NC(=O)CCl
Reactant: COCCl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: COCN(C(=O)CCl)c1c(OC)cccc1OC
Temperature: 40 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a mixture containing alpha-chloro-N-(2,6-dimethoxyphenyl)acetamide (11.0 g; 0.048 mole), 10 ml. of (chloromethyl)methyl ether and 3.0 g. of benzyltriethylammonium bromide in 100 ml. of methylene chloride was added 50 ml. of a 50% sodium hydroxide solution. The temperature of the reaction mixture increased to 40° C. The reaction mixture was stirred for 1 hour after which time the layers were separated, and the organic methylene chloride layer was concentrated in vacuo yielding a white solid. The white solid was recrystallized from isopropanol to yield alpha-chloro-N-(methoxymethyl)-N-(2,6-dimethoxyphenyl)acetamide (11.8 g; 90% yield) as a white solid having a melting point of 104°-106° C. and the following analysis:
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH3:5][C:6]([C:8]([CH3:10])=[CH2:9])=[CH2:7]>C1(C)C=CC=CC=1>[CH3:7][C:6]1[CH2:5][CH:2]([C:1]#[N:4])[CH2:3][CH2:9][C:8]=1[CH3:10]
Reactant: C=CC#N
Reactant: C=C(C)C(=C)C
Solvent: Cc1ccccc1
Product: CC1=C(C)CC(C#N)CC1
Yield: 87 %

Procedure:
A solution of acrylonitrile (1 eq.) and 2,3-dimethylbuta-1,3-diene (1.1 eq.) in toluene (2M) was pumped through a heated coil reactor at 240° C. with a residence time of 10 minutes. The resulting mixture was concentrated under reduced pressure and yielded the product as colorless oil (87% yield).
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6]1.C([O-])(=O)C.[Na+].C(O)(=O)C.[Cl:20][CH2:21][C:22](Cl)=[O:23].C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:2][O:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:22](=[O:23])[CH2:21][Cl:20])[CH2:6]1
Reactant: COC[C@@H]1CCCNC1
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC[C@@H]1CCCN(C(=O)CCl)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To a suspension of (R)-3-methoxymethylpiperidine hydrochloride (6.00 g, 36.3 mmol), sodium acetate (6.55 g, 79.9 mmol) and acetic acid (4.57 ml, 79.9 mmol) in tetrahydrofuran (120 ml) was added dropwise chloroacetyl chloride (3.18 ml, 39.9 mmol) under ice-cooling, and the mixture was stirred overnight at room temperature. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:4) to give (R)-3-methoxymethyl-N-(chloroacetyl)piperidine (6.00 g, yield 80.0%).
Reaction SMILES: [OH:1][C:2]1([C:13]([NH:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:19].O1CCOCC1>CO>[ClH:19].[OH:1][C:2]1([C:13]([NH:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH2:5][NH:4][CH2:3]1
Reactant: C=CCNC(=O)C1(O)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C=CCNC(=O)C1(O)CNC1

Procedure:
1-(Diphenylmethyl)-3-hydroxyazetidine-3-carboxylic acid (assume 3.90 mmol) was suspended in methanol (40 mL) and 4 N hydrochloric acid in dioxane (1 mL, 4 mmol) was added. 20 wt % Palladium hydroxide on carbon (100 mg) was added to the solution and the mixture was treated with hydrogen at 40 psi for 2 h. The mixture was filtered and the filtrate was concentrated in vacuo to afford 3-hydroxyazetidine-3-carboxylic acid hydrochloride which was dissolved in tetrahydrofuran (5 mL) and water (5 mL) and treated with potassium carbonate (1.615 g, 11.7 mmol) and di-tert-butyl dicarbonate (935 mg, 4.29 mmol) were added. The mixture was stirred at ambient for 17 h and then the mixture was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate and then was acidified to pH ˜3-4 and extracted twice more with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 1-{[(1,1-dimethylethyl)oxy]carbonyl}-3-hydroxyazetidine-3-carboxylic acid which was dissolved in DMF (3 mL). Benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (2.028 g, 3.90 mmol) and N,N-diisopropylethylamine (0.7 mL, 4.03 mmol) were added. The mixture was stirred at ambient for 5 minutes and then allylamine (0.6 mL, 8.03 mmol) was added and the mixture was stirred for 17 h. The mixture was partitioned between ethyl acetate and 5% lithium chloride. The organic portion was washed with 20% citric acid, saturated sodium bicarbonate and brine, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, ethyl acetate) gave 1,1-dimethylethyl 3-hydroxy-3-[(prop-2-en-1-ylamino)carbonyl]azetidine-1-carboxylate (782 mg, 3.05 mmol, 78% yield from 1-(diphenylmethyl)-3-hydroxyazetidine-3-carboxamide). 1,1-Dimethylethyl 3-hydroxy-3-[(prop-2-en-1-ylamino)carbonyl]azetidine-1-carboxylate (782 mg, 3.05 mmol) was dissolved in methanol (10 mL) and 4 N hydrochloric acid in dioxane (2 mL, 8 mmol) was added. The mixture was refluxed for 15 minutes and then was concentrated in vacuo to afford 3-hydroxy-N-prop-2-en-1-ylazetidine-3-carboxamide hydrochloride (3.05 mmol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[N:4]=[C:5]([S:35][CH3:36])[C:6](=[N:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:19]=1)[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]([OH:15])[C:8]=1[F:16].CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:50][CH2:51][O:52][Si:53]([CH:60]([CH3:62])[CH3:61])([CH:57]([CH3:59])[CH3:58])[CH:54]([CH3:56])[CH3:55]>O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:37])[N:4]=[C:5]([S:35][CH3:36])[C:6](=[N:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([CH2:26][NH:27][C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH:19]=1)[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]([O:15][CH2:50][CH2:51][O:52][Si:53]([CH:57]([CH3:58])[CH3:59])([CH:54]([CH3:56])[CH3:55])[CH:60]([CH3:61])[CH3:62])[C:8]=1[F:16]
Reactant: CCc1cc(O)c(F)c(C(=Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)C(=NC(=O)OC)SC)c1
Reactant: CC(C)[Si](OCCI)(C(C)C)C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1cc(OCCO[Si](C(C)C)(C(C)C)C(C)C)c(F)c(C(=Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)C(=NC(=O)OC)SC)c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a mixture of {2-[3-(t-butoxycarbonylaminomethyl)-4-cyanophenylimino]-2-(5-ethyl-2-fluoro-3-hydroxyphenyl)-1-methylsulfanylethylidene}carbamic acid methyl ester (346 mg) and DMF (6 mL) there were added cesium carbonate (235 mg) and (2-iodoethoxy)triisopropylsilane [CAS No. 93550-77-7] (323 mg) in that order, under a nitrogen atmosphere The mixture was stirred for 40 hours at room temperature, and then ethyl acetate (200 mL) and water (50 mL) were added. The mixture was sufficiently shaken, and then the organic layer was separated oft washed twice with water (50 mL) and once with saturated aqueous sodium chloride (50 mL) in that order, and dried over anhydrous magnesium sulfate. The mixture was filtered to obtain a filtrate, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane mixture) to obtain the target compound (406 mg) as an off-white oil.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].CO[C:21](OC)([CH3:23])[CH3:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CC(C)=O>[CH3:22][C:21]1([CH3:23])[O:9][CH:8]2[CH:10]([C@@H:12]([CH2:13][OH:14])[O:15][C@H:7]2[N:6]2[C:5](=[O:17])[NH:4][C:3](=[O:18])[C:2]([F:1])=[CH:16]2)[O:11]1
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1F
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)OC2C(O1)[C@@H](CO)O[C@H]2n1cc(F)c(=O)[nH]c1=O
Reaction time: 8 h
Yield: 84 %

Procedure:
In 750 ml of acetone were added 15 g of 5-fluorouridine, 7.5 ml of 2,2-dimethoxypropane and 1.1 g of p-toluenesulfonic acid monohydrate, and the mixture was reacted at room temperature for 4.5 hours under stirring. After allowed to stand overnight at room temperature, 5 g of sodium hydrogen carbonate was added to the reaction mixture and the mixture was stirred at room temperature for 2.5 hours. After insolubles were filtered off, the filtrate was condensed under reduced pressure, and the obtained crystals were recrystallized from ethanol to give 15.7 g (Yield: 84%) of the title compound as colorless needle crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]([CH2:16][S:17]([NH2:20])(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=1.O.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:11]=[C:12]([CH2:16][S:17]([NH2:20])(=[O:18])=[O:19])[CH:13]=[CH:14][CH:15]=2)[N:7]=1
Reactant: Nc1cccc(CS(N)(=O)=O)c1
Reactant: Clc1ncnc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2,4-dichloro-1,3,5-triazine (1.0 eq) in dry DMF (0.7 M) at 0° C. under N2 atmosphere was added a solution of (3-aminophenyl)-methanesulfonamide (1.0 eq) in dry DMF (0.7 M). The reaction mixture was stirred for 2.5 h at 0° C. Then water was added and the aqueous solution was neutralized with sat. aq. NaHCO3 solution. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4. Evaporation of solvent gave A1 as a white solid which was used in the next step without further purification. 1H NMR (400 MHz, d6-DMSO, 300K) δ 4.26 (s, 2H), 6.89 (s, 2H), 7.15 (d, J=7.4 Hz, 1H), 7.36 (d, J=7.4 Hz, 1H), 7.66 (d, J=7.4 Hz, 1H), 8.64 (s, 1H), 9.75 (br. s, 1H), 10.83 (s, 1H). MS (ES) C10H10ClN5O2S requires: 299. found: 300 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[CH3:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:30][O:31][CH2:32]Cl>C1COCC1>[Br:1][C:2]1[C:7]([N:8]([CH2:30][O:31][CH3:32])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[CH3:20])[CH:13]=2)(=[O:10])=[O:11])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1
Reactant: COCCl
Reactant: CC(F)(F)c1cc(S(=O)(=O)Nc2cc(Cl)cnc2Br)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(C)(F)F)c1

Procedure:
Prepared from 460 mg (1.03 mmol) of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-3-(1,1-difluoro-ethyl)-benzenesulfonamide, 355 mg of potassium carbonate and 195 μL of methoxymethyl chloride in 2 mL THF using procedure x. Yield: 162 mg of a white solid. LC-MSD, m/z for C15H13BrCl2F2N2O3S [M+H]+=488.8, 490.8, 492.8; HPLC retention time: 2.9 min.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].[H-].[Na+].[Cl:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14](Cl)[N:13]=[CH:12][N:11]=1.O>CN(C)C=O>[CH3:6][O:5][C:1](=[O:4])[CH2:2][O:3][C:14]1[C:15]([N+:16]([O-:18])=[O:17])=[C:10]([Cl:9])[N:11]=[CH:12][N:13]=1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ncnc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.5 %

Procedure:
In a 50 ml flask at low temperature, methyl glycolate (0.22 ml, 2.8 mmol) and sodium hydride (114 mg, 2.8 mmol) were dissolved in N,N-dimethyl formamide (7 ml) and then stirred for 10 minutes. 4,6-dichloro-5-nitro-pyrimidine (500 mg, 2.6 mmol) dissolved in N,N-dimethyl formamide (6.5 ml) was added thereto dropwise and then stirred at the same temperature for additional 10 minutes, and then the temperature was raised to room temperature and stirred for additional 10 hours. After completion of the reaction by adding water, the mixture was extracted with dichloromethane, and the combined organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography eluting with a solvent of dichloromethane to obtain yellow liquid (280 mg, 44%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[CH:22][C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.O>ClCCl>[NH:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[CH:22][C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[CH:17][CH:16]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=CC(=O)N3CCOCC3)cc2)CC1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(C=Cc1ccc(OC2CCNCC2)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.4 %

Procedure:
A solution of 3-[4-(1-t-Butyloxycarbonyl piperidin-4-yloxy)phenyl]-1-(morpholin-4-yl)prop-2-ene-1-one (29.8 grams, 0.071 moles) in dichloromethane (400 mL) was treated with trifluoroacetic acid (55.6 mL, 0.726 moles) at room temperature. The reaction mass was stirred for 6 hours at room temperature. The progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, the reaction mass was poured on to chilled water (500 mL) and basified with 40% lye solution (pH˜9). The layers were separated and the aqueous layer was extracted with dichloromethane (2×200 mL) and the combined organic phase was washed with water (150 mL), brine solution (150 mL) and dried over sodium sulphate. The organic phase was concentrated on rotavacuum to afford the title compound (21.2 grams).
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.[F:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][NH:17][C:18]([N:20]2[CH:25]3[CH2:26][CH2:27][CH:21]2[CH2:22][CH2:23][CH2:24]3)=O)=[N:14][CH:15]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH:25]12[N:20]([C:18]3[N:14]4[CH:15]=[C:10]([F:9])[CH:11]=[CH:12][C:13]4=[N:16][N:17]=3)[CH:21]([CH2:27][CH2:26]1)[CH2:22][CH2:23][CH2:24]2
Reactant: O=C(NNc1ccc(F)cn1)N1C2CCCC1CC2
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Fc1ccc2nnc(N3C4CCCC3CC4)n2c1
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 76.6 %

Procedure:
Hexachloroethane (296 mg, 1.25 mmol) was added portionwise over 5 min at RT to a stirred mixture of Intermediate 122b (165 mg, 0.62 mmol), triethylamine (350 μL, 2.50 mmol) and triphenylphosphine (327 mg, 1.25 mmol) in THF (10 mL). The reaction mixture was stirred for 3.5 h and then heated to 60° C. overnight. The temperature was increased to 70° C. for 5 days, then cooled and concentrated in vacuo. The residue was taken up in dioxane, and re-treated with hexachloroethane (150 mg, 0.63 mmol) and triethylamine (200 μL, 1.43 mmol) at 115° C. overnight. The mixture was cooled and concentrated in vacuo. The residue was taken up in methanol and loaded onto an SCX cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3 in MeOH and concentrated in vacuo to give the title compound (117 mg, 76%). LCMS (Method 3): Rt 2.88 min, m/z 247 [MH+].
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8]([NH2:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.BrC1C=CC2N=C(N)SC=2C=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].BrC1C=CC2N=C(NC(=O)C)SC=2C=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:23](=[O:25])[CH3:24])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc2cccc(Br)c2s1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)Nc1nc2ccc(Br)cc2s1
Agent: CN(C)c1ccncc1
Agent: Nc1nc2ccc(Br)cc2s1
Solvent: ClCCl
Product: CC(=O)Nc1nc2cccc(Br)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
The mixture (1.02 g, 4.45 mmol) of 7-bromobenzo[d]thiazol-2-amine and 6-bromobenzo[d]thiazol-2-amine and DMAP (620.6 mg, 5.079 mmol) were suspended in DCM (40 mL) and acetic anhydride (0.46 mL, 4.9 mmol) was added. The reaction was stirred under nitrogen at RT for 2 hours and was then quenched with 1 N HCl (25 mL). The layers were separated, and the aqueous phase was extracted with DCM, and the organic extracts were washed with 1 N HCl, dried over sodium sulfate, filtered, and concentrated to provide the mixture (865 mg, 72% yield) of N-(7-bromobenzo[d]thiazol-2-yl)acetamide and N-(6-bromobenzo[d]thiazol-2-yl)acetamide. MS (ESI pos. ion) m/z: 271 (MH+, 79Br), 273 (MH+, 81Br). Calculated exact mass for C9H7BrN2S: 270 (79Br), 272 (81Br).