Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:30][C:29]([F:32])([F:31])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[NH:33]1[CH:37]=[CH:36][CH:35]=[N:34]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:33]4[CH:37]=[CH:36][CH:35]=[N:34]4)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:28][C:29]([F:32])([F:31])[CH2:30]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Reactant: c1cn[nH]c1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(-n4cccn4)cc3Cl)C[C@H]2C(=O)N2CC(F)(F)C2)CC1

Procedure:
The title compound was prepared in analogy to example 134 using (1R,2R,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(3,3-difluoro-azetidine-1-carbonyl)-cyclopentanecarboxylic acid-(1-cyano-cyclopropyl)-amide (example 119 step 4) and pyrazole. White solid (36%). MS (EI): 538.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:19][C:20]1[O:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=1.C(=O)([O-])O.[Na+]>COCCOC.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[CH:9]([CH2:19][C:20]2[O:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)o1)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
To a solution of ethyl 3-(4-fluorophenyl)-3-oxopropionate (5.0 g, 24 mmol) in 1,2-dimethoxyethane (40 ml) was added sodium hydride (60% in oil, 576 mg, 24 mmol) under ice-cooling and the mixture was stirred at room temperature for 1 hr. To the reaction solution was dropwise added a solution of. 2-(bromomethyl)-5-(trifluoromethyl)furan (6 g, 26 mmol) in 1,2-dimethoxyethane (50 ml) and the reaction solution was stirred overnight at room temperature. The reaction solution was poured into water (200 ml), saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl 3-(4-fluorophenyl)-3-oxo-2-((5-(trifluoromethyl)-2-furanyl)methyl)propionate (4.5 g, 52%).
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3][CH3:4].N[C:7]1([O:16]O)[CH2:12][CH:11]([CH3:13])[CH2:10][C:9]([CH3:15])([CH3:14])[CH2:8]1.S([O-])([O-])(=O)=O.[Mg+2]>S(=O)(=O)(O)O>[CH:1](=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:13][CH:11]1[CH2:10][C:9]([CH3:15])([CH3:14])[CH2:8][C:7](=[O:16])[CH2:12]1
Reactant: CC1CC(C)(C)CC(N)(OO)C1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCCC=O
Product: CC1CC(=O)CC(C)(C)C1
Reaction time: 8 h

Procedure:
Butyraldehyde (14.4 g.) was mixed with petrol (b.p. 40° - 60°) (50 c.c.) and to the stirred solution at <0° was added 1-amino-3,3,5-trimethylcyclohexyl hydroperoxide (17.3 g.; 89% pure). The peroxide dissolved within a few minutes. To the solution were added magnesium sulphate and concentrated sulphuric acid (6 drops) and the mixture stored at 0° overnight. The solution was filtered, the filtrate washed with water, dried and distilled to give unreacted butyraldehyde, dihydroisophorone and a product (11.1 g.), b.p. 85° - 110°/1.0mm. with a peroxide equivalent of 231, and a perchloric equivalent of 233. The elemental analysis gave C, 68.6%; H, 11.:5%; N, 6.6%. The product was identified as: ##SPC22##
Reaction SMILES: C1(CCC(Cl)=O)CCCC1.[CH:11]1([CH2:16][CH2:17][C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][C:39]=1[F:45].C1(C)C=CC=CC=1>C(O)C>[CH:11]1([CH2:16][CH2:17][C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15]1.[CH:11]1([CH2:16][CH2:17][C:18]([NH:20][C:21]([NH:42][C:41]2[CH:43]=[CH:44][C:38]([O:37][C:28]3[C:27]4[C:32](=[CH:33][C:34]([O:35][CH3:36])=[C:25]([O:24][CH3:23])[CH:26]=4)[N:31]=[CH:30][CH:29]=3)=[C:39]([F:45])[CH:40]=2)=[S:22])=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(CCC1CCCC1)N=C=S
Agent: O=C(Cl)CCC1CCCC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)CCC4CCCC4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
3-Cyclopentylpropanoyl isothiocyanate was prepared using commercially available 3-cyclopentylpropanoyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Cyclopentylpropanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (69 mg, yield 88%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:23][O:24][C:25](=[O:36])[C:26]1[CH:31]=[C:30]([C:32]#[N:33])[CH:29]=[CH:28][C:27]=1[CH2:34]Br.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:23][O:24][C:25](=[O:36])[C:26]1[CH:31]=[C:30]([C:32]#[N:33])[CH:29]=[CH:28][C:27]=1[CH2:34][N:10]([CH2:9][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=1)[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21])(=[O:12])=[O:13]
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Reactant: Cc1cnc(CNS(=O)(=O)c2ccccc2[N+](=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1ncc(C)cc1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
To a solution of N-(3,5-dimethyl-pyridin-2-ylmethyl)-2-nitro-benzenesulfonamide (0.60 g, 1.87 mmol) dissolved in CH3CN (10 mL) was added 2-bromomethyl-5-cyano-benzoic acid methyl ester (0.50 g, 1.96 mmol) and K2CO3 (0.72 g, 5.61 mmol). The mixture was stirred at 80° C. for 3 hours, then concentrated in vacuo and redissolved in CH2Cl2 (50 mL). Saturated aqueous NaHCO3 (50 mL) was added and the mixture was extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to give a brown oil. Purification via column chromatography on silica gel (CH2Cl2:MeOH, 99:1, v/v) afforded 5-cyano-2-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(2-nitro-benzenesulfonyl)-amino]-methyl}-benzoic acid methyl ester as a yellow solid (0.90 g, 97%). 1H NMR (CDCl3) δ 2.15 (s, 3H), 2.22 (s, 3H), 3.88 (s, 2H), 5.15 (s, 2H), 7.05 (s, 1H), 7.61-7.72 (m, 5H), 7.83 (s, 1H), 7.95 (d, 1H, J=7.5 Hz), 8.06 (s, 1H).
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH3:18])=[CH:11][CH:10]=1)=[S:7])([O:3][CH3:4])=[O:2].[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+]>O.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[CH3:4][O:3][C:1](=[O:2])[NH:5][C:6]1[S:7][C:10]2[CH:11]=[C:12]([O:15][CH2:16][CH2:17][CH3:18])[CH:13]=[CH:14][C:9]=2[N:8]=1
Reactant: CCCOc1ccc(NC(=S)NC(=O)OC)cc1
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCOc1ccc2nc(NC(=O)OC)sc2c1
Reaction time: 2 h

Procedure:
To a stirred suspension of 2.2 g. 1-carbomethoxy-3-(p-n-propoxyphenyl) thiourea in a solution of 2.42 g. sodium hydroxide in 35 ml of water, in an erlenmeyer flask at 64° (by water bath) is added a solution of 8.8 g. potassium ferricyanide in 20 ml water. The stirring is continued for 2 additional hrs. Potassium carbonate, 6 g. is then added to this reaction mixture and stirring is continued for another 2 hr. period. It is then extracted by 2 × 50 ml chloroform. The chloroform extracts are dried over anhydrous Na2SO4 and the solvent is removed by evaporation to give 2 g. of the product. m.p. 178°-180° C.
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1COC([N:15]1[CH2:20][CH2:19][C@H:18]([O:21][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[C:31]=2[N:30]=[C:29]([C:32]2[N:36]4[CH:37]=[CH:38][C:39]([O:41][CH2:42][CH2:43][O:44][CH3:45])=[CH:40][C:35]4=[N:34][CH:33]=2)[CH:28]=[CH:27]3)[C@H:17]([OH:46])[CH2:16]1)=O>CCO.[Pd]>[CH3:45][O:44][CH2:43][CH2:42][O:41][C:39]1[CH:38]=[CH:37][N:36]2[C:32]([C:29]3[CH:28]=[CH:27][C:26]4[C:31](=[C:22]([O:21][C@H:18]5[CH2:19][CH2:20][NH:15][CH2:16][C@H:17]5[OH:46])[CH:23]=[CH:24][CH:25]=4)[N:30]=3)=[CH:33][N:34]=[C:35]2[CH:40]=1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(O[C@H]5CCN(C(=O)OCc6ccc7ccccc7c6)C[C@H]5O)c4n3)cnc2c1
Agent: [Pd]
Solvent: CCO
Product: COCCOc1ccn2c(-c3ccc4cccc(O[C@H]5CCNC[C@H]5O)c4n3)cnc2c1
Reaction time: 72 h
Yield: 14.4 %

Procedure:
(cis)-Naphthalen-2-ylmethyl-3-hydroxy-4-(2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-yloxy)piperidine-1-carboxylate (0.030 g, 0.048 mmol) was dissolved in EtOH (1 mL), treated with 10% palladium on carbon (Degussa type, 50 mg), placed under a hydrogen atmosphere (balloon pressure) and stirred for 3 days. The reaction was filtered through a nylon membrane and concentrated in vacuo. The mixture was purified by preparative TLC (10 cm×20 cm×0.5 mm) eluting with 20% (6% NH4OH in MeOH)/ethyl acetate. The recovered product was dissolved in MeOH and treated with 4 M HCl in dioxane then concentrated in vacuo. The residue was re-dissolved in MeOH and re-concentrated three times. The residue was slurried in MeOH (0.3 mL) and added dropwise to Et2O (20 mL). The resultant solid was filtered and dried under N2 to provide the desired product (3 mg). MS ESI (+) m/z 435.1 (M+1) detected.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH2:28][CH2:29][C@H:30]([O:41][C:42]1[N:47]=[CH:46][N:45]=[C:44]2[N:48]([C:51]3[C:56]([Cl:57])=[CH:55][CH:54]=[CH:53][N:52]=3)[N:49]=[CH:50][C:43]=12)[C:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][N:35]=1)=[O:32])(C(C)(C)C)(C)C>C1COCC1>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:31](=[O:32])[C@@H:30]([O:41][C:42]2[N:47]=[CH:46][N:45]=[C:44]3[N:48]([C:51]4[C:56]([Cl:57])=[CH:55][CH:54]=[CH:53][N:52]=4)[N:49]=[CH:50][C:43]=23)[CH2:29][CH2:28][CH2:27][OH:26])=[N:35][CH:36]=1
Reactant: CC(C)(C)[Si](C)(C)OCCC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(Cl)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cn1)[C@H](CCCO)Oc1ncnc2c1cnn2-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tetrabutylammonium fluoride (1M in THF) (1.177 mL, 1.18 mmol) was added to (2S)-5-(tert-butyldimethylsilyloxy)-N-(5-chloropyridin-2-yl)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)pentanamide (Intermediate AW1) (693 mg, 1.18 mmol) in THF (5 mL) under nitrogen. The resulting mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with saturated NH4Cl (2 mL), diluted with DCM (25 mL) and poured onto a phase separator. The organic layer was loaded onto a silica column and purified by flash silica chromatography, elution gradient 50 to 100% EtOAc in isohexane to afford the product (171 mg, 30.6%, 95% ee). 1H NMR (400 MHz, CDCl3) δ 1.59 (1H, t), 1.81-1.91 (2H, m), 2.21-2.39 (2H, m), 3.73-3.86 (2H, m), 5.95 (1H, t), 7.44-7.50 (1H, m), 7.64-7.72 (1H, m), 7.98-8.04 (1H, m), 8.20-8.27 (2H, m), 8.44 (1H, s), 8.59-8.65 (2H, m), 8.72 (1H, s); m/z (ES+) (M+H)+=474.36; HPLC tR=1.89 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12](CC(O)=O)=[CH:11][CH:10]=2)[O:3]1.[CH3:20][CH:21]([CH3:24])[CH2:22][OH:23]>C(O)C>[CH3:7][C:6]1([CH3:8])[C:2]([CH3:19])([CH3:1])[O:3][B:4]([C:9]2[CH:10]=[CH:11][C:12]([CH2:7][CH2:6][C:2]([O:23][CH2:22][CH:21]([CH3:24])[CH3:20])=[O:3])=[CH:13][CH:14]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(CC(=O)O)cc2)OC1(C)C
Reactant: CC(C)CO
Solvent: CCO
Product: CC(C)COC(=O)CCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Yield: 67 %

Procedure:
Isobutyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (67%) was prepared according to Example 192, Step A described above, substituting 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoic acid for 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid and 2-methylpropan-1-ol for ethanol.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[CH:13]=[C:12]([CH:14]3[O:18][CH2:17][CH2:16][O:15]3)[S:11][C:10]=2[CH2:19][CH3:20])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.S(Cl)([Cl:29])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:29][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:13]=[C:12]([CH:14]2[O:18][CH2:17][CH2:16][O:15]2)[S:11][C:10]=1[CH2:19][CH3:20]
Reactant: O=S(Cl)Cl
Reactant: CCc1sc(C2OCCO2)cc1C(O)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCc1sc(C2OCCO2)cc1C(Cl)C1CCCCC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of cyclohexyl[5-(1,3-dioxolan-2-yl)-2-ethylthiophen-3-yl]methanol (3.00 g) synthesized above in toluene (60 mL) were added pyridine (979 μL) and thionyl chloride (883 μL) at 0° C., and the mixture was stirred at 0° C. for 1.5 hr, and then at room temperature for 30 min. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (3.28 g, quantitative) as a pale-yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:18])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][C:5]([CH2:3][OH:2])([CH3:18])[CH2:6][CH2:7]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Yield: 96.7 %

Procedure:
4-Methylpiperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (1.48 g, 5.73 mmol) is dissolved in THF (15 mL) and cooled to 0° C. 1.0 M lithium aluminum hydride in THF (6.30 mL, 6.30 mmol) is added dropwise. After 1.25 hours the reaction is quenched with MeOH, then stirred with saturated Rochelle's salt until two layers form. The two layers are separated and the aqueous layer is treated with 5 N NaOH and extracted with diethyl ether. The organic layers are combined, concentrated, and chromatographed using silica gel, eluting with EtOAc in hexanes 0-40%, to give the title compound (1.27 g, 97% yield).
Reaction SMILES: CN(C)C=O.O.[NH2:7][NH2:8].Cl([O-])(=O)(=O)=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:35]=[CH:36][C:37]=1[OH:38])[CH:19]=[CH:20][CH2+:21]1[C:26]2[CH:27]=[C:28]3[O:33][CH2:32][O:31][C:29]3=[CH:30][C:25]=2[CH:24]=[C:23]([CH3:34])O1>O>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:35]=[CH:36][C:37]=1[OH:38])[CH:19]=[CH:20][C:21]1[C:26]2[CH:27]=[C:28]3[O:33][CH2:32][O:31][C:29]3=[CH:30][C:25]=2[CH2:24][C:23]([CH3:34])=[N:8][N:7]=1
Reactant: NN
Reactant: COc1cc(C=C[CH2+]2OC(C)=Cc3cc4c(cc32)OCO4)ccc1O
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=CC2=NN=C(C)Cc3cc4c(cc32)OCO4)ccc1O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of 12.5 ml of dimethylformamide and 2.1 ml (42 mM) of 100% hydrazine hydrate is cooled to 5° to 6° C. with ice-water, then 6.14 g (14 mM) of 1-(3-methoxy-4-hydroxystyryl)-3-methyl-6,7-methylenedioxy-2-benzopyrylium perchlorate (m.p. 300° C. carboniz.) are added at stirring during 15 minutes. The orange solution is stirred for a further 15 minutes, then 12.5 ml of distilled water are added at cooling which initiates the precipitation of the end-product. The crystal mash is stored for 12 hours at 5° C., filtered, washed with 3×20 ml of distilled water and dried at 80° to 100° C. Yield 4.81 g, m.p. 210° to 213° C. d. For further purification this product is refluxed with 24 ml of 99.5% ethanol, cooled, filtered, washed with 3×20 ml of ethanol and dried. Yield 4.59 g (93.7%), m.p. 214° to 216° C. (decomp.)
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][S:18]2(=[O:23])=[O:22])=[CH:11][CH:10]=1.O.[BH4-].[Na+]>C(O)C>[CH2:1]([N:9]1[CH2:10][CH:11]=[C:12]([CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][S:18]2(=[O:23])=[O:22])[CH2:13][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCCN1CCc1ccncc1
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S1(=O)CCCN1CCC1=CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl bromide (3.1 cm3) was added at room temperature to a stirred solution of 2-[2-(4-pyridyl)ethyl]isothiazolidine-1,1-dioxide (4.9 g) in ethanol (30 cm3) and the mixture was heated under reflux for 3 hours. After cooling to room temperature, water (30 cm3) was added followed by sodium borohydride (1.2 g) and the mixture was stirred for 1 hour. Volatile material was removed in vacuo and the residue was treated with 2M hydrochloric acid to pH1, followed by neutralisation with sodium carbonate solution and subsequent extraction with chloroform (3×100 cm3). The dried (MgSO4) chloroform extract was evaporated to give an oil which was chromatographed on silica ("Merck" 60.9385) eluting with methanol:chloroform, 1:49, to give 2-[2-(1-benzyl-1,2,3,6-tetrahydropyrid-4-yl)ethyl]isothiazolidine-1,1-dioxide as an oil (4.5 g).
Reaction SMILES: [N+:1](=[CH2:3])=[N-:2].[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9](Cl)=[O:10]>CCOCC>[N+:1](=[CH:3][C:9]([C:5]1[O:4][CH:8]=[CH:7][CH:6]=1)=[O:10])=[N-:2]
Reactant: C=[N+]=[N-]
Reactant: O=C(Cl)c1ccco1
Solvent: CCOCC
Product: [N-]=[N+]=CC(=O)c1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
N-Nitroso-N-methylurea (16.14 g, 61.53 mmol) was treated with a concentrated NaOH aqueous solution to produce diazomethane. The diazomethane was combined with dry ether (100 ml), dried over KOH, and the resulting ethereal solution was cooled in an ice-salt bath. A solution of furan-2-carbonyl chloride (1.6 g, 12.3 mmol) in dry ether (25 ml) was then added very slowly to the diazomethane solution. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated to dryness (under an argon atmosphere, and keeping the water bath temperature below 25° C.), and the resulting crude material was purified by column chromatography using 230-400 mesh silica gel and 1% triethylamine in DCM solvent system. Evaporation of solvent yielded 2-diazo-1-(furan-2-yl)ethanone as a yellow oil (900 mg, 49%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][N:21]=[N+]=[N-])=[N+:2]=[N-:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>Cl.CCOCC>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH2:21])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCOCCOCCOCCOCCOCCN=[N+]=[N-]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: [N-]=[N+]=NCCOCCOCCOCCOCCOCCN
Reaction time: 24 h
Yield: 95.7 %

Procedure:
To a vigorously stirred suspension of 1,17-diazido-3,6,9,12,15-pentaoxaheptadecane (25 g, 75 mmol) in 5% HCl (200 mL) was added a solution of triphenylphosphine (19.2 g, 73 mmol) in ether (150 mL) over 3 hrs at room temperature. The reaction mixture was stirred for additional 24 hrs. The phases were separated and the aqueous phase was extracted with dichloromethane (3×40 mL). The aqueous phase was cooled in an ice/water bath and the pH was adjusted to 12 by addition of solid potassium hydroxide. The aqueous phase was concentrated and the product was taken up in dichloromethane (150 mL). The organic phase was dried (Na2SO4) and concentrated giving of 22 g (95%) of a yellow oil. The product was identified by electrospray mass spectrometry (ESI-MS) (MH+ calculated: 307.19; found 307.4). The crude oil was used in the nest step without further purification.
Reaction SMILES: C1([O:4][S:5](=O)(=[O:7])[NH2:6])CC1.[CH2:9]([OH:14])[C:10]([CH3:13])([CH3:12])[CH3:11]>>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][O:14][S:5](=[O:7])(=[O:4])[NH2:6]
Reactant: NS(=O)(=O)OC1CC1
Reactant: CC(C)(C)CO
Product: CC(C)(C)COS(N)(=O)=O

Procedure:
Neopenylsulfamate was synthesized according to the method presented in the synthesis of sulfamic acid cyclopropyl ester in Example 1 with the exception of utilizing neopentylalcohol to obtain sulfamic acid 2,2-dimethyl-propyl ester.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[O:36][CH:37]([CH3:39])[CH3:38].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:27]([C:3]1[N:4]=[C:5]([CH2:24][CH2:25][CH3:26])[N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7](=[O:8])[C:2]=1[C:32]1[CH:33]=[CH:34][C:35]([O:36][CH:37]([CH3:38])[CH3:39])=[C:30]([F:29])[CH:31]=1)[CH3:28]
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)Oc1ccc(B(O)O)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(-c2ccc(OC(C)C)c(F)c2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 90.8 %

Procedure:
To a solution of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.5 g) and 3-fluoro-4-isopropoxyphenylboronic acid (0.34 g) in 1,4-dioxane (15 mL) were added 2 M aqueous cesium carbonate solution (3 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.05 g), and the mixture was stirred at 90° C. for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.53 g, 91%) as a colorless amorphous solid.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[F:26]>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[CH:19][C:18]=1[F:26]
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(Cl)c(F)c1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-chloro-3-fluorophenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C16H10ClFN4, 314. Found, 313, 315.