Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[N+:12]([CH2:15][CH3:16])([O-:14])=[O:13].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1C)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COCCOC>[N+:12]([CH:15]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1)[CH3:16])([O-:14])=[O:13]
Reactant: CC[N+](=O)[O-]
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: Cc1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: COC(=O)c1ccc(C(C)[N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of 2.0 g of methyl 4-bromobenzoate, 1.3 ml of nitroethane, 172 mg of tris(dibenzylideneacetone)dipalladium(0), 232 mg of 2-(di-tert-butylphosphino)-2′-methylbiphenyl, 3.33 g of cesium carbonate, and 44 ml of 1,2-dimethoxyethane (DME) was stirred at 60° C. for 18 hours. The reaction mixture was left to be cooled to room temperature, followed by adding a saturated aqueous ammonium chloride solution and extracting with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.44 g of methyl 4-(1-nitroethyl)benzoate.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.C(OCC)(=O)C.C(O)C.[CH3:22][NH2:23]>>[CH3:22][NH:23][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CN
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1ccc(C(=O)OC)cc1
Yield: 74.4 %

Procedure:
Methyl 4-(bromomethyl)benzoate was dissolved in methylamine ethanol solution and the mixture was stirred at reflux for 3 hr. The mixture was condensed under vacuum and poured into ethyl acetate and filtered. The cake was dried to get methyl 4-((methylamino)methyl)benzoate (2.5 g, 74.4%), LC-MS (ESI) m/e 180 [M+1]−.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH2:15][CH2:16][C:17](=[O:23])[NH:18]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>>[C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17](=[O:23])[NH:18]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCc2c(cccc2OCCCCSc2ccccc2)N1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Product: O=c1ccc2c(OCCCCSc3ccccc3)cccc2[nH]1

Procedure:
Prepared analogous to Example 86 from 5-(4-phenylmercapto-butoxy)-3,4-dihydro-carbostyril and 2,3-dichloro-5,6-dicyano-benzoquinone.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14]O>S(=O)(=O)(O)O>[CH3:14][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]([CH3:13])[CH3:12])[C:2]=1[OH:1]
Reactant: CO
Reactant: CC(C)c1cccc(C(=O)O)c1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C(C)C)c1O
Temperature: 45 °C

Procedure:
To a solution of 2-hydroxy-3-isopropylbenzoic acid (4.5 g, 25 mmol) in MeOH (75 mL) is added 10 drops of sulfuric acid and the mixture is heated in an oil bath at 45° C. for 18 h. Extra sulfuric acid (10 drops) is added and the mixture is heated again at 60° C. for 18 h. Solvent is evaporated under reduced pressure and the residue is dissolved in EtOAc. The organic phase is then washed with saturated NaHCO3 (4×), water (1×) and brine and is dried with Na2SO4 and MgSO4, and concentrated. The residue is purified by flash column chromatography to give the title compound as an oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Cl)(C)C.[C:26]([O:30][C:31](=[O:41])[NH:32][C:33]1[S:34][C:35]([CH:39]=[O:40])=[C:36]([Cl:38])[N:37]=1)([CH3:29])([CH3:28])[CH3:27].[Cl-].[NH4+]>O1CCCC1>[C:26]([O:30][C:31](=[O:41])[NH:32][C:33]1[S:34][C:35]([CH:39]([C:12]2[C:13]3[C:14](=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=3)[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:11]=2)[OH:40])=[C:36]([Cl:38])[N:37]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2cc(Cl)cnc21
Reactant: CC(C)(C)OC(=O)Nc1nc(Cl)c(C=O)s1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nc(Cl)c(C(O)c2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)s1
Temperature: -25 °C
Yield: 60.3 %

Procedure:
To a solution of 1-benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (581, 4.40 g, 10.5 mmol) in tetrahydrofuran (30.0 mL) at −45° C. under nitrogen, a solution of isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 5.4 mL) was added slowly over 10 minutes. The reaction was allowed to warm to −25° C. over 30 minutes. The reaction was cooled to −65° C., followed by adding the cold deprotonated (4-chloro-5-formyl-thiazol-2-yl)-carbamic acid tert-butyl ester 589, which was prepared in situ by adding isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 5.0 mL) to (4-chloro-5-formyl-thiazol-2-yl)-carbamic acid tert-butyl ester (589, 2.51 g, 9.55 mmol) in tetrahydrofuran (23.0 mL) at −78° C. under an atmosphere of nitrogen. The reaction was allowed to warm to room temperature in 2 hours, there poured into aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 25% to 100% ethyl acetate in hexane to give the desired compound (590, 3.70 g, 60.3%). MS (ESI) [M+H+]+=554.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[CH:12]2[CH2:17][CH2:16][N:15]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: CO
Product: CS(=O)(=O)N1CCC(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 40 h
Yield: 53.2 %

Procedure:
The product of Step (b) (72 mg, 0.15 mmol) in 96% formic acid (2 ml) was stirred at room temperature under nitrogen for 17 hours. Methanol was added and the mixture was evaporated in vacuo. The residue was dissolved in a small volume of water (10 ml), basified with saturated potassium carbonate solution and extracted with dichloromethane (10 ml). The combined organic extracts were dried (MgSO4) and evaporated in vacuo. This residue was dissolved in dichloromethane (2 ml) under nitrogen and triethylamine (0.029 ml, 0.21 mmol) and methanesulfonyl chloride (0.016 ml, 0.21 mmol) were added sequentially. The resulting mixture was stirred at room temperature for 40 hours and then partitioned between dichloromethane (10 ml) and water (10 ml). The aqueous layer was separated and re-extracted with dichloromethane and the combined organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography, eluting with 40% ethyl acetate in iso hexane to give the title compound as a white solid (37 mg, 58%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[C:4]([F:15])[CH:3]=1.[C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O)(=[O:18])[CH3:17]>>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:16](=[O:18])[CH3:17])=[CH:3][C:4]=2[F:15])=[N:9][CH:10]=1
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Reactant: CC(=O)c1ccccc1B(O)O
Product: CC(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine and (2-acetylphenyl)boronic acid. MS (ESI): mass calcd. for C18H14FN3O, 307.11; m/z found, 307.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.03 (d, J=1.2, 1H), 7.91 (m, 1H), 7.69 (d, J=7.5, 1H), 7.61 (m, 1H), 7.53 (d, J=7.5, 1H), 7.48 (d, J=8.2, 1H), 7.26 (d, J=12.4, 1H), 7.19 (dd, J=8.0, 1.3, 1H), 6.75 (s, 2H), 2.31 (s, 3H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](O)(=[O:17])=[O:16])=[CH:11][CH:10]=1.ClS(O)(=O)=O.Cl>O>[CH:11]1[C:12]([S:15]([C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)(=[O:17])=[O:16])=[CH:13][CH:14]=[C:9]([I:8])[CH:10]=1
Reactant: O=S(=O)(O)c1ccc(I)cc1
Reactant: Ic1ccccc1
Agent: Cl
Agent: O=S(=O)(O)Cl
Solvent: O
Product: O=S(=O)(c1ccc(I)cc1)c1ccc(I)cc1
Reaction time: 1 h
Yield: 26.2 %

Procedure:
To 204 g (1 mole) of iodobenzene was added 312 g (1.1 moles) of 4-iodobenzenesulfonic acid and the mixture was cooled with water while 123 g of (1.1 moles) of chlorosulfonic acid was added thereto at about 10° to about 20° C. over a period of 1 hour. After the addition, the reaction system was stirred for 3 hours while being maintained at 20° to 30° C. The hydrochloric acid gas evolved during the reaction was continuously removed from the reaction system. After the completion of the reaction, about 400 ml of water was added to the reaction mixture and 20 g of (0.1 mole) of the unreacted iodobenzene was was recovered by distillation. Separation of the precipitate by filtration gave 123 g of 4,4'-diiododiphenylsulfone in 58% yield. M.P. 201° to 202° C. Purity of 99.6%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)/[S:6][C:5]1=[O:20].[CH3:21][N:22]1[CH:26]=[C:25]([S:27](Cl)(=[O:29])=[O:28])[N:24]=[CH:23]1.CCN(C(C)C)C(C)C.C(OC1C=CC(/C=C2/C(=O)N(CCNC(=O)C)C(=O)S/2)=CC=1)C>>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11](/[CH:10]=[C:7]2/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][S:27]([C:25]3[N:24]=[CH:23][N:22]([CH3:21])[CH:26]=3)(=[O:29])=[O:28])[C:5](=[O:20])[S:6]/2)=[CH:12][CH:13]=1)[CH3:19]
Reactant: CCOc1ccc(/C=C2\SC(=O)N(CCN)C2=O)cc1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Agent: CCOc1ccc(/C=C2\SC(=O)N(CCNC(C)=O)C2=O)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(/C=C2\SC(=O)N(CCNS(=O)(=O)c3cn(C)cn3)C2=O)cc1

Procedure:
The title compound 27c was prepared from compound 76 (101 mg, 0.25 mmol), 1-methylimidazole-4-sulfonyl chloride (50 mg, 0.28 mmol) and DIPEA (131 μL, 0.75 mmol) in a manner similar to that described for 25a in 98.0% (108 mg) yield as a light-yellow solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([CH2:8][O:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]1.[H-].[Na+].[CH3:22][C:23]1[O:27][C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=[N:25][C:24]=1[CH2:35]I.C(OC)(C)(C)C>CN(C)C=O.O>[CH3:22][C:23]1[O:27][C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=[N:25][C:24]=1[CH2:35][O:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([CH2:8][O:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]1
Reactant: Cc1ccc(-c2nc(CI)c(C)o2)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)OC[C@H]1CCC[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COC(C)(C)C
Product: Cc1ccc(-c2nc(CO[C@@H]3CCC[C@H](COC(C)(C)C(=O)OC(C)(C)C)C3)c(C)o2)cc1
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
50 mg of tert-butyl 2-(cis-3-hydroxycyclohexylmethoxy)-2-methylpropionate are dissolved in 0.5 ml of dimethylformamide and 22 mg of NaH (60%) are added. After 30 min of stirring, 112 mg of 5-methyl-2-p-tolyloxazol-4-yl-methyl iodide are added at room temperature. The mixture is placed in an ultrasonic bath for 10 min and then stirred at room temperature for 3 h. 10 ml of methyl tert-butyl ether and 10 ml of water are then added. The phases are separated, the aqueous phase is extracted once with methyl tert-butyl ether and the organic phases are dried over MgSO4 and concentrated. The residue is chromatographed on silica gel (heptane/ethyl acetate 5/1->1/1). 60 mg of the crude tert-butyl 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethoxy]-2-methylpropionate are obtained as a yellow oil. C27H39NO5 (457), LCMS(ESI): 458 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH2:7]Br.[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]([CH2:7][C:6]2[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:10])([OH:24])[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Fc1ccc(Cl)cc1CBr
Reactant: O=C1CCN(Cc2ccccc2)CC1
Product: OC1(Cc2cc(Cl)ccc2F)CCN(Cc2ccccc2)CC1

Procedure:
A sample of 5-chloro-2-fluorobenzyl bromide is converted to its Grignard reagent which is reacted with N-benzyl-4-piperidone to provide 1-benzyl-4-(5-chloro-2-fluorobenzyl)-4-piperidinol. The above is performed in a manner consistent with the procedure of Example 2A. This product is distilled at 210° C., 0.15 mm giving an orange oil. The oil is dissolved in ether where it is converted to its hydrochloride salt which is recrystallized thrice from an ethyl alcohol-ether mixture to provide the product, 1-benzyl-4-(5-chloro-2-fluorobenzyl)-4-piperidinol hydrochloride, mp 217°-219° C.
Reaction SMILES: [C:1]1([NH:7][S:8]([C:11]2[CH:12]=[C:13]([C:17]#[C:18]/[CH:19]=[CH:20]/[C:21]([OH:23])=O)[CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>O>[OH:29][NH:28][C:21](=[O:23])/[CH:20]=[CH:19]/[C:18]#[C:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([S:8](=[O:10])(=[O:9])[NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=1
Reactant: O=C(O)/C=C/C#Cc1cccc(S(=O)(=O)Nc2ccccc2)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(/C=C/C#Cc1cccc(S(=O)(=O)Nc2ccccc2)c1)NO
Reaction time: 0.17 h

Procedure:
To a solution of (E)-5-(3-phenylsulfamoylphenyl)pent-2-en-4-ynoic acid (56a) (0.25 g 0.77 mmol) in methylene chloride (5 ml) oxalyl chloride (0.42 g 3.1 mmol) was added. The resultant mixture was stirred for 1 hour at ambient temperature and the solvents were removed under reduced pressure. The crude product (57a) was dissolved in acetonitrile (5 ml) and the obtained solution to a mixture of hydroxylamine hydrochloride (0.3 g, 4.3 mmol) and NaHCO3 (0.3 g, 3.6 mmol) in water (8 ml) was added. The reaction mixture was stirred for 10 min. and the product was extracted with ethyl acetate (30 ml). The extract was washed with 10% Na2CO3, and the aqueous phase was acidified with 3% HCl. The precipitate was filtered and dried to give the title compound (0.12 g, (46%). M.p 88-90° C. 1H NMR (DMSO-d6, HMDSO) δ: 6.41 (1H, d, J=15.8 Hz, CH); 6.82 (1H, d, J=15.8 Hz, CH); 6.92-7.41 (5H, m, C6H5); 7.47-8.01 (4H, m, C6H4); 8.94-11.21 (3H, br s, NH, NH, OH). Anal. Calcd for C17H14N2O4S*0.4H2O: C 58.58, H 4.27, N 8.01. Found: C 58.12, H 4.03, N 7.80.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([C:11]1[N:15]([S:16]([N:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[N:14]=[CH:13][CH:12]=1)[CH3:10]>O1CCCC1>[Br:1][C:12]1[CH:13]=[N:14][N:15]([S:16]([N:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[C:11]=1[CH2:9][CH3:10]
Reactant: CCc1ccnn1S(=O)(=O)N(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCc1c(Br)cnn1S(=O)(=O)N(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
1-Bromopyrrolidine-2,5-dione (20.8 g) was added to a stirring solution (300 mL) of 5-ethyl-N,N-dimethyl-1H-pyrazole-1-sulfonamide (19.8 g) in tetrahydrofuran at room temperature. The reaction system was heated to 50° C., stirred for 2 hr and concentrated under reduced pressure. The residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (26.2 g) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1(N=C=NC2CCCCC2)CCCC[CH2:18]1.N1C=CC=CC=1.FC(F)(F)C(O)=O>CS(C)=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:14](=[O:15])[CH2:13][CH:9]1[C:10]([O:12][CH2:17][CH3:18])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C1CC(=O)CN1C(=O)OC(C)(C)C

Procedure:
Ethyl ester of 1-t-butoxycarbonyl-L-hydroxy-proline (7.77 g) was dissolved in DMSO (30 ml), added dicyclohexylcarbodiimide (18.4 g) and 2.4 ml of pyridine and 1.2 ml of trifluoroacetic acid were added dropwise at room temperature while stirring. The mixture was stirred for two hours at that temperature, then ethyl acetate was added to the reaction mixture and insolubles were filtered off. The filtrate was washed with water, dried over Na2SO4 and distilled off the solvent used, under reduced pressure. The residue was passed through a column packed with 120 g of silica gel and eluted with benzene-ethyl acetate (98: 2 v/v) and thus the objective compound was obtained (yield: 7.1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:12]3=[N:13][CH:14]=[C:15]([N:17]([CH3:19])[CH3:18])[N:16]=[C:11]3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:22].[C:23]([C:27]1[CH:31]=[C:30]([N:32]=[C:33]=[O:34])[N:29]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:1][C:2]2[CH:21]=[CH:20][C:5]([O:6][C:7]3[C:12]4=[N:13][CH:14]=[C:15]([N:17]([CH3:18])[CH3:19])[N:16]=[C:11]4[N:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[F:22])=[O:34])[N:29]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CN(C)c1cnc2c(Oc3ccc(N)c(F)c3)ccnc2n1
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Product: CN(C)c1cnc2c(Oc3ccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccccc4)c(F)c3)ccnc2n1

Procedure:
Method F2 was used with 8-(4-amino-3-fluorophenoxy)-N,N-dimethylpyrido[3,2-b]pyrazin-3-amine and 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole to give the product as a light yellow solid. Yield: 65 mg (90%).
Reaction SMILES: [N:1]([C:4]1[C:13]([CH3:14])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)=[C:2]=O.C1C=C(OC(OC2N=CC=CC=2)=[S:23])N=CC=1.NC1C(C)=C2C(C=CC=N2)=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:14][C:13]1[C:4]([N:1]=[C:2]=[S:23])=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2
Reactant: Cc1c(N=C=O)ccc2cccnc12
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Agent: CN(C)c1ccncc1
Agent: Cc1c(N)ccc2cccnc12
Solvent: ClCCl
Product: Cc1c(N=C=S)ccc2cccnc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
7-Isocyanato8-methylquinoline. To a solution of di-2-pyridyl thionocarbonate (2.29 g) and 4-dimethylaminopyridine (0.02 g) in methylene chloride (50 mL) is added dropwise a solution of 7-amino-8-methylquinoline (1.3 g) in methylene chloride (50 mL). The mixture is stirred for 5 hours at room temperature then rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with 25% ethyl acetate/hexanes to afford 8-methyl-7-quinolinylisothiocyanate as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7](Cl)=[N:6][N:5]2[CH:11]=1.O1C[CH2:15][CH2:14][CH2:13]1.C([Mg]Cl)CC>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH2:13][CH2:14][CH3:15])=[N:6][N:5]2[CH:11]=1
Reactant: Clc1cn2nc(Cl)ccc2n1
Reactant: C1CCOC1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: CCC[Mg]Cl
Solvent: O
Product: CCCc1ccc2nc(Cl)cn2n1

Procedure:
2,6-Dichloroimidazo[1,2-b]pyridazine (1.6 g, 8.5 mmol), [1,3-bis(diphenylphosphino)propane]nickel (II) dichloride (catalytic amount) and dehydrated tetrahydrofuran (20 ml) were introduced into a 100-ml three-necked flask under a nitrogen stream and stirred under ice-cooling, and a solution of propylmagnesium chloride in tetrahydrofuran (2 M, 6.4 ml, 12.8 mmol) was added dropwise thereto at 10° C. or less. After dropping, the mixture was stirred for 1 hour at the same temperature, for 1 hour at room temperature and for 2 hours at 50 to 60° C. After the reaction was completed, the reaction solution was left and cooled, and water (50 ml) was added thereto, and the mixture was stirred and extracted with ethyl acetate (20 ml×2). The organic layers were combined, washed with water, dried over magnesium sulfate and concentrated, and the residues were purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the title compound as orange crystals (containing a small amount of impurities). The yield was 0.8 g (48.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][C:27]=2[S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])[C:22]([Cl:41])=[CH:21][N:20]=1>>[Cl:41][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][C:27]=2[S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: CN(C)c1ccc(Nc2nc(Cl)ncc2Cl)c(S(=O)(=O)N(C)C)c1
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Product: CCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4ccc(N(C)C)cc4S(=O)(=O)N(C)C)n3)cc21

Procedure:
The title compound was prepared from 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-5-dimethylamino-N,N-dimethyl-benzenesulfonamide in an analogous manner to Example 61e. Product isolated as a tan solid (0.077 g, 64%). MP: 240-243° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.90 (s, 1H), 8.15 (d, J=9.1 Hz, 1H), 8.07 (s, 1H), 7.66 (d, J=2.3 Hz, 1H), 7.30-7.19 (m, 2H), 7.14 (d, J=3.0 Hz, 1H), 6.93 (br s, 1H), 6.85 (dd, J=9.2 Hz and 2.9 Hz, 1H), 3.75-3.62 (m, 2H), 3.02 (s, 6H), 2.72 (s, 6H), 2.37-2.26 (m, 2H), 2.10-1.95 (m, 2H), 1.32 (s, 6H), 1.17 (t, J=7.1 Hz, 3H). MS: 586.24 (MH)+.
Reaction SMILES: [OH:1][B:2]([OH:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[CH2:13](O)[CH2:14][CH2:15]O>C1(C)C=CC=CC=1>[O:1]1[CH2:15][CH2:14][CH2:13][O:12][B:2]1[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1
Reactant: OCCCO
Reactant: O=C(O)c1ccc(B(O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(B2OCCCO2)cc1
Reaction time: 6 h

Procedure:
A mixture of 4-(dihydroxyboryl)benzoic acid (30.00 g, 181 mmol) and 1,3-propanediol (15.20 g, 200 mmol) in toluene (750 mL) at 140° C. was stirred for 6 hours while collecting the water removed by azeotrope formation. The mixture was concentrated to provide the desired product.