Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:21]4[CH:22]=[CH:23][CH:24]=[C:20]4[C:19](=[O:25])[NH:18][N:17]=3)=[CH:12][CH:11]=2)C=CC=CC=1.[CH2:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][NH:28]1>CS(C)=O.C(OCC)(=O)C>[O:25]=[C:19]1[NH:18][N:17]=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:8]([N:28]3[CH2:29][C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:27]3)=[O:26])=[CH:15][CH:14]=2)[N:21]2[CH:22]=[CH:23][CH:24]=[C:20]12
Reactant: c1ccc2c(c1)CNC2
Reactant: O=C(Nc1ccc(-c2n[nH]c(=O)c3cccn23)cc1)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(Nc1ccc(-c2n[nH]c(=O)c3cccn23)cc1)N1Cc2ccccc2C1
Temperature: 25 °C

Procedure:
40 mg [4-(1-Oxo-1,2-dihydro-pyrrolo[1,2-d][1,2,4]triazin-4-yl)-phenyl]-carbamic acid phenyl ester (0.115 mmol) were dissolved in 0.3 ml DMSO. A mixture of 15 mg isoindoline (0.121 mmol) in 0.2 ml DMSO was added at room temperature and the reaction was stirred at room temperature over night. The reaction mixture was diluted in ethyl acetate and washed with water, aqueous HCl, water, aqueous NaOH, and water. The solvent was evaporated under reduced pressure to afford the title compound.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.C1(N)CCCCC1>C(O)(=O)C>[CH:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Solvent: NC1CCCCC1
Product: O=c1c2scc(-c3ccccc3)c2ncn1C1CCCCC1
Yield: 82.2 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), cyclohexylamine (0.113 ml, 0.99 mmol), and acetic acid (0.1 ml) were used to give 109.7 mg (0.35 mmol, 82.2% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][N:19]2[C:24]([O:26]CC)=O)=[S:17])=[CH:13][C:5]2[N:6]([CH2:10][CH:11]=[CH2:12])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.C[O-].[Na+]>O>[CH2:10]([N:6]1[C:5]2[CH:13]=[C:14]([N:15]3[C:24](=[O:26])[N:19]4[CH2:20][CH2:21][CH2:22][CH2:23][N:18]4[C:16]3=[S:17])[C:2]([F:1])=[CH:3][C:4]=2[S:8][C:7]1=[O:9])[CH:11]=[CH2:12]
Reactant: C=CCn1c(=O)sc2cc(F)c(NC(=S)N3CCCCN3C(=O)OCC)cc21
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: C=CCn1c(=O)sc2cc(F)c(-n3c(=O)n4n(c3=S)CCCC4)cc21
Yield: 13.3 %

Procedure:
Ethyl 2-[6-fluoro-3-(2-propenyl)-2(3H)-benzothiazolon-5-ylaminothiocarbonyl]hexahydropyridazine-1-carboxylate (2.61 g) was added to a methanolic solution (2.97 g) of 10% sodium methoxide, and the resultant mixture was heated under reflux for 1.5 hours and allowed to cool. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, concentrated and purified by silica gel thin layer chromatography with a mixture of ethyl acetate and toluene (1:9) as an eluent to give 2-[3-(2-propenyl)-6-fluoro-2(3H)-benzothiazolon-5-yl]-hexahydro-3-thioxo-1H-[1,2,4]triazolo-[1,2-a]pyridazin-1-one (0.31 g). m.p., 179°-181° C.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][C@H:18]1[CH3:23])(=[O:16])=[O:15].N1C=CC=CC=1>C(Cl)Cl>[CH3:13][S:14]([N:17]1[CH2:22][CH2:21][N:20]([C:2]([Cl:1])=[O:4])[CH2:19][C@H:18]1[CH3:23])(=[O:15])=[O:16]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@@H]1CNCCN1S(C)(=O)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)Cl)CCN1S(C)(=O)=O
Temperature: 25 °C
Yield: 178.8 %

Procedure:
Second step: To a stirred solution of carbonic acid ditrichloromethyl ester (triphosgene) (1.17 g, 3.95 mmol) in CH2Cl2 (20 mL) at −78° C., was added a solution of (R)-1-methanesulfonyl-2-methyl-piperazine (1.76 g, 9.9 mmol) and pyridine (1.60 mL, 20 mmol) in CH2Cl2 (20 mL) over 1 hour. The temperature was raised to RT, and stirring was continued over night. The organic phase was washed with H2O, dried over Na2SO4. Concentration under vacuo and flash chromatography (SiO2, EtOAc/H, 1:1) yielded 1.70 g (71%) of (R)-4-methanesulfonyl-3-methyl-piperazine-1-carbonyl chloride as a light yellow solid.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:14]2[N:15]([CH3:20])[C:16](=[O:19])[CH:17]=[CH:18][C:13]=2[CH:12]=[N:11]1>C(O)(=O)C.O>[Br:1][C:17]1[C:16](=[O:19])[N:15]([CH3:20])[C:14]2[N:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[Cl:3])[N:11]=[CH:12][C:13]=2[CH:18]=1
Reactant: BrBr
Reactant: Cn1c(=O)ccc2cnn(-c3ccccc3Cl)c21
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(=O)c(Br)cc2cnn(-c3ccccc3Cl)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
At RT, bromine (206 mg, 1.29 mmol) was added to a solution of 1(2-chlorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (319 mg, 1.23 mmol) in 1.5 mL of glacial acetic acid. After stirring at RT for 30 min, it was diluted with water and stirred for 5 min. The precipitated white solid was filtered off and rinsed with water, collected and dried to afford 5-bromo-1-(2-chlorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (323 mg). The filtrate was extracted three times with EtOAc. The combined EtOAc layers were washed with 2 N NaOH followed by brine, dried and concentrated to afford additional 5-bromo-1-(2-chlorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (82 mg). The crude material was used without further purification. MS (ESI, pos.ion) m/z: 338.0/340.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH2:9][CH3:10].[Li]CCCC.[CH2:16]([N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH4+].[Cl-]>C1COCC1>[CH2:16]([N:23]1[CH2:28][CH2:27][C:26]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=2[CH2:9][CH3:10])([OH:29])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CCc1c(Br)cccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1c(Br)cccc1C1(O)CCN(Cc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 4 h
Yield: 71.5 %

Procedure:
To a solution of 1,3-dibromo-2-ethyl-benzene (30 g, 113.65 mmol) in THF (150 mL) was added 45.5 mL of BuLi (2.5M in hexane, 113.65 mmol) under nitrogen. The mixture was stirred for 4 hr at −78° C. Then N-benzyl-4-piperidone (21.51 g, 113.65 mmol) was added to the above mixture and stirred overnight, The mixture was poured into sat. aqueous NH4Cl solution and extracted with DCM. The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure give the crude 1-benzyl-4-(3-bromo-2-ethyl-phenyl)-piperidin-4-ol (D116) (30.4 g). MS (ES): C20H24BrNO requires 373. found 374 (M+H+).
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C>[NH2:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][CH2:16][N:13]2[CH2:12][CH2:11][CH:10]([CH2:9][O:8][CH:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:15][CH2:14]2)=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(CCN2CCC(COC(c3ccccc3)c3ccccc3)CC2)cc1
Solvent: CCO
Product: Nc1ccc(CCN2CCC(COC(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 70 °C
Yield: 49.9 %

Procedure:
A mixture of 4-(diphenylmethoxymethyl)-1-(4-nitrophenethyl)piperidine (1.40 g, 3.3 mmol) (see Example 13) and stannous (II) dichloride dihydrate (3.68 g, 16.3 mmol) in ethanol (20 ml) was heated at 70° C. for 2 hours, allowed to cool to room temperature and filtered. The filtrate was evaporated and the residue partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The layers were separated and the aqueous layer extracted into ethyl acetate. The combined organic layers were washed with saturated brine, dried over magnesium sulphate and evaporated. The residue was triturated with ether and the resulting solid collected, washed with ether and dried to give the title compound (0.66 g) as a fawn solid, m.p. 188°-190° C., which was characterized by its 1H-NMR spectrum.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:7]([Br:10])=[CH:8][N:9]=1)[C:5]#[N:6].C([O-])(O)=O.[Na+].Cl[CH2:17][CH:18]=O>CCO>[Br:10][C:7]1[C:4]([C:5]#[N:6])=[CH:3][C:2]2[N:9]([CH:17]=[CH:18][N:1]=2)[CH:8]=1
Reactant: O=CCCl
Reactant: N#Cc1cc(N)ncc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cc2nccn2cc1Br
Temperature: 25 °C
Yield: 53 %

Procedure:
A mixture of 2-amino-5-bromo-isonicotinonitrile (5.0 g, 25.3 mmol), NaHCO3 (3.6 g, 42.9 mmol) and chloracetaldehyde (17.0 mL, 114.0 mmol) in EtOH (160 mL) was vigorously stirred and refluxed for 14 h. The reaction mixture was cooled to RT, concentrated under vacuum and the remaining residue was suspended in DCM (500 mL) and brine (100 mL). The aqueous layer was separated and extracted with DCM (5×), and the combined organic fractions were dried over Na2SO4, filtered, and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→3:7) to yield the title compound (2.97 g, 13.4 mmol, 53%) as an orange solid. MS: 223 [M+1]+; HPLC: AtRet=0.54; TLC: RF 0.17 (hexane/DCM/TBME 1:1:2).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][N:3]=1.[CH3:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([B:19]2[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]2)[CH:18]=1)[NH2:15].O1CCOCC1.CS(O)(=O)=O>C(OCC)(=O)C>[F:10][C:5]1[C:6]([O:8][CH3:9])=[N:7][C:2]([NH:15][C:14]2[CH:16]=[C:17]([B:19]3[O:23][C:22]([CH3:24])([CH3:25])[C:21]([CH3:27])([CH3:26])[O:20]3)[CH:18]=[C:12]([CH3:11])[CH:13]=2)=[N:3][CH:4]=1
Reactant: COc1nc(Cl)ncc1F
Reactant: Cc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1nc(Nc2cc(C)cc(B3OC(C)(C)C(C)(C)O3)c2)ncc1F
Temperature: 100 °C
Yield: 50 %

Procedure:
To a flask containing 2-chloro-5-fluoro-4-methoxypyrimidine (0.32 g, 1.97 mmol) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.40 g, 1.72 mmol) were added dioxane (17 mL) and methanesulfonic acid (0.13 mL, 1.97 mmol). The reaction was heated at 100° C. overnight. The reaction was then cooled to room temperature, diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. Flash chromatography was used for purification to yield 5-fluoro-4-methoxy-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine (0.31 g, 0.86 mmol, 50% yield). MS ESI: [M+H]+ m/z 360. 1H NMR (500 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.27 (d, J=3.2, 1H), 8.00 (s, 1H), 7.57 (s, 1H), 7.07 (s, 1H), 4.01 (s, 3H), 2.25 (s, 3H), 1.26 (s, 12H).
Reaction SMILES: C([O-])=O.[NH4+].C([O:12][NH:13][C:14](=[O:36])[CH2:15][C:16]1([CH2:32][CH:33]([CH3:35])[CH3:34])[C:20](=[O:21])[N:19]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18](=[O:30])[N:17]1[CH3:31])C1C=CC=CC=1>[Pd].CCO>[OH:12][NH:13][C:14](=[O:36])[CH2:15][C:16]1([CH2:32][CH:33]([CH3:34])[CH3:35])[C:20](=[O:21])[N:19]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18](=[O:30])[N:17]1[CH3:31]
Reactant: CC(C)CC1(CC(=O)NOCc2ccccc2)C(=O)N(CCc2ccccc2)C(=O)N1C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)CC1(CC(=O)NO)C(=O)N(CCc2ccccc2)C(=O)N1C
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 89.5 %

Procedure:
Ammonium formate (59.0 mg, 0.936 mmol) is added to a mixture of N-benzyloxy-3-methyl-4-(2-methylpropyl)-2,5-dioxo-1-(2-phenylethyl)-4-imidazolidineacetamide (91.0 mg, 0.208 mmol), EtOH (2.5 mL), and 10% Pd/C (15 mg). The mixture is stirred at room temperature for 5.5 hours. Additional ammonium formate (35.0 mg, 0.555 mmol) is added after 2.5 hours. The mixture is filtered, the solids washed with MeOH (3×15 mL) and CHCl3 (3×15 mL), and the filtrate concentrated. The residue was taken up into CHCl3 (40 mL), dried (MgSO4), filtered, and concentrated to give 64.7 mg (90%) of the title compound as an oil. Crystallization from ether/hexane provided 46.4 mg (64%) of the title compound as a white powder (mp 127°-129° C.).
Reaction SMILES: NC(N)=O.[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([OH:13])[C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>>[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:32]([NH:31][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([Cl:30])[C:24]=2[Cl:23])=[O:33])=[C:8]([OH:13])[C:7]=1[S:14]([N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1)(=[O:15])=[O:16]
Reactant: Nc1ccc(Cl)c(S(=O)(=O)N2CCOCC2)c1O
Reactant: O=C=Nc1cccc(Cl)c1Cl
Agent: NC(N)=O
Product: O=C(Nc1ccc(Cl)c(S(=O)(=O)N2CCOCC2)c1O)Nc1cccc(Cl)c1Cl
Yield: 52 %

Procedure:
Following the general procedure for urea formation outlined in example 15, 4-chloro-2-hydroxy-3-(4-morpholinylsulfonyl)aniline (90 mg, 0.31 mmol) and 2,3-dichlorophenylisocyanate (70 μL, 0.37 mmnol) were coupled to form the desired urea (77 mg, 52%). EI-MS (m/z) 477.68, 479.72, 481.63 (M−).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=2)[O:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][NH:16][C:17](=[O:23])[CH2:18][S:19][CH2:20][CH2:21][NH2:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:27]([O:29][C:30](Cl)=[O:31])[CH3:28].[Cl-].[Na+]>N1C=CC=CC=1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=2)[O:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][NH:16][C:17](=[O:23])[CH2:18][S:19][CH2:20][CH2:21][NH:22][C:30]([O:29][CH2:27][CH3:28])=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)Cl
Reactant: NCCSCC(=O)NC/C=C\COc1cccc(CN2CCCCC2)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOC(=O)NCCSCC(=O)NC/C=C\COc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.7 %

Procedure:
There was dissolved 2.7 g (0.0072 mol) of N-[4-[3-(piperidinomethyl)phenoxy]-cis-2-butenyl]-2(2-aminoethylthio)acetamide in 20 ml of pyridine and added dropwise 0.78 g (0.0072 mol) of ethylchlorocarbonate under cooling with ice, and the mixture was stirred for 18 hours at room temperature. The obtained reaction mixture was poured into ice water and saturated with sodium chloride. The deposited oily matter was extracted with chloroform and washed with saturated aqueous solution of sodium chloride, and then dried over Glauber's salt. Then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to give 0.8 g of the titled compound as oily matter.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][N:7]1[C:11]([CH3:12])=[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[CH:24][CH:23]=4)[CH:20]=3)[N:15]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:14]=2)[CH:9]=[N:8]1.[CH3:47][C@H:48]1[CH2:50][O:49]1>C(O)C>[F:2][C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][N:7]1[C:11]([CH3:12])=[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:33][CH2:32][N:31]([CH2:47][C@@H:48]([OH:49])[CH3:50])[CH2:30][CH2:29]5)=[CH:24][CH:23]=4)[CH:20]=3)[N:15]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:35])=[O:36])[CH:14]=2)[CH:9]=[N:8]1
Reactant: C[C@H]1CO1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)cc4)cnc32)cc1

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (230 mg, 0.349 mmol) was alkylated using (S)-2-methyloxirane (41 mg, 0.69 mmol) DIPEA (136 mg, 10 mmol) and ethanol (5 mL) to get 200 mg (crude) of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([NH:1][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13])=[CH:3][C:4]=1[F:12]
Reactant: COC(=O)c1ccc(N)cc1F
Reactant: CCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC)c(F)c1

Procedure:
A mixture of 8.3 g. of methyl 4-amino-2-fluorobenzoate, 15.0 g of hexadecylbromide, 6.8 g of anhydrous potassium carbonate and 50 ml of hexamethylphosphoramide is heated to 135° for 20 hours. Upon cooling, dilution with water and extraction with ether, the orange colored ethereal extract is washed with water, dried and evaporated to yield an off-white solid. Recrystallization of this material from hexane affords methyl-2-fluoro-4-(hexadecylamino)benzoate.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[OH:5][C:6]1[C:10](=[C:11]([O:18][CH3:19])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:9][C:8](=[O:20])[CH:7]=1>C(O)(=O)C>[CH3:19][O:18][C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:10]1[NH:9][C:8](=[O:20])[C:7](=[N:1][OH:3])[C:6]1=[O:5]
Reactant: COC(=C1NC(=O)C=C1O)c1ccccc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=C1NC(=O)C(=NO)C1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An aqueous solution of 1.1 mmol (0.075 g) sodium nitrite was added dropwise to an ice-cooled solution of 2 mmol 4-hydroxy-5-(methoxyphenyl-methylene)-1,5-dihydropyrrol-2-one (prepared in accordance with H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, 331, 389-394) and H. -D. Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in 5 ml glacial acetic acid, while stirring. The resulting solution was then stirred at room temperature for 30 minutes and concentrated in vacuo. The residue is purified by recrystallization from ethanol. The yield of 5-(methoxyphenylmethylene)-pyrrolidine-2,3,4-trione 3-oxime was 60%, with a melting point of 174° C.
Reaction SMILES: [CH2:1]([S:4][CH:5]1[NH:8][C:7](=[O:9])[CH:6]1[CH2:10][CH3:11])[CH:2]=[CH2:3].Br[CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([S:4][CH:5]1[N:8]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:7](=[O:9])[CH:6]1[CH2:10][CH3:11])[CH:2]=[CH2:3]
Reactant: COC(=O)CBr
Reactant: C=CCSC1NC(=O)C1CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCSC1C(CC)C(=O)N1CC(=O)OC
Reaction time: 8 h

Procedure:
To a solution of 2.34 g of 4-allylthio-3-ethylazetidinone in 20 ml of redistilled dimethylformamide were added 1.37 ml of methyl bromoacetate and 4.16 g of ground potassium carbonate. The solution was stirred overnight then filtered through a pad of Hyflo, (Hyflo being a Trade Mark), poured into 75 ml of water, and extracted five times with ethyl acetate. The combined organic extracts were washed with water, dried over magnesium sulphate, and evaporated in vacuo to give the title compound. (Yield 3 g)
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:14][CH2:12][C:11]1[C:2]([Cl:1])=[C:3]([CH:8]=[CH:9][C:10]=1[Cl:13])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(Cl)c(C)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(Cl)c(CBr)c1Cl
Yield: 95.4 %

Procedure:
1.0 g of azobisisobutyronitrile was added to a solution of 84.0 g (0.38 mol) of methyl 2,4-dichloro-3-methylbenzoate and 67.6 g (0.38 mol) of N-bromosuccinimide in 380 ml of carbon tetrachloride. After heating for 3.5 hours under reflux, the reaction mixture was cooled and the resulting precipitate was filtered off with suction. The filtrate was concentrated under reduced pressure and the resulting residue was triturated with methyl tert-butyl ether. 108.0 g of methyl 3-bromomethyl-2,4-dichlorobenzoate were obtained.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[NH:15]1[CH2:20][CH2:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21]2)[CH2:17][CH2:16]1.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:15]3[CH2:20][CH2:19][C:18]4([C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH2:22][CH2:21]4)[CH2:17][CH2:16]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1ccc2c(c1)CCC21CCNCC1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC2(CCc3ccccc32)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and spiro[indane-1,4'-piperidine]. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 76% overall yield. mp 110°-112°. FDMS m/e=376 (M+ of free base). α[D]589 =-11.60 (c=0.46, methanol).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[CH3:9][N:10]1[CH:14]2[CH2:15][CH:16](O)[CH2:17][CH:11]1[CH2:12][CH2:13]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>CN(C=O)C>[CH3:9][N:10]1[CH:14]2[CH2:13][CH2:12][CH:11]1[CH2:17][CH:16]([N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)[CH2:15]2
Reactant: CN1C2CCC1CC(O)C2
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CN1C2CCC1CC(n1cc([N+](=O)[O-])cn1)C2
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 4-Nitro-1H-pyrazole (10 g, 88.4 mmol) in DGM:DMF (3:1, 400 mL) were added Tropine (12.5 g, 88.4 mmol, 1 eq.), triphenyl phosphine (69.5 g, 265 mmol), followed by di-tert-butyl azodicarboxylate (61 g, 265 mmol) portionwise at 10-15° C. The reaction mixture was stirred at RT for 4 days. It was then concentrated under reduced pressure. The crude was purified by flash chromatography on silica (PetEther/EtOAc) to give the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.31 (s, 1H), 4.92-4.86 (m, 1H), 3.99 (m, 2H), 2.66-2.56 (m, 5H), 2.26-2.17 (m, 4H), 2.06-2.01 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]O)#[CH:2].[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][N:15]1[C:11](=[O:21])[C:12]2[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:14]1=[O:16])#[CH:2]
Reactant: C#Cc1ccccc1CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C#Cc1ccccc1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.8 %

Procedure:
To a solution of 2-ethynylbenzyl alcohol (1.00 g), phthalimide (2.20 g) and triphenylphosphine (3.96 g) in tetrahydrofuran (30 mL), a solution of diisopropyl azodicarboxylate (1.9 mol/L) in toluene (7.9 mL) was added under ice cooling, and the mixture was stirred at room temperature for 5 hours. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, 96 to 66% hexane in ethyl acetate) to obtain 2-(2-ethynylbenzyl)isoindoline-1,3-dione (F8, 1.44 g) as pale orange solid.