Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[CH2:14]([NH2:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[ClH:1].[CH2:14]([NH:20][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCN
Reactant: Cc1cc(Cl)c2cc(O)ccc2n1
Product: CCCCCCNc1cc(C)nc2ccc(O)cc12
Product: Cl

Procedure:
In a manner similar to that described in Example 39, Part B, 4-chloro-2-methylquinolin-6-ol and hexylamine were transformed into the title compound: m.p. 234°-236° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]([CH3:24])=[N:22][N:23]=2)=[CH:15][CH:14]=1.[C:25](Cl)(=[O:29])[C:26](Cl)=[O:27]>>[CH3:24][C:21]1[O:20][C:19]([C:16]2[CH:15]=[CH:14][C:13]([N:12]3[C:3]4[CH:4]=[CH:5][C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=5[C:2]=4[NH:1][C:26](=[O:27])[C:25]3=[O:29])=[CH:18][CH:17]=2)=[N:23][N:22]=1
Reactant: Cc1nnc(-c2ccc(Nc3ccc4ccccc4c3N)cc2)o1
Reactant: O=C(Cl)C(=O)Cl
Product: Cc1nnc(-c2ccc(-n3c(=O)c(=O)[nH]c4c5ccccc5ccc43)cc2)o1
Yield: 68 %

Procedure:
1-Amino-2-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)phenyl]aminonaphthalene (190 mg, 0.6 mmol) and oxalyl chloride were used in a process similar to Example 1(3) to give the titled compound (150 mg, yield 68%) as a gray crystal.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([C:14]2[CH:18]=[C:17]([CH2:19][CH3:20])[O:16][N:15]=2)[O:7][C@H:6]1[N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][C:24]([Cl:36])=[N:25][C:26]=2[NH:30][CH:31]([CH2:34][CH3:35])[CH2:32][CH3:33])(=[O:3])C.O1CCN(CCN)CC1>CS(C)=O>[CH:1]([OH:4])=[O:3].[Cl:36][C:24]1[N:23]=[C:22]2[C:27]([N:28]=[CH:29][N:21]2[C@H:6]2[C@H:5]([OH:4])[C@H:9]([OH:10])[C@@H:8]([C:14]3[CH:18]=[C:17]([CH2:19][CH3:20])[O:16][N:15]=3)[O:7]2)=[C:26]([NH:30][CH:31]([CH2:32][CH3:33])[CH2:34][CH3:35])[N:25]=1
Reactant: CCc1cc([C@H]2O[C@@H](n3cnc4c(NC(CC)CC)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)no1
Agent: NCCN1CCOCC1
Solvent: CS(C)=O
Product: CCc1cc([C@H]2O[C@@H](n3cnc4c(NC(CC)CC)nc(Cl)nc43)[C@H](O)[C@@H]2O)no1
Product: O=CO
Reaction time: 60 h
Yield: 43.2 %

Procedure:
A mixture of (2R,3R,4R,5R)-4-(acetyloxy)-2-{2-chloro-6-[(1-ethylpropyl)amino]-9H-purin-9-yl}-5-(5-ethylisoxazol-3-yl)tetrahydrofuran-3-yl acetate (30 mg) and 2-morpholinoethylamine (0.037 ml) was heated at 90° C. for 24 h in dimethylsulphoxide (0.5 ml). Heating was continued for 60 h at 90° C. Purification by preparative HPLC (gradient profile 5-95% (ii) over 18.25 min) gave the title compound as a white solid (6 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:13]1[S:17][C:16]([C:18]([O:20]CC)=[O:19])=[N:15][C:14]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:30]#[N:31])[CH:24]=1.C(=O)(O)[O-].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:30]([C:25]1[CH:24]=[C:23]([C:14]2[N:15]=[C:16]([C:18]([OH:20])=[O:19])[S:17][C:13]=2[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:8]=2)[CH:28]=[CH:27][C:26]=1[F:29])#[N:31]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1nc(-c2ccc(F)c(C#N)c2)c(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1cccc(-c2sc(C(=O)O)nc2-c2ccc(F)c(C#N)c2)c1

Procedure:
At room temperature, 217 mg (1.48 mmol) of (3-cyanophenyl)boronic acid are added to 350 mg (0.985 mmol) of the compound from Example 29A and 56.9 mg (0.049 mmol) of tetrakis(triphenylphosphine)palladium in 26 ml of DME. 252 mg (3.01 mmol) of sodium bicarbonate in 11 ml of water are subsequently added, and the mixture is stirred under reflux for 2 h. The reaction solution is subsequently concentrated under reduced pressure and the residue is taken up in ethyl acetate and washed with a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). 47.3 mg (14% of theory) of the title compound are obtained.
Reaction SMILES: [I:1][CH:2]=[CH:3][C:4]([CH3:11])([OH:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C)C=O>[I:1][CH:2]=[CH:3][C:4]([O:10][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])([CH3:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCCC(C)(O)C=CI
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCCCCC(C)(C=CI)O[Si](C)(C)C(C)(C)C

Procedure:
A solution of 2.625 g. of dl-1-iodo-3-methyl-1-octen-3-ol, 3.2 g. of imidazole and 3.6 g. of t-butyldimethylsilyl chloride in 10 ml. of dimethylformamide is stirred at 60° C. for 35 hours under nitrogen. After vacuum evaporation of the solvent, the residue is extracted with hexane and chromatogaphed on neutral alumina (Activity 3). Elution with hexane gives the title product as an oil, 2.15 g.
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[C:6]([CH:16]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])=[CH:7][C:8]([N:11]([CH3:15])[CH2:12][CH2:13][OH:14])=[N:9][CH:10]=1.[CH2:35]([N:37]=[C:38]=[O:39])[CH3:36]>N1C=CC=CC=1>[CH2:35]([NH:37][C:38](=[O:39])[O:14][CH2:13][CH2:12][N:11]([C:8]1[CH:7]=[C:6]([CH:16]([S:25]([C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)(=[O:27])=[O:26])[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[C:5]([Cl:4])=[CH:10][N:9]=1)[CH3:15])[CH3:36]
Reactant: CCN=C=O
Reactant: CN(CCO)c1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCNC(=O)OCCN(C)c1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Reaction time: 19 h
Yield: 74 %

Procedure:
To a methylene chloride (1.0 ml) solution of 2-[[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl](methyl)amino]ethanol (73 mg, 0.15 mmol) was added pyridine (0.5 ml), followed by further addition of ethyl isocyanate (100 μl). The resulting mixture was stirred for 19 hours. After the reaction mixture was concentrated under reduced pressure, the residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to yield the title compound (65 mg, 74%) as an oil.
Reaction SMILES: C(O[O:5][C:6]1[CH:20]=[C:19](CC)[C:9]2[C:10]([C:13]3[O:14][C:15]([CH3:18])=[CH:16][CH:17]=3)=[N:11][O:12][C:8]=2[C:7]=1[Cl:23])(=O)C.[OH-:24].[Na+].Cl.[CH2:27]([OH:29])[CH3:28]>O>[Cl:23][C:7]1[C:8]2[O:12][N:11]=[C:10]([C:13]3[O:14][C:15]([CH3:18])=[CH:16][CH:17]=3)[C:9]=2[CH:19]=[CH:20][C:6]=1[O:5][CH2:28][C:27]([OH:24])=[O:29]
Reactant: [OH-]
Reactant: CCc1cc(OOC(C)=O)c(Cl)c2onc(-c3ccc(C)o3)c12
Reactant: CCO
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc(-c2noc3c(Cl)c(OCC(=O)O)ccc23)o1
Reaction time: 1.5 h

Procedure:
To a suspension of 15.0 g of ethyl[7-chloro-3-(5-methyl-2-furyl)-1,2-benzisoxazol-6-yl]oxy acetate, Example 10, in 800 ml of ethyl alcohol there is added 10 ml of a 50% sodium hydroxide solution. The reaction mixture is refluxed with vigorous stirring for 1.5 hours and 100 ml of 5% hydrochloric acid is added thereto. The resulting solution is sequentially chilled and diluted with water as the product begins to crystallize. The product is collected by filtration and recrystallized from methyl alcohol to yield {[7-chloro-3-(5-methyl-2-furyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid, mp 217°-219° C.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([N:27]([CH3:35])C(=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[N:36]1[CH:41]=[C:40](B(O)O)[CH:39]=[N:38][CH:37]=1>>[CH3:35][NH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:40]3[CH:41]=[N:36][CH:37]=[N:38][CH:39]=3)=[CH:7][C:6]([C:8]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:21])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cncnc1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Product: CN[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncnc2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 93 using (R)-tert-butyl (1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (Stage 99.1) and pyrimidin-5-ylboronic acid. LC-MS (Condition 6) tR=0.89 min, m/z=459.0 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:3][CH2:2]1.Br[CH:23]1[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2.C(Cl)(Cl)Cl.[OH-].[Na+]>C(#N)C>[CH:25]1[C:24]2[CH:23]([N:1]3[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[CH2:3][CH2:2]3)[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]=2[CH:28]=[CH:27][CH:26]=1
Reactant: BrC1c2ccccc2-c2ccccc21
Reactant: O=C(CCc1cccnc1)NCCCCC1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: O=C(CCc1cccnc1)NCCCCC1CCN(C2c3ccccc3-c3ccccc32)CC1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
8.0 g (27.7 mmol) N-(4-piperidin-4-yl-butyl)-3-(pyridin-3-yl)-propionamide and 5.6 g (55.3 mmol) TEA are placed in 100 ml acetonitrile and cooled to ca. 0° C. under moisture exclusion. 6.8 g (27.7 mmol) 9-bromofluorene are added in solid form and the mixture is stirred two days at ca. 65° C. and two days at RT. Subsequently, the solvent is drawn off under vacuum to a large extent, and the residue is dispersed between CHCl3 and 10% NaOH. The organic phase is washed twice with water and dried over sodium sulfate. After the removal of the solvent, the residue is chromatographically purified over silica gel with CHCl3/CH3OH (98/2 to 94/6) and crystallized from 30 ml acetonitrile after drawing off the solvent. Colorless crystals with an MP of 131-132° C.; yield 2.5 g (20%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CC1(C)C(C)(C)OB([C:28]2[CH:40]=[CH:39][C:31]([CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:30][CH:29]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:5]1[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:3][C:2]([C:28]2[CH:29]=[CH:30][C:31]([CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:39][CH:40]=2)=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccc(CN3CCOCC3)cc2)cc(NC2CCOCC2)c1C
Temperature: 100 °C
Yield: 64.4 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (600 mg, 1.83 mmol) and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine (833 mg, 2.75 mmol) in dioxane (9 mL), aqueous 2M Na2CO3 solution (3.30 mL, 6.60 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (211 mg, 0.18 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (500 mg, 77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH:13]([CH3:15])[NH:12][CH:11]([CH3:16])[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[F:17][C:18]([F:42])([F:41])[CH2:19][NH:20][C:21]([C:23]1([CH2:36][CH2:37][CH2:38][CH2:39]Br)[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22]>>[F:17][C:18]([F:41])([F:42])[CH2:19][NH:20][C:21]([C:23]1([CH2:36][CH2:37][CH2:38][CH2:39][N:12]2[CH:11]([CH3:16])[CH2:10][N:9]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=3)[CH2:14][CH:13]2[CH3:15])[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22]
Reactant: COc1cccc(N2CC(C)NC(C)C2)n1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: COc1cccc(N2CC(C)N(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)C(C)C2)n1

Procedure:
Prepared analogously to Example 2 b from 1-(6-methoxy-pyridin-2-yl)-3,5-dimethyl-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [C:1]1([O:7][CH:8]=[CH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10]([CH:12]=[CH2:13])=[O:11].C1(C=CC(O)=CC=1)O>>[O:7]([CH:8]1[CH2:9][CH2:13][CH:12]=[CH:10][O:11]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=COc1ccccc1
Reactant: C=CC=O
Agent: Oc1ccc(O)cc1
Product: C1=COC(Oc2ccccc2)CC1

Procedure:
45 g (375 mmol) of phenylvinyl ether, 21 g (375 mmol) of acrolein and 0.66 g (6 mmol) of hydroquinone are reacted in a pressure reactor for 1 h at 185° C. After cooling, 2-phenoxy-3,4-dihydro-2H-pyran is isolated by distillation at 80° C./0.0267 kPa in a yield of 30.2 g (172 mmol; 46%) as a clear liquid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)=[O:4].[C:13]([O:17][C:18](=[O:21])[CH:19]=[CH2:20])([CH3:16])([CH3:15])[CH3:14].N12CCN(CC1)CC2>>[C:13]([O:17][C:18](=[O:21])[C:19](=[CH2:20])[CH:9]([OH:10])[C:8]1[CH:11]=[CH:12][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: C1CN2CCN1CC2
Product: C=C(C(=O)OC(C)(C)C)C(O)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 73 %

Procedure:
4-(Methoxycarbonyl)benzaldehyde (3.3 g, 20 mM), t-butylacrylate (3.5 ml, 24 mM) and 1,4-diazabicyclo[2,2,2]octane (449 mg, 4 mM) were mixed and stirred in a vessel at room temperature for 5 days. The resulting mixture was extracted with diethyl ether. The organic layer was separated, washed with 2N hydrochloric acid, water, and sodium bicarbonate in order, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography, to obtain 4.2 g of the title compound as a white solid (yield 73%).
Reaction SMILES: [CH2:1]([N:3]1[C:11](=[O:12])[C:10]2[NH:9][C:8]([C:13]3[CH:18]=[CH:17][C:16]([S:19](O)(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[N:7][C:6]=2[N:5]([CH2:23][CH3:24])[C:4]1=[O:25])[CH3:2].S(Cl)([Cl:28])=O.[CH3:30][N:31]([CH3:36])[CH2:32][CH2:33][CH2:34][NH2:35]>CN(C)C=O>[ClH:28].[CH2:1]([N:3]1[C:11](=[O:12])[C:10]2[NH:9][C:8]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH:35][CH2:34][CH2:33][CH2:32][N:31]([CH3:36])[CH3:30])(=[O:21])=[O:20])=[CH:17][CH:18]=3)=[N:7][C:6]=2[N:5]([CH2:23][CH3:24])[C:4]1=[O:25])[CH3:2]
Reactant: CCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)O)cc3)nc2n(CC)c1=O
Reactant: CN(C)CCCN
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)NCCCN(C)C)cc3)nc2n(CC)c1=O
Product: Cl
Temperature: 25 °C
Yield: 22.5 %

Procedure:
A mixture of 4-(1,3-diethyl-2,3,6,7-tetrahydro-2,6,-dioxo-1H-purin-8-yl)benzenesulfonic acid, (5.0 g, 0.014 moles) and N,N-dimethylformamide (150 ml) is cooled to 0° and treated with thionyl chloride (3.3 g, 0.027 moles). When the addition is complete, the reaction mixture is permitted to warm to ambient temperature and stirred vigorously until a thick slurry is formed. To this slurry is added 3-(dimethylamino)propylamine (14 g, 0.137 moles) in one portion, the mixture is stirred until a clear solution is obtained, and concentrated on a rotary evaporator. The residue is taken up in water, filtered, recrystallized from ethanol, and dried at 78° to yield 1.53 grams of 4-(1,3-diethyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)-N-[3-(dimethylamino)-propyl]benzenesulfonamide monohydrochloride, mp 291°-292° C.(d).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[C:18]1([CH2:24][CH2:25][NH2:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])=[N:26][CH2:25][CH2:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)#[N:2]
Reactant: NCCc1ccccc1
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Solvent: CC#N
Product: Cc1nc[nH]c1CSCCNC(=NCCc1ccccc1)NC#N
Yield: 40.9 %

Procedure:
A solution of N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (2.69 g) and 2-phenylethylamine (7.2 g) in acetonitrile (50 ml) was heated under reflux for 24 hours. Following concentration and ether extraction to remove excess 2-phenylethylamine the crude product was chromatographed on a column of silica gel and eluted with ethyl acetate-isopropyl alcohol (4:1). Recrystallisation from ethanol-ether afforded the title compound (1.4 g) m.p. 135°-136°. (Found: C, 59.8; H, 6.8; N, 24.8; S, 9.4% C17H22N6S requires: C, 59.6; H, 6.5; N, 24.5; S, 9.4%).
Reaction SMILES: [Si]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[N:13]([C@@H:25]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[C:26]([CH3:28])=[CH2:27])[C:12]1=[O:42])[CH3:10])(C(C)(C)C)(C)C.B(F)(F)F.CCOCC>C(#N)C.C(OCC)(=O)C>[OH:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[N:13]([C:25]([C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:30])=[C:26]([CH3:28])[CH3:27])[C:12]1=[O:42])[CH3:10]
Reactant: C=C(C)[C@H](C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1CC(=O)Sc1ccccc1
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@H]([C@@H](C)O)[C@H]1CC(=O)Sc1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
64 mg (0.104 mmole) of (3S, 4R)-3-[(R)-1-t-butyldimethylsilyloxyethyl]-1-[(R)-2-methyl-1-(p-nitrobenzyloxycarbonyl)prop-2-enyl]-4-[(phenylthio)-carbonylmethyl]-2-azetidinone were dissolved in 1.5 ml of acetonitrile. To the solution were added, with stirring at -15° C., 15 mg (0.106 mmole) of boron trifluoride etherate. After 30 minutes, the reaction mixture was diluted with ethyl acetate and washed with a dilute aqueous solution of sodium bicarbonate. The solvent was distilled off under reduced pressure and the resulting residue was subjected to thin layer chromatography using silica gel, developed with a 2:3 by volume mixture of benzene and ethyl acetate, to afford 48 mg (yield 92%) of the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH2:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[Br:16]Br>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]([Br:16])[C:8](=[O:13])[C:9]([CH3:10])([CH3:11])[CH3:12])=[CH:14][CH:15]=1
Reactant: BrBr
Reactant: CC(C)(C)C(=O)CCc1ccc(Cl)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)C(Br)Cc1ccc(Cl)cc1

Procedure:
4-Chlorobenzylpinacolone (11.2 g) in carbon tetrachloride (80 ml) was cooled to about 5° and bromine (8 g) in carbon tetrachloride (20 ml) added dropwise at that temperature over 2 hours. Care was taken to keep free bromine to a minimum in the reaction mixture in order to avoid byproduct formation. The solution was washed with saturated aqueous sodium bicarbonate and with water, dried (magnesium sulphate), and concentrated in vacuo to afford, as a white crystalline solid, crude 1-(4'-chlorophenyl)-2-bromo-4,4-dimethylpentan-3-one, m.p. 48°-50°.
Reaction SMILES: [S:1]([CH:5]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:6]([OH:8])=[O:7])([OH:4])(=[O:3])=[O:2].[Cl:16][CH:17](OC(Cl)Cl)Cl>S(=O)(=O)(O)O>[S:1]([CH:5]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:17][Cl:16])[CH:10]=1)[C:6]([OH:8])=[O:7])([OH:4])(=[O:3])=[O:2]
Reactant: ClC(Cl)OC(Cl)Cl
Reactant: O=C(O)C(c1ccc(O)cc1)S(=O)(=O)O
Agent: O=S(=O)(O)O
Product: O=C(O)C(c1ccc(O)c(CCl)c1)S(=O)(=O)O

Procedure:
α-Sulfo-4-hydroxybenzeneacetic acid, 0.3 mole, is dissolved in aqueous sulfuric acid (50%). One equivalent of dichloromethyl ether is added to the solution maintained at between 35° to 45° C. Hydrogen chloride is then bubbled through this reaction mixture for 3 hours. The desired compound is recovered by pouring the reaction mixture into water and extracting the title compound with ethyl acetate. The ethyl acetate is dried over magnesium sulfate. The magnesium sulfate is removed by filtration and evaporation of the ethyl acetate gives the title compound.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4].[CH2:21]([O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[OH:33])[CH3:22].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC.C(OCC)(=O)C>[CH2:21]([O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[O:33][CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4])[CH3:22]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CCl
Reactant: CCOC(=O)Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Yield: 97.8 %

Procedure:
To a solution of 2-chloro-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (3.3 g, 11.0 mmol) in 2-butanone (100 mL) was added (5-chloro-2-hydroxy-phenyl)-acetic acid ethyl ester (2.3 g, 11.0 mmol), potassium carbonate (3.05 g, 22.1 mmol), and potassium iodide (1.83 g, 11.0 mmol). The reaction was heated at reflux for 48 hrs. The solution was cooled, diluted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by dissolving in dichloromethane and passing through a pad of silica gel. Concentration in vacuo gave the title compound (5.13 g).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8]1[CH2:12][CH:11]=[CH:10][CH:9]=1.N1CCCC1.CC(O)=O>CO>[CH2:4]1[CH2:5][CH2:6][C:1](=[C:11]2[CH:10]=[CH:9][CH:8]=[CH:12]2)[CH2:2][CH2:3]1
Reactant: C1=CCC=C1
Reactant: O=C1CCCCC1
Solvent: C1CCNC1
Solvent: CC(=O)O
Solvent: CO
Product: C1=CC(=C2CCCCC2)C=C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
7 g of cyclohexanone (71 mmol) and 14.35 ml of cyclopentadiene(175 mmol) were charged in a 300 ml reaction bottle. 70 ml of CH3OH was added as a solvent. Then, 8.75 ml of pyrrolidine (105 mmol) was added gradually and the mixture was stirred at room temperature for 30 minutes. Next, 6.3 ml of CH3COOH (105 mmol) was added gradually and stirred for 10 minutes. 200 ml of H2O and 200 ml of pentane were used for extraction. The upper pentane portion was collected. The lower water portion was further extracted with pentane three times. The collected pentane portion was dehydrated with MgSO4, held still for 30 minutes, filtered, and concentrated under reduced pressure to afford a yellow liquid product (8.7 g, yield=83.3%).