Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.Cl[C:19]1[N:20]=[C:21]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[C:22]2[CH:27]=[C:26]([CH2:28][N:29]3[CH2:34][CH2:33][N:32]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:31][CH2:30]3)[S:25][C:23]=2[N:24]=1>>[CH3:8][C:7]1[CH:6]=[C:5]([C:19]2[N:20]=[C:21]([N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)[C:22]3[CH:27]=[C:26]([CH2:28][N:29]4[CH2:30][CH2:31][N:32]([S:35]([CH3:38])(=[O:36])=[O:37])[CH2:33][CH2:34]4)[S:25][C:23]=3[N:24]=2)[CH:4]=[N:3][C:2]=1[CH3:1]
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cnc1C
Product: Cc1cc(-c2nc(N3CCOCC3)c3cc(CN4CCN(S(C)(=O)=O)CC4)sc3n2)cnc1C

Procedure:
2,3-Dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine was reacted with 2-chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine in General Procedure A. Purification on silica yielded 371. NMR: (CDCl3): (400 MHz, CDCl3): 2.40 (3 H, s, Me), 2.59 (3 H, s, Me), 2.63-2.68 (4 H, m), 2.82 (3 H, s, Me), 3.29-3.31 (4 H, m), 3.84 (2 H, s, CH2), 3.90-3.92 (4 H, m), 3.98-4.00 (4 H, m), 7.17 (1 H, s, Ar), 8.41 (1 H, s, Ar) and 9.35 (1 H, s, Ar). MS: (ESI+): MH+ 503.15
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[F:16][C:17]([F:31])([CH3:30])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([NH2:28])[CH3:27])=[CH:22][C:21]=1[CH3:29]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:28]([CH:26]([C:23]3[CH:24]=[CH:25][C:20]([O:19][CH2:18][C:17]([F:16])([F:31])[CH3:30])=[C:21]([CH3:29])[CH:22]=3)[CH3:27])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(C(C)N)ccc1OCC(C)(F)F
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ccc1OCC(C)(F)F
Yield: 76 %

Procedure:
The title compound is prepared in 76% yield (437 mg, yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (419 mg, 1.51 mmol, Step-1 of Intermediate-1) and 1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethanamine hydrochloride (400 mg, 1.51 mmol, Amine-81, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]2([F:19])[CH2:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.Cl.[O:21]=[S:22]1(=[O:30])[CH2:26][CH:25]([C:27]([NH2:29])=[O:28])[NH:24][CH2:23]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:24]3[CH:25]([C:27]([NH2:29])=[O:28])[CH2:26][S:22](=[O:30])(=[O:21])[CH2:23]3)=[O:14])[CH:9]=[CH:8][C:7]=2[C:15]2([F:19])[CH2:18][CH2:17][CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2(F)CCC2)c(OCC2CC2)n1
Reactant: NC(=O)C1CS(=O)(=O)CN1
Agent: Cl
Product: NC(=O)C1CS(=O)(=O)CN1C(=O)c1ccc(C2(F)CCC2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 127 e), 6-(cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carboxylic acid (Example 130 f) was reacted with 1,1-dioxo-1,3-thiazolidine-4-carboxamide hydrochloride (Example 127 d) to give the title compound as yellow oil, MS (EI): m/e=412.13 [MH+].
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([I:12])[CH:8]=2)[N:3]=1.[OH-].[NH4+:14]>>[I:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH2:14])[CH:11]=[CH:10]2
Reactant: Clc1ccc2cc(I)ccc2n1
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1ccc2cc(I)ccc2n1
Temperature: 140 °C
Yield: 84 %

Procedure:
A suspension of 2-chloro-6-iodo-quinoline (1 g, 3.46 mmol) in ammonium hydroxide (28%, 20 mL) was heated at 140° C. for 3 days under pressure tube. After cooling, the solvent was removed by rotary evaporator. The solid was collected by filtration, washed with water and dried to obtain 6-iodo-quinolin-2-ylamine (0.78 g, 84%) as a black solid. LC-MS m/e 271 (MH+).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15]Cl)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl.C1(C)C=CC=CC=1>CN(C)C=O>[C:1]([N:9]1[CH2:14][CH2:13][C:12](=[CH2:15])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCC(CCl)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C=C1CCN(C(=O)c2ccccc2)CC1
Temperature: 5 °C
Reaction time: 0.67 h
Yield: 96.3 %

Procedure:
In 1 l of N,N-dimethylformamide was dissolved 248.96 g (about 1 mol) of N-benzoyl-4-chloromethyl-piperidine (D) obtained in Example 3. The resulting solution was cooled to 5° C. and thereto was added 168.32 g (1.5 mol) of potassium tert-butoxide in five portions at 10° to 20° C. over about 1 hour. After the addition, the mixture was stirred at 10° to 20° C. for 40 minutes. Then, the reaction mixture was poured into a mixed liquid of 500 ml of 1N hydrochloric acid and 500 g of fragmentary ice. Subsequently, thereto was added 200 ml of toluene to separate an organic layer. The aqueous layer was extracted with 200 ml of toluene and the organic layers were combined. The combined organic layer was washed with 500 ml of water. The solvent was removed by distillation under reduced pressure to obtain 193.78 g of N-benzoyl-4-methylenepiperidine (E) as a yellowish brown oily matter. The NMR spectrum of the obtained compound was measured. The result is shown below.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[N:21])[C:6]1=[O:22])[CH2:2][CH2:3][CH3:4].[NH2:23][OH:24]>CCO>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[NH:21])[NH:23][OH:24])[C:6]1=[O:22])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)n(CCCCC#N)c(=O)c2[nH]c(Cl)nc21
Reactant: NO
Solvent: CCO
Product: CCCCn1c(=O)n(CCCCC(=N)NO)c(=O)c2[nH]c(Cl)nc21
Temperature: 80 °C
Yield: 63.6 %

Procedure:
5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanenitrile (8.5 g, 26 mmol) was dissolved in EtOH (100 ml). Hydroxylamine (50% in water; 2.6 ml, 39 mmol) was added and the mixture heated at 80° C. for 48 h under nitrogen. The reaction mixture was concentrated in vacuo, the resultant solid washed with methanol and dried to give the title compound as a solid (5.9 g, 47%).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C@@H:5]1[NH:34][C:32](=[O:33])[CH2:31][NH:30][C:28](=[O:29])[C@H:27]2[NH:35][C:36]([C@H:38]([C@H:58]([C@@H:60]([OH:63])[CH2:61][OH:62])[CH3:59])[NH:39][C:40]([C@H:42]3[N:46]([C:47]([C@H:49]([CH2:53][C:54]([NH2:56])=[O:55])[NH:50][C:51](=[O:52])[C@@H:13]([CH2:14][S+:15]([O-:64])[C:16]4[NH:24][C:23]5[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=5[C:17]=4[CH2:26]2)[NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6]1=[O:7])=[O:48])[CH2:45][C@H:44]([OH:57])[CH2:43]3)=[O:41])=[O:37])[CH3:4].[O:65]=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:79]1(=[O:86])[O:85][C:83](=[O:84])[CH2:82][CH2:81][CH2:80]1>N1C=CC=CC=1>[CH3:1][CH2:2][C@@H:3]([C@@H:5]1[NH:34][C:32](=[O:33])[CH2:31][NH:30][C:28](=[O:29])[C@H:27]2[NH:35][C:36]([C@H:38]([C@H:58]([C@@H:60]([OH:63])[CH2:61][OH:62])[CH3:59])[NH:39][C:40]([C@H:42]3[N:46]([C:47]([C@H:49]([CH2:53][C:54]([NH2:56])=[O:55])[NH:50][C:51](=[O:52])[C@@H:13]([CH2:14][S+:15]([O-:64])[C:16]4[NH:24][C:23]5[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=5[C:17]=4[CH2:26]2)[NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6]1=[O:7])=[O:48])[CH2:45][C@H:44]([OH:57])[CH2:43]3)=[O:41])=[O:37])[CH3:4].[C:79]([O-:85])(=[O:86])[CH2:80][CH2:81][CH2:82][C:83]([O-:65])=[O:84]
Reactant: O=C1CCCC(=O)O1
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: CC[C@H](C)[C@@H]1NC(=O)CNC(=O)[C@@H]2Cc3c([nH]c4cc(O)ccc34)[S+]([O-])C[C@@H](NC(=O)CNC1=O)C(=O)N[C@@H](CC(N)=O)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H]([C@@H](C)[C@@H](O)CO)C(=O)N2
Solvent: c1ccncc1
Product: O=C([O-])CCCC(=O)[O-]

Procedure:
3.0 mg (3.3 μmol) of α-amanitin, dried in vacuo over P4O10 was dissolved in 0.25 ml of dry pyridine and reacted with 0.9 mg (79 μmol) glutaric anhydride in 0.1 ml pyridine for 24 h at RT in the dark. The peptide was precipitated by addition of 7 ml of dry diethylether, centrifuged, and the solid washed a second time with diethylether and centrifuged. By way of this reaction an α-amanitin derivative is obtained wherein R1=—OH (in FIG. 1) is replaced by R1=—O—C(O)—(CH2)3—COOH.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11][C:12]([Mg]Br)=[CH:13][CH3:14].[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:13]([CH3:14])=[C:12]([CH3:11])[NH:8][C:7]=12
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CC=C(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1[nH]c2c(Cl)nccc2c1C
Temperature: -20 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
2-Chloro-3-nitropyridine (8 g, 50.46 mmol) was dissolved in anhydrous tetrahydrofuran (200 ml) at nitrogen atmosphere. 1-Methyl-1-propenyl magnesium bromide (0.5M in tetrahydrofuran solution, 252 ml, 126.15 mmol) was slowly added at −78° C. to the solution. The reaction mixture was stirred for 2 hours at −20° C. and 20% ammonium chloride solution was added thereto. The reaction mixture was extracted with ethyl acetate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/3, v/v) to give 2.73 g of the titled compound as a pale yellow solid. (Yield: 30%)
Reaction SMILES: [O-:1][Mn](=O)(=O)=O.[K+].C[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[F:18])=[O:9]>>[F:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=1[C:8]([OH:9])=[O:1]
Reactant: COc1ccc(C(C)=O)c(F)c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: COc1ccc(C(=O)O)c(F)c1

Procedure:
2-Fluoro-4-methoxybenzoic acid was synthesized by KMnO4 oxidation of 2-fluoro-4-methoxyacetophenone (Clarke, H. T.; Taylor, E. R., Org. Synth. Coll. Vol II, 135-136).
Reaction SMILES: C(O)C#C.BrCCC(OCC)=O.[CH2:13]([O:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:14][C:15]#C>>[CH2:13]([O:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:14]#[CH:15]
Reactant: C#CCCOCCC(=O)O
Agent: C#CCO
Agent: CCOC(=O)CCBr
Product: C#CCOCCC(=O)O

Procedure:
3-(Prop-2-ynyloxy)propionic acid was prepared from propargyl alcohol and ethyl 3-bromopropionate using methodology analogous to that describing the synthesis of 3-(but-3-yn-1-yloxy)propionic acid (Example XIX).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=[O:13].[Br:14]Br.[O-]S([O-])(=S)=O.[Na+].[Na+]>CC(O)=O>[Br:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3]([CH:12]=[O:13])=[C:2]([OH:1])[CH:11]=[CH:10]2
Reactant: BrBr
Reactant: O=Cc1c(O)ccc2ccccc12
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: O=Cc1c(O)ccc2cc(Br)ccc12
Reaction time: 1 h
Yield: 32.9 %

Procedure:
To a solution of 2-hydroxy-1-naphthaldehyde (60.0 g) in AcOH (300 mL) was added dropwise a solution of bromine (66.8 g) in AcOH (30 mL) over 30 min. After being stirred for 1 h, the mixture was poured into aqueous Na2S2O3 solution, and the resulting mixture was extracted with AcOEt. The combined organic layers were washed with water, 1N-NaOH, and brine followed by drying over MgSO4. After removal of the solvent in vacuo, the residue was washed with EtOH to give a yellow powder. The powder was crystallized from iPrOH to afford the title compound (28.8 g) as pale yellow needles.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[S:14]([N:17]1[CH2:23][CH2:22][CH2:21][CH:20]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:19][CH2:18]1)(=[O:16])=[O:15])[CH:2]=C.[O-:32]S([O-])(=S)=O.[Na+].[Na+].[BH3-]C#N.[Na+]>C1COCC1.O.O=[Os](=O)(=O)=O>[CH2:25]([O:24][CH:20]1[CH2:21][CH2:22][CH2:23][N:17]([S:14]([C:5]2[CH:6]=[C:7]([CH:12]=[CH:13][C:4]=2[CH2:1][CH2:2][OH:32])[C:8]([O:10][CH3:11])=[O:9])(=[O:15])=[O:16])[CH2:18][CH2:19]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C=CCc1ccc(C(=O)OC)cc1S(=O)(=O)N1CCCC(OCc2ccccc2)CC1
Reactant: O=S([O-])([O-])=S
Agent: O=[Os](=O)(=O)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCO)c(S(=O)(=O)N2CCCC(OCc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.88 %

Procedure:
To a solution of methyl 4-allyl-3-(4-benzyloxyazepan-1-yl)sulfonyl-benzoate (630.00 mg, 1.42 mmol, 1.00 Eq) in THF (10 mL) and H2O (2 mL) were added OsO4 (36.10 mg, 142.00 umol, 0.10 Eq) and NaIO4 (607.45 mg, 2.84 mmol, 2.00 Eq) at 0° C. The mixture was stirred at 25° C. for 3 hr. TLC detected the reaction was complete, the mixture was poured into saturated Na2S2O3 solution, extracted with DCM, the combined organic layer was dried over anhydrous Na2SO4, concentrated, the residue was diluted in MeOH (10 mL), to the formed mixture was added NaBH3CN (88.86 mg, 1.41 mmol, 1.00 Eq). The mixture was stirred at 25° C. for 3 hr. TLC detected the reaction was complete, the reaction was quenched with water, extracted with EA, the combined organic layer was dried over anhydrous Na2SO4, concentrated, the residue was purified by chromatography (silica gel, eluting with PE:EA=3:1 to 1:1) to afford product methyl 3-(4-benzyloxyazepan-1-yl)sulfonyl-4-(2-hydroxyethyl)benzoate (340.00 mg, 759.71 umol, 53.88% yield). LCMS: 448 [M+1].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][CH2:50][O:51][CH3:52])=[CH:44][CH:43]=1)[C:9]1[N:14]2[N:15]=[CH:16][CH:17]=[C:13]2[N:12]=[C:11]([NH:18][C@H:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]2)[C:10]=1[CH2:32][CH2:33][O:34][Si](C(C)(C)C)(C)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]([C:42]1[CH:43]=[CH:44][C:45]([O:48][CH2:49][CH2:50][O:51][CH3:52])=[CH:46][CH:47]=1)[C:9]1[N:14]2[N:15]=[CH:16][CH:17]=[C:13]2[N:12]=[C:11]([NH:18][C@H:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:20]2)[C:10]=1[CH2:32][CH2:33][OH:34])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CCO[Si](C)(C)C(C)(C)C)c(N[C@H]3CCCN(C(=O)OC(C)(C)C)C3)nc3ccnn23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: COCCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CCO)c(N[C@H]3CCCN(C(=O)OC(C)(C)C)C3)nc3ccnn23)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 142.4 %

Procedure:
To a tetrahydrofuran (5 mL) solution containing tert-butyl (S)-3-{7-{tert-butoxycarbonyl-[4-(2-methoxyethoxy)phenyl]amino}-6-[2-(tert-butyldimethylsilanyloxy)ethyl]pyrazolo[1,5-a]pyrimidin-5-ylamino}piperidine-1-carboxylate (193 mg, 0.261 mmol), tetrabutylammonium fluoride (474 μL, 0.474 mmol) was added, and this mixture was stirred at room temperature for 1.5 hr. After the reaction, aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The combined ethyl acetate layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the filtrate was concentrated to obtain the title compound (233 mg).
Reaction SMILES: [Mg].II.[C:4]1([CH2:10][CH2:11][C:12](=[O:16])[CH2:13][CH2:14][CH3:15])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl>C1COCC1>[OH:16][C:12]([CH2:11][CH2:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH2:13][CH2:14][CH3:15])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCCC(=O)CCc1ccccc1
Reactant: CCOC(=O)CCl
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCC(O)(CCc1ccccc1)CC(=O)OCC
Temperature: 30 °C
Reaction time: 0.17 h

Procedure:
Magnesium (1.98 g, 81.4 mmole) was suspended in THF (15 mL), and iodine (10 mg) was added thereto. To the suspension was added 1 mL from a mixture (total amount: 20 mL) of 1-phenyl-3-hexanone (8.93 g, 50.7 mmole) and ethyl chloroacetate (9.94 g, 81.1 mmole) at 25° C. in a thin stream. The mixture was stirred for 10 min and allowed to warm the internal temperature to 30° C. The remaining (19 mL) of the above-mentioned mixture (total amount: 20 mL) of 1-phenyl-3-hexanone and ethyl chloroacetate was added at 30° C.-40° C. over 2 hr in a thin stream. The mixture was stirred at 30° C. for 1 hr, and 10% hydrochloric acid (30 mL) was added for partitioning, which have a THF solution containing ethyl 3-hydroxy-3-(2-phenylethyl)hexanoate (10.2 g, 76%; quantified by absolute calibration curve method (external standard method) using HPLC).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH3:15])[C:12]([OH:14])=O.C(Cl)(C(Cl)=O)=O.[CH2:22]([O:24][C:25]([N:27]1[C:31]2[CH2:32][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][C:30]=2[C:29]([NH2:42])=[N:28]1)=[O:26])[CH3:23].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C.C1COCC1.C(OCC)(=O)C.C1CCCCC1>[CH2:22]([O:24][C:25]([N:27]1[C:31]2[CH2:32][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][C:30]=2[C:29]([NH:42][C:12](=[O:14])[CH:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH3:15])=[N:28]1)=[O:26])[CH3:23]
Reactant: CCOC(=O)n1nc(N)c2c1CN(C(=O)OC(C)(C)C)C2
Reactant: CC(C(=O)O)c1ccc2ccccc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)n1nc(NC(=O)C(C)c2ccc3ccccc3c2)c2c1CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
To a solution of 2-naphthalen-2-yl-propionic acid (1.48 g. 7.4 mmol) in DCM (40 ml) and DMF cat., (COCl)2 (0.83 ml, 9.65 mmol) in DCM (10 ml) was added dropwise. The mixture was stirred at r.t. for 30 min. The reaction mixture was concentrated under vacuum, reconstituted twice with toluene and concentrated. A solution of the obtained acyl-chloride in THF (40 ml) was added slowly to a mixture of 3-amino-4,6-dihydro-pyrrolo[3,4-c]pyrazole-1,5-dicarboxylic acid 5-tert-butyl ester 1-ethyl ester (2.0 g, 6.75 mmol) and DIEA (5.8 ml, 33.3 mmol) in THF (40 ml) at 0-5° C. The reaction was allowed to reach r.t. and stirred overnight. The mixture was filtered and the solution evaporated to dryness under vacuum. The resulting residue was dissolved in DCM and the obtained solution washed with brine, dried over sodium sulfate, filtered and evaporated to dryness. The crude product was purified by flash-chromatography (eluent:ethyl acetate/cyclohexane 3/7 then 4/6) to give 3.0 g (93% yield) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[N:14]=[CH:13][C:12]([CH:15]3[O:20][CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.FC(F)(F)C(O)=O.CCOC(C)=O.C1COCC1>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH:15]3[O:20][CH2:19][CH2:18][NH:17][CH2:16]3)=[CH:13][N:14]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Nc3ccc(Cl)cn3)nc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc(Nc2ccc(C3CNCCO3)cn2)nc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
To a stirred solution of tert-butyl 2-(6-(5-chloropyridin-2-ylamino)pyridin-3-yl)morpholine-4-carboxylate (22 mg) in acetonitrile (1.5 ml) and water (4.5 ml) was added trifluoroacetic acid (43 μl). The reaction mixture was then capped and the mixture was shaken at 80° C. for 3 h. The reaction mixture was then cooled to room temperature and poured into EtOAc/THF (1:1) and washed with 1 M aq. NaOH. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis; gradient: heptane/EtOAc/MeOH) to afford (RS)-5-chloro-N-(5-(morpholin-2-yl)pyridin-2-yl)pyridin-2-amine (15 mg, 92%) as a colourless amorphous solid. MS (ISP): 293.1 ([{37Cl}M+H]+), 291.1 ([{35Cl}M+H]+).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[CH:19]=[C:18]([S:21]([CH2:24][CH2:25][C:26](Cl)=[O:27])(=O)=O)[CH:17]=[CH:16]2)=[O:7].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC(Cl)C(Cl)Cl>[O:27]=[C:26]1[C:19]2[C:20]3[C:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]4[CH:29]=[CH:30][CH:31]=[C:3]([C:2]([F:33])([F:32])[F:1])[CH:4]=4)=[CH:12][CH:13]=[CH:14][C:15]=3[CH:16]=[CH:17][C:18]=2[S:21][CH2:24][CH2:25]1
Reactant: O=C(Cl)CCS(=O)(=O)c1ccc2cccc(CCNC(=O)c3cccc(C(F)(F)F)c3)c2c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)C(Cl)Cl
Product: O=C(NCCc1cccc2ccc3c(c12)C(=O)CCS3)c1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The product obtained in Step C (3 mmol), dissolved in 1,1,2,2-tetrachloroethane (30 ml), is poured dropwise into a solution of aluminium chloride (10 mmol) in the same solvent (20 ml) under nitrogen. The reaction mixture is heated at 60° C., with stirring, until the reaction has ceased. The solution is then poured into a mixture of ice (10 g) and concentrated HCl (0.3 ml) and stirring is carried out for one hour. The aqueous phase is extracted with chloroform (twice); the combined organic phases are then dried over magnesium sulphate, concentrated under reduced pressure and then chromatographed on silica gel to yield the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]/[C:10](/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11]\[C:12]([O:14]CC)=[O:13])=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9]/[C:10](/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:11]\[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C(\CCc1ccc(Cl)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)/C=C(\CCc1ccc(Cl)cc1)c1ccccc1
Yield: 72 %

Procedure:
A solution of (E)-ethyl 5-(4-chlorophenyl)-3-phenylpent-2-enoate (160 mg) and 4M NaOH (1.3 ml) in EtOH (10 ml) was stirred at rt for 4 h. The mixture was poured into water (30 ml), acidified to pH 2 with 10% HCl and extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated to afford a crude, which was purified by crystallisation from hexane/ethylacetate to afford (E)-5-(4-chlorophenyl)-3-phenylpent-2-enoic acid (105 mg) as colourless solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH3:18])[C:4](=[O:19])[C:3]=1[N:20]=O.C1(CN2C(N)=C(N)C(=O)N(CCC)C2=O)CCCCC1.[CH:42]([C:44]1[CH:45]=[C:46]([CH:52]=[CH:53][CH:54]=1)[CH:47]=[CH:48][C:49]([OH:51])=[O:50])=O>>[CH:9]1([CH2:8][N:7]2[C:2]3[NH:1][C:42]([C:44]4[CH:45]=[C:46]([CH:52]=[CH:53][CH:54]=4)/[CH:47]=[CH:48]/[C:49]([OH:51])=[O:50])=[N:20][C:3]=3[C:4](=[O:19])[N:5]([CH2:16][CH2:17][CH3:18])[C:6]2=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=Cc1cccc(C=CC(=O)O)c1
Reactant: CCCn1c(=O)c(N=O)c(N)n(CC2CCCCC2)c1=O
Agent: CCCn1c(=O)c(N)c(N)n(CC2CCCCC2)c1=O
Product: CCCn1c(=O)c2nc(-c3cccc(/C=C/C(=O)O)c3)[nH]c2n(CC2CCCCC2)c1=O
Yield: 75 %

Procedure:
In the manner of step (d) of Example 1, 6amino-1-(cyclohexylmethyl)-3-propyl-5-nitrosouracil (step (c) example 12, 2.355 g, 8.00 mmol) was reduced to 1-(cyclohexylmethyl)-5,6-diamino-3-propyluracil, which was condensed with 3-formylcinnamic acid (T. Higa, A. J. Krubsack, J. Org. Chem. 1975, 40: 3037-3045, 1.424 g, 8.00 mmol) to give (E)-3-[3-(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6dioxo-1-propyl-9H-purin-8-yl]cinnamic acid as a pale yellow solid (2.632 g, 75%), m.p. >350° C.; 1H-NMR (DMSO-d6) consistent with structure.