Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[N:10]=[C:11]([N:20]3[CH2:25][CH2:24][C:23](=[CH:26][C:27]([O:29]CC)=[O:28])[CH2:22][CH2:21]3)[C:12]3[CH2:17][S:16](=[O:19])(=[O:18])[CH2:15][C:13]=3[N:14]=2)=[C:4]([F:32])[CH:3]=1.Cl>C1COCC1>[ClH:1].[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[N:10]=[C:11]([N:20]3[CH2:25][CH2:24][C:23](=[CH:26][C:27]([OH:29])=[O:28])[CH2:22][CH2:21]3)[C:12]3[CH2:17][S:16](=[O:18])(=[O:19])[CH2:15][C:13]=3[N:14]=2)=[C:4]([F:32])[CH:3]=1
Reactant: CCOC(=O)C=C1CCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3c2CS(=O)(=O)C3)CC1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)C=C1CCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3c2CS(=O)(=O)C3)CC1
Temperature: 90 °C
Reaction time: 5.5 h
Yield: 63.5 %

Procedure:
A mixture of 390 mg of ethyl {1-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxo-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperidin-4-ylidene}acetate, 10 ml of 6M hydrochloric acid aqueous solution, and 10 ml of THF was stirred at 90° C. for 5.5 hours. The solvent was distilled off under reduced pressure, and the resultant solid was recrystallized from water-acetonitrile to yield 126 mg of {1-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxo-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperidin-4-ylidene}acetic acid hydrochloride.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:13]([CH2:21][C:22](=[O:28])[C:23](=C)[CH:24]([CH3:26])[CH3:25])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]=C)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](OC[C@@H]1C=C(C)C(=O)CN1C(OC(C)(C)C)=O)(C(C)(C)C)(C)C>CC1C=C(C)C=C(C)C=1N1CCN(C2C(C)=CC(C)=CC=2C)C1=[Ru](Cl)(Cl)=CC1C=CC=CC=1OC(C)C>[Si:1]([O:8][CH2:9][C@@H:10]1[CH:11]=[C:23]([CH:24]([CH3:25])[CH3:26])[C:22](=[O:28])[CH2:21][N:13]1[C:14]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:20])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)C(=C)C(C)C)C(=O)OC(C)(C)C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: CC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)CC1=O
Product: CC(C)C1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)CC1=O

Procedure:
The title compound was prepared from (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)but-3-en-2-yl(4-methyl-3-methylene-2-oxopentyl)carbamate (Intermediate 34, 0.839 g, 2.04 mmol) following the procedure described for Intermediate 7, using 0.32 eq of (1,3-Bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium. The desired product was obtained as a colorless oil (0.667 g, 85%).
Reaction SMILES: [CH:1]1[C:2]([I:10])=[CH:3][C:4]([I:9])=[C:5]([OH:8])[C:6]=1[I:7].[C:11](Cl)(=[O:16])[CH:12]=[CH:13][CH2:14][CH3:15].C(N(CC)CC)C>ClCCl>[C:11]([O:8][C:5]1[C:6]([I:7])=[CH:1][C:2]([I:10])=[CH:3][C:4]=1[I:9])(=[O:16])[CH2:12][CH2:13][CH:14]=[CH2:15]
Reactant: Oc1c(I)cc(I)cc1I
Reactant: CCC=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCC(=O)Oc1c(I)cc(I)cc1I

Procedure:
First, 9 g of triiodophenol was dissolved in 150 mL dichloromethane under argon. Then, 3.15 mL of pentenoyl chloride was added while stirring. Triethylamine was then added slowly and stirred for 4 hr. The solution was washed with 100 mL of water and evaporated to dryness, leaving 2,4,6-triiodophenyl penta-4-enoate.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:9]([NH:11][C@@H:12]([C:25]([NH:27][C@H:28]([C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH:23]=[O:24])[CH:15]=1)=[O:10])[CH2:4][CH2:5][C:6](=[O:8])[NH2:7].[CH:46]([O-])=[O:47].[Na+].CC(OC(C)=O)=O>C(O)=O.O>[CH:46]([NH:2][C@H:3]([C:9]([NH:11][C@@H:12]([C:25]([NH:27][C@H:28]([C:36]([O:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:37])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:26])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH:23]=[O:24])[CH:15]=1)=[O:10])[CH2:4][CH2:5][C:6](=[O:8])[NH2:7])=[O:47]
Reactant: NC(=O)CC[C@H](N)C(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: NC(=O)CC[C@H](NC=O)C(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 78.2 %

Procedure:
To a solution of HCl.H-Gln-D-Trp(CHO)-Phe-OBzl (0.33 g) and sodium formate (0.35 g) in formic acid (21 ml) was added dropwise Ac2O (7 ml) under ice-cooling. The mixture was stirred for three and half an hour at room temperature. Water (10 ml) was added to the mixture and then evaporated. To the residue, water was added and evaporated. The residue was pulverized with water, filtered. The solids were dissolved in DMF and reprecipitated with ethyl acetate, filtered and dried to give HCO-Gln-D-Trp(CHO)-Phe-OBzl (0.27 g).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.[CH3:13][N:14](C)C=O>[Zn].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:13]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1)#[N:14]
Reactant: COC(=O)c1ccc(Br)cc1F
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1ccc(C#N)cc1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of methyl 4-bromo-2-fluorobenzoate (10.0 g, 43 mmol), zinc cyamide (10.0 g, 86 mmol) and palladium tetrakis(triphenylphosphine) (2.5 g, 0.64 mmol) in anhydrous N,N-dimethylformamide (100 mL) was purged with nitrogen and the mixture stirred at 80° C. overnight. After cooling, the mixture was partitioned between ethyl acetate and brine and the organic phase washed with water and concentrated. The solid was purified on silica gel using 1:5 ethyl acetate/hexane to afford the title compound (6.1 g, 80%). MS (DCI): m/z 180 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([C:10](=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18])=[CH:6][N:7](C)C)[CH3:2].O1CCOCC1.Cl.NO>O>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[N:7][O:21][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18])=[O:22])[CH3:2]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1C(F)(F)F
Agent: Cl
Agent: NO
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cnoc1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 14 h
Yield: 56.2 %

Procedure:
Ethyl-2-(2'-trifluoromethylbenzoyl)-3-dimethylaminopropenoate (3.14 g.; 0.01 mol.) was dissolved in 15 ml. of dioxane. To this solution was added a solution of hydroxylamine hydrochloride (1.05 g.; 0.015 mol.) in 5 ml. of water. The resulting solution was stirred for 14 hours at 25° C. Extraction with water and diethyl ether yielded ethyl-5-(2'-trifluoromethylphenyl)-4-isoxazolecarboxylate as an oil (1.6 g.; 56.2% yield) having the following analysis:
Reaction SMILES: O=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1CCCCC1>[C:11]1([NH:10]/[C:2](/[CH2:8][CH3:9])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccccc1
Reactant: CCC(=O)CC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCCCC1
Product: CC/C(=C/C(=O)OC)Nc1ccccc1
Yield: 72.2 %

Procedure:
A mixture of methyl 3-oxovalerate (5.21 g, 40.0 mmol), aniline (3.66 mL, 40.0 mmol), p-toluenesulfonic acid monohydrate (533 mg, 2.80 mmol) and cyclohexane (25 mL) was stirred with heating under reflux for 2 hr. The mixture was concentrated under reduced pressure, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluate, hexane:ethyl acetate=98:2→94:6) to give the title compound (5.93 g, 72%) as a colorless oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[NH2:7][C:8]1[CH:28]=[CH:27][C:11]([NH:12][C:13]2[N:18]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:16]([Br:26])=[CH:15][N:14]=2)=[CH:10][CH:9]=1.C(N(CC)CC)C.O>CN(C=O)C>[NH:19]([C:17]1[C:16]([Br:26])=[CH:15][N:14]=[C:13]([NH:12][C:11]2[CH:10]=[CH:9][C:8]([NH:7][C:4](=[O:5])[CH2:3][CH2:2][Cl:1])=[CH:28][CH:27]=2)[N:18]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Reactant: O=C(Cl)CCCl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCCl)Nc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Temperature: 25 °C
Yield: 41.6 %

Procedure:
Chloropropionyl chloride (0.143 g, 1.13 mmol) was added to a stirred solution of 2-(4-aminoanilino)-4-anilino-5-bromopyrimidine (Method 38; 0.40 g, 1.13 mmol) and triethylamine (0.173 ml, 1.24 mmol) in DMF (1 ml). The mixture was stirred at room temperature and then water (4 ml) was added. The precipitated solid was collected by filtration and washed with ether (1 ml) to give the product (0.21 g, 42%) as a brown solid. MS (MH+): 448, 450.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH2:13][NH:14][C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16].[C:22]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]([CH3:46])=[C:31]([CH2:33][CH2:34]OS(C3C=CC(C)=CC=3)(=O)=O)[N:32]=2)=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:34][CH2:33][C:31]2[N:32]=[C:28]([C:25]3[CH:26]=[CH:27][C:22]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[CH:23][CH:24]=3)[O:29][C:30]=2[CH3:46])=[CH:8][C:7]=1[CH2:13][NH:14][C:15]([O:17][CH:18]([CH3:19])[CH3:20])=[O:16]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Reactant: COC(=O)CCc1ccc(O)cc1CNC(=O)OC(C)C
Product: COC(=O)CCc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1CNC(=O)OC(C)C

Procedure:
3-[4-Hydroxy-2-(isopropoxycarbonylamino-methyl)-phenyl]-propionic acid methyl ester (Preparation 17) and toluene-4-sulfonic acid 2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)ethyl ester (Preparation 1) were combined according to Standard procedure A to give the title compound.
Reaction SMILES: [N:1]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=3)[N:8]=[CH:7]2)[CH2:3][CH2:2]1.C(OC(C)(C)C)=O>>[N:1]1([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=3)[NH:8][CH2:7]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc2c(c1)C1(C=N2)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)OC=O
Product: CCOC(=O)c1ccc2c(c1)C1(CCN(C(=O)OC(C)(C)C)CC1)CN2

Procedure:
1′-tert-butyl 5-ethyl spiro[indoline-3,4′-piperidine]-1′,5-dicarboxylate was prepared by the procedures described in Example 1, Step 2, substituting tert-butyl 5-chlorospiro[indole-3,4′-piperidine]-1′-carboxylate with 1′-tert-butyl 5-ethyl spiro[indole-3,4′-piperidine]-1′,5-dicarboxylate. LCMS (APCI+) m/z 261.3 [M+H−Boc]+; Rt=3.76 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH:15]CC2C=CC=CC=2)[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH2:15])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@H](CNCc2ccccc2)C[C@@H]2C[C@@H]21
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2C[C@@H]21
Reaction time: 24 h

Procedure:
A solution of (1S,3S,5S)-3-(b enzylamino-methyl)-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (16.7 mmol) in EtOH (100 mL) is treated with Pd/C (2.0 g, 50% H2O) and stirred under a hydrogen atmosphere (1 bar) for 1 d. An additional amount of Pd/C (2.0 g) is added and the mixture is stirred for further 3 d. After filtration through celite and removal of the solvents the desired amine is obtained which is used without further purification. LC-MS (acidic): tR=0.64 min; [M+H]+=213.3.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:18][C:17]2[CH:16]=[C:15]3[C:10]([O:11][C@@H:12]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=5)=[CH:21][CH:20]=4)[CH2:13][NH:14]3)=[CH:9][C:8]=2[CH2:7][N:6]1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:4].C=O.[C:44](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)Cl>C1COCC1.ClCCCl>[CH3:1][O:2][C:3]([CH:5]1[CH2:18][C:17]2[CH:16]=[C:15]3[C:10]([O:11][C@@H:12]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=5)=[CH:21][CH:20]=4)[CH2:13][N:14]3[CH3:44])=[CH:9][C:8]=2[CH2:7][N:6]1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:4]
Reactant: COC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CN3
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: C1CCOC1
Product: COC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CN3C
Reaction time: 4 h
Yield: 90.8 %

Procedure:
To a solution of (S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester 7-methyl ester (298 mg) in THF/DCE (30 mL, 2:1) was added paraformaldehyde (90 mg, 4 eq.) and sodium triacetoxy-borohydride (208 mg) and the mixture stirred 4 hours. DCM was added to the mixture and the organic washed with 10% Na2CO3 solution and brine. The organic was dried over sodium sulfate and the solvent removed under reduced pressure to afford the crude amine. The residue was purified by flash chromatography (hexanes/ethyl acetate from 80:20 to 60:40) to provide the product (277 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@:11]([C@H:17]2[CH2:21][CH2:20][O:19][CH2:18]2)([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[F:24][C:25]([F:39])([F:38])[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)Cl>[O:19]1[CH2:20][CH2:21][C@H:17]([C@:11]2([C:14]([N:35]3[CH2:36][CH2:37][N:32]([C:28]4[CH:27]=[C:26]([C:25]([F:39])([F:24])[F:38])[CH:31]=[CH:30][N:29]=4)[CH2:33][CH2:34]3)=[O:16])[CH2:12][CH2:13][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]2)[CH2:18]1
Reactant: FC(F)(F)c1ccnc(N2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@](C(=O)O)([C@H]2CCOC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@](C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)([C@H]2CCOC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
(1S,3R)-3-[(tert-Butoxycarbonyl)amino]-1-[(3R)-tetrahydrofuran-3-yl]cyclopentanecarboxylic acid (350.0 mg, 1.169 mmol), 1-[4-(trifluoromethyl)pyridin-2-yl]piperazine dihydrochloride (391.1 mg, 1.286 mmol), triethylamine (0.652 mL, 4.68 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (665.1 mg, 1.754 mol) (HBTU) were mixed in dry DMF (8.0 mL). After being stirred at room temperature overnight, the reaction mixture was diluted with CH2Cl2 and washed with saturated Na2CO3. The aqueous layer was extracted with CH2Cl2 four times. The combined organic layers were dried (MgSO4), concentrated and purified by flash chromatography (Combi-flash system, 0-50% EtOAc in hexanes, gradient elution, 40 gram column) to provide the desired product (270 mg, 45%). MS calculated for C25H36F3N4O4 (M+H) 513.3; found 513.3.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][C:9]12[CH:20]3[CH2:21][C:16]([CH:28]=[O:29])([C:17]1([C:25]([O-:27])=[O:26])[C:18]([CH:22]([CH3:24])[CH3:23])=[CH:19]3)[CH:15]1[CH:11]([CH:12]([CH3:30])[CH2:13][CH2:14]1)[CH2:10]2)=[O:6])=[N+]=[N-].[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH2:1][CH2:4][C:5]([O:7][CH2:8][C:9]12[CH:20]3[CH2:21][C:16]([CH:28]=[O:29])([C:17]1([C:25]([OH:27])=[O:26])[C:18]([CH:22]([CH3:24])[CH3:23])=[CH:19]3)[CH:15]1[CH:11]([CH:12]([CH3:30])[CH2:13][CH2:14]1)[CH2:10]2)=[O:6]
Reactant: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC(=O)CN=[N+]=[N-])C13C(=O)[O-]
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC(=O)CN)C13C(=O)O

Procedure:
The azide obtained above was dissolved in methanol and palladium hydroxide on carbon was added. The reaction was stirred under one atmosphere of hydrogen for a time sufficient to remove the benzyl ester group and reduce the azide. Concentration under reduced pressure gave the title compound. 1H NMR (CD3OD): δ0.77 (3H, d, J=6.4), 0.93 (3H, d, J=6.7), 0.94 (3H, d, J=6.6), 1.50-2.30 (11H, m), 2.36 (1H, m), 2.51 (1H, m), 3.60-4.60 (4H, m), 5.90 (1H, s), 9.81 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH3:19][O:20][CH2:21][C:22](Cl)=O>O1CCOCC1>[CH3:19][O:20][CH2:21][C:22]1[N:12]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1cc(C(F)(F)F)ccc1NC1CCOCC1
Reactant: COCC(=O)Cl
Solvent: C1COCCO1
Product: COCc1nc2cc(C(F)(F)F)ccc2n1C1CCOCC1
Reaction time: 2 h
Yield: 77.5 %

Procedure:
A 4-neck flask equipped with a reflux condenser was charged with 2-amino-1-(tetrahydropyran-4-yl)amino-4-trifluoromethylbenzene (see Synthesis Example 4) (0.62 g, 2.38 mmol) and anhydrous 1,4-dioxane (8.5 mL) and this was refluxed. Methoxyacetyl chloride (0.57 g, 5.25 mmol) in 1,4-dioxane solution (approx. 1.5 mL) was added dropwise to this over approximately 10 m. This was stirred under these conditions for 2 hours. This was allowed to cool, distilled water was added, and the solvent was distilled off under reduced pressure. This was successively extracted with t-butyl methyl ether, washed with brine, and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to yield the title compound (0.58 g, 77.4% yield) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:40][C:41]2[CH:42]=[N:43][CH:44]=[C:45](B3OC(C)(C)C(C)(C)O3)[CH:46]=2)(=[O:39])=[O:38])=[CH:33][CH:32]=1.CC1(C)C(C)(C)OB(C2C=C(N)C=NC=2)O1.COC1C=CC(S(Cl)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(P([Pd-4](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)C=CC=CC=1>[NH2:1][C:2]1[C:3]([C:45]2[CH:46]=[C:41]([NH:40][S:37]([C:34]3[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)(=[O:39])=[O:38])[CH:42]=[N:43][CH:44]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cncc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)OB(c2cncc(N)c2)OC1(C)C
Agent: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)Nc2cncc(-c3c(N)ncnc3N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c2)cc1
Yield: 76 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (65 mg, 0.15 mmol) was treated with 4-methoxy-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (87 mg, 0.22 mmol, prepared from 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinamine, as described in WO 2009155527 A2 20091223, and 4-methoxybenzene-1-sulfonyl chloride according to the method described In Preparation 15b), 2M sodium carbonate (221 μl, 0.44 mmol) and tetrakis(triphenylphosphino)palladium(0) (9 mg, 0.01 mmol) according to the method described in Example 3 to give 92 mg (76% yield) of the title compound as a solid. Purity 53%.
Reaction SMILES: [NH:1]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C@H:2]([C:10]([O:12]N1C(=O)CCC1=O)=O)[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[NH2:30][C@H:31]([C:38]([O:40][CH3:41])=[O:39])[CH2:32][O:33][C:34]([CH3:37])([CH3:36])[CH3:35].Cl.C(OCC)(=O)C>C(N(CC)CC)C>[NH:1]([C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[C@H:2]([C:10]([NH:30][C@H:31]([C:38]([O:40][CH3:41])=[O:39])[CH2:32][O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:12])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: COC(=O)[C@@H](N)COC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C
Temperature: 20 °C
Reaction time: 15 h

Procedure:
16.25 g of Z-Thr(But)-OSu and 8.47 g of H-Ser(But)-OMe. HCl are added to 200 ml of ethyl acetate, 5.6 ml of triethylamine are added at 0°C and the solution is stirred for 15 hours at 20°C and washed with 1 N citric acid, 1 N sodium bicarbonate and water. After drying over sodium sulphate, the solution is evaporated, whereupon the product, which is pure according to thin layer chromatography, is obtained as an oil.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=CC=1.C1(O)CCCC1>>[CH:1]1([O:9][C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)[CH2:2][CH2:7][CH2:6][CH2:5]1
Reactant: O=C(Oc1cccc(O)c1)c1ccccc1
Agent: OC1CCCC1
Product: Oc1cccc(OC2CCCC2)c1
Yield: 120.2 %

Procedure:
By using 3-hydroxyphenyl benzoate (50 mg) and cyclopentanol (23.5 μl) as starting materials, the title compound (50 mg) was obtained in the same manner as that of Reference Example 15.
Reaction SMILES: C[Li].C(NC(C)C)(C)C.[CH2:10]1[CH:14]2[CH2:15][C:16](=[O:17])[CH:12]([CH2:13]2)[CH2:11]1.Cl[Si:19]([CH3:22])([CH3:21])[CH3:20]>C(OCC)C>[CH3:20][Si:19]([CH3:22])([CH3:21])[O:17][C:16]1[CH:12]2[CH2:13][CH:14]([CH:15]=1)[CH2:10][CH2:11]2
Reactant: O=C1CC2CCC1C2
Reactant: C[Si](C)(C)Cl
Agent: [Li]C
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: C[Si](C)(C)OC1=CC2CCC1C2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Methyllithium in diethyl ether (141 ml of 1.8 M solution) was added dropwise to a solution of 27.6 g of diisopropylamine in 38 ml of dry diethyl ether. The resulting solution was cooled to -78° C. and 19.7 g of norcamphor in 20 ml of diethyl ether were added dropwise. The reaction mixture was warmed to 0° C. and 46 ml of chlorotrimethylsilane were added. The reaction mixture was warmed to 25° C., stirred for 30 minutes, extracted with cold 5% aqueous sodium bicarbonate, dried (over MgSO4) and then distilled to give 22.3 g of 2-trimethylsiloxybicyclo[2.2.1]-hept-2-ene as a colorless liquid: bp 70°-73° C. (14 mm).
Reaction SMILES: [CH:1]1([N:7]2[C:10]([CH3:12])([CH3:11])[C:9](=[O:13])[N:8]2[CH:14]2[CH:21]3[CH2:22][CH:17]4[CH2:18][CH:19]([CH2:23][CH:15]2[CH2:16]4)[CH2:20]3)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1>C(O)C.[C].[Pd]>[CH:1]1([N:7]2[C:10]([CH3:11])([CH3:12])[C:9](=[O:13])[N:8]2[CH:14]2[CH:21]3[CH2:20][CH:19]4[CH2:18][CH:17]([CH2:16][CH:15]2[CH2:23]4)[CH2:22]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1C1C=CCCC1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.1 %

Procedure:
A solution of 1-(cyclohexa-2-ene-1-yl)-4,4-dimethyl-2-(adamantan-2-yl)-1,2-diazetidin-3-one (3.20 mg, 0.0100 mmol) in ethanol (2 mL) was added with 10% palladium carbon (catalyst amount), and under hydrogen atmosphere, the resultant was stirred at room temperature for 2 hours. The reaction solution was filtered using celite and concentrated in vacuo. The obtained residue was purified using Preparative Thin-Layer chromatography (hexane:ethyl acetate=3:1), and the title compound (3.2 mg, quant.) was obtained as a colorless oil.