Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[CH:40][C:6]([C:7]([O:22][CH2:23][C@:24]23[C@H:30]([OH:31])[C@H:27]([O:28][CH2:29]2)[C@H:26]([N:32]2[CH:39]=[CH:38][C:36](=[O:37])[NH:35][C:33]2=[O:34])[O:25]3)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.N1C=CN=C1.[Si:47](Cl)([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48]>CN(C=O)C.CCOC(C)=O>[Si:47]([O:31][C@@H:30]1[C@@H:27]2[O:28][CH2:29][C@@:24]1([CH2:23][O:22][C:7]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:6]1[CH:40]=[CH:41][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[O:25][C@H:26]2[N:32]1[CH:39]=[CH:38][C:36](=[O:37])[NH:35][C:33]1=[O:34])([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(C(OC[C@]23CO[C@H]([C@H](n4ccc(=O)[nH]c4=O)O2)[C@H]3O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(OC[C@]23CO[C@H]([C@H](n4ccc(=O)[nH]c4=O)O2)[C@H]3O[Si](C)(C)C(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 94 %

Procedure:
A solution of compound 112 (1.5 g) in anhydrous DMF (10 mL) was stirred with imidazole (0.913 g), trethylamine (375 μL) and t-butyldimethylsilylchloride (0.81 g) for 15 h. The reaction mixture was diluted with EtOAc (40 mL) and washed with aqueous sodium bicarbonate solution (2×20 mL). The organic layer was separated and dried over anhydrous Na2SO4. The solvent was removed and the product purified on silica gel using 10% acetone in CH2Cl2. The appropriate fractions were concentrated and dried to give Compound 114 in 94% yield.
Reaction SMILES: [CH:1]1([C:7]2[CH:32]=[CH:31][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO[C:35](OC)([N:37]([CH3:39])[CH3:38])[CH3:36]>>[CH:1]1([C:7]2[CH:32]=[CH:31][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27]([NH:29][N:30]=[C:35]([N:37]([CH3:39])[CH3:38])[CH3:36])=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NNC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Reactant: COC(C)(OC)N(C)C
Product: CC(=NNC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2)N(C)C

Procedure:
A stirred mixture of 10-(4-cyclohexyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid hydrazide of Example 8 (0.50 g) and N,N-dimethylacetamide dimethyl acetal (5 mL) was refluxed for one hour and then evaporated to dryness under reduced pressure. The residue was dissolved in dichloromethane, washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and filtered through a short column of Magnesol®. After eluting with several additional volumes of dichloromethane, the combined eluate was evaporated to provide the title compound as a light tan amorphous solid, m.p. 164–175° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:3]=1.[C:26]([N:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1)(=[O:28])[CH3:27]>CO.C(Cl)Cl>[C:26]([N:29]1[CH2:34][CH2:33][C:32]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=3)=[O:10])=[C:4]([C:18]3[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=3)[CH:3]=2)([OH:35])[CH2:31][CH2:30]1)(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1CCC(O)(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCC(C)(C)CC3)c2)CC1
Yield: 64 %

Procedure:
The title compound was prepared by the procedure of Example 11 using 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 1, step (g), 80.0 mg, 0.200 mmol) and 1-acetyl-piperidin-4-one (123 μL, 1.00 mmol). Silica gel chromatography (2-5% MeOH/DCM) afforded the title compound (59.1 mg, 64%) as a colorless oil. 1H-NMR (CD3OD; 400 MHz): δ 8.18 (d, 1H, J=8.6 Hz), 8.00 (s, 1H), 7.39 (dd, 1H, J=8.6, 2.3 Hz), 7.35 (d, 1H, J=2.3 Hz), 5.74 (m, 1H), 4.45 (m, 1H), 3.84 (m, 1H), 3.60 (m, 1H), 3.11 (m, 1H), 2.28-2.35 (m, 2H), 2.15 (s, 3H), 1.91-2.10 (m, 4H), 1.76 (m, 2H), 1.59 (t, 2H, J=6.3 Hz), 1.09 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C26H31N5O3, 462.2 (M+H). found 462.0.
Reaction SMILES: CO.C[O:4][C:5]1[C:10]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]3)[C:15]([CH3:32])=[C:14]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:13]=2)=[CH:9][CH:8]=[CH:7][N:6]=1.Cl>O1CCOCC1>[CH3:32][C:15]1[C:14]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[N:13][C:12]([NH:11][C:10]2[C:5](=[O:4])[NH:6][CH:7]=[CH:8][CH:9]=2)=[N:17][C:16]=1[NH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]1
Reactant: COc1ncccc1Nc1nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c(C)c(N2CCOCC2)n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(N[C@@H]2CCCNC2)nc(Nc2ccc[nH]c2=O)nc1N1CCOCC1
Temperature: 40 °C
Reaction time: 3 h
Yield: 50.7 %

Procedure:
Methanol was added to a stirred mixture of (R)-tert-butyl 3-(2-(2-methoxypyridin-3-ylamino)-5-methyl-6-morpholinopyrimidin-4-ylamino)piperidine-1-carboxylate (Preparation 26a, 0.212 g, 0.42 mmol) and 4N solution of hydrogen chloride in 1,4-dioxane (4 mL) in a sealed tube at ambient temperature until a clear solution was formed. After stirring for an additional 3 hours, further 4N hydrogen chloride solution in 1,4-dioxane (3 mL) was added and the resulting mixture was stirred and heated at 40° C. overnight. The solvents were evaporated under reduced pressure and the residue was partitioned between ethyl acetate and an saturated aqueous solution of sodium hydrogencarbonate. The organic layer was separated and the aqueous phase was washed with ethyl acetate (×2). The combined organic extracts were dried (Na2SO4) and the solvent evaporated under reduced pressure to give the title compound (0.082 g, 37%) as an orange foam that was used in the next synthetic step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:18])[CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:4]([O:19][CH3:20])[CH:3]=1.C(N(CC)CC)C.Br[CH2:29][CH2:30][CH3:31]>CN(C=O)C>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:18])[CH2:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:29][CH2:30][CH3:31])[CH2:16][CH2:17]2)=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)CCC1CCNCC1
Reactant: CCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCN1CCC(CCC(=O)c2cc(Cl)c(N)cc2OC)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1-(4-Amino-5-chloro-2-methoxyphenyl)-3-(piperidin-4-yl)propan-1-one (0.2 g, 0.67 mmol), prepared as in Example 3 or Example 7, triethylamine (0.2 mL), and 1-bromopropane (0.065 mL, 0.75 mmol) were dissolved in DMF (4 mL) and the solution was stirred at room temperature for 12 hours. The solution was partitioned between aqueous ammonium hydroxide and ethyl acetate. The ethyl acetate layer was separated, washed with water and then brine, dried over sodium sulfate, and evaporated. Purification of the residue by silica gel chromatography (10% CH3OH--CH2Cl2) gave 1-(4-amino-5-chloro-2-methoxyphenyl)-3-(1-(prop-1-yl) piperidin-4-yl]propan-1-one which was then dissolved in ethanolic hydrochloric acid. Crystallization with ether gave 1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-(prop-1-yl) piperidin-4-yl]propan-1-one hydrochloride (0.15 g, 0.4 mmol), m.p. 200°-201° C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][N:20]([CH3:52])[S:21]([N:24]1[C:28]([C:29]2([OH:44])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:30]2)=[CH:27][N:26]=[C:25]1[Si](C(C)(C)C)(C)C)(=[O:23])=[O:22]>O1CCCC1>[CH3:19][N:20]([CH3:52])[S:21]([N:24]1[C:28]([C:29]2([OH:44])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:30]2)=[CH:27][N:26]=[CH:25]1)(=[O:22])=[O:23]
Reactant: CN(C)S(=O)(=O)n1c(C2(O)CC(c3ccccc3)c3ccccc32)cnc1[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cncc1C1(O)CC(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1.1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (1.4 ml, 1.54 mmol) was added dropwise to the solution of 2-(tert-butyidimethylsilanyl)-5-(2,3-dihydro-1-hydroxy-3-phenyl-1H-inden-1-yl)-1H-imidazole-1-sulfonic acid dimethylamide (637 mg, 1.28 mmol) in tetrahydrofuran (13 ml). The reaction was stirred overnight at room temperature. The reaction was quenched with water and then extracted with ethyl acetate. The organic layer was washed with water and brine. The organic phase was dried and the solvent removed under reduced pressure. The product was recrystallized in ethyl acetate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19]([NH2:21])=[S:20])=[N:2]1.[C:22](OCCCl)(=[O:24])[CH3:23].N>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19]2[S:20][CH2:23][C:22](=[O:24])[N:21]=2)=[N:2]1
Reactant: CC(=O)OCCCl
Reactant: NC(=S)Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Agent: N
Solvent: CCO
Product: O=C1CSC(Nc2ccccc2/C=C/c2n[nH]c3ccccc23)=N1
Yield: 11.4 %

Procedure:
Compound 161 (0.10 g, 0.34 mmol) was added with ethanol (3.0 mL) and chloroethyl acetate (43 μL, 0.41 mmol), and after heating under reflux for 7 hours, the aqueous ammonia was added to stop the reaction. The mixture was extracted with ethyl acetate, concentrated and purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to 1/4), followed by triturating in ethyl acetate to obtain Compound 172 (13 mg, 12%).
Reaction SMILES: [C:1]([CH:3]([CH2:9][C:10]#[N:11])C(OCC)=O)#[N:2].N1C=CC=CC=1.F[B-](F)(F)F.[C:23]1([N+:29]#[N:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[C:23]1([N:29]=[N:30][CH:3]([CH2:9][C:10]#[N:11])[C:1]#[N:2])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: N#[N+]c1ccccc1
Reactant: CCOC(=O)C(C#N)CC#N
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: CO
Product: N#CCC(C#N)N=Nc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28 %

Procedure:
A solution of ethyl 2,3-dicyanopropanoate (1.58 g, 10.38 mmol) in methanol (52 mL) and pyridine (2.52 mL, 31.14 mmol) was cooled to 10° C. in an ice bath. Benzenediazonium tetrafluoroborate was added portion-wise over 20 minutes at 10° C. and the reaction stirred at room temperature for 18 hours. The reaction was concentrated in vacuo and partitioned between DCM and water. The organic layer was dried over magnesium sulphate and concentrated in vacuo to afford the title compound (2.8 g, 28%). The crude product was taken on directly to the next step.
Reaction SMILES: Cl.[CH:2]1[C:14]2[CH:13]([CH2:15][O:16][C:17]([NH:19][NH2:20])=[O:18])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:21](O)(=[O:29])[C@@H:22]([C@H:24]([C:26]([OH:28])=[O:27])[OH:25])[OH:23].C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+].S([O-])(O)(=O)=O.[K+]>C(OCC)C.CN(C)C=O>[CH:11]1[C:12]2[CH:13]([CH2:15][O:16][C:17]([NH:19][NH:20][C:21](=[O:29])[CH:22]([OH:23])[CH:24]([OH:25])[C:26]([OH:28])=[O:27])=[O:18])[C:14]3[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Reactant: NNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NNC(=O)C(O)C(O)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
N-(9H-9-fluorenylmethoxycarbonyl)hydrazine hydrochloride (Compound 40; 500 mg, 1.72 mmol) and L-(+)-tartaric acid (Compound 15; 634 mg, 4.22 mmol) were dissolved by the addition of N,N-dimethylformamide (10 ml) and diisopropylethylamine (300 μl, 1.72 mmol). Next, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (485 mg, 2.53 mmol) was added, and this was followed by overnight stirring at room temperature. This was concentrated under reduced pressure; to the residue obtained, aqueous sodium hydrogen carbonate and diethyl ether were added; two liquid phases were separated. The water phase obtained was acidified with a 2N aqueous solution of potassium hydrogen sulfate under ice cooling, after which it was extracted with ethyl acetate. The organic phase was washed with saturated brine, after which it was dried with sodium sulfate. The solid was filtered and concentrated under reduced pressure, after which it was crystallized from methanol-diethyl ether to yield the desired 4-[N′-(9H-fluoren-9-ylmethoxycarbonyl)-hydrazino]-2,3-dihydroxy-4-oxo-butanoic acid (Compound 41: 413 mg, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][C:12]([CH3:18])([CH3:17])[CH2:13][C:14]([OH:16])=O)[CH2:9][CH3:10])=[C:4]([F:19])[C:3]=1[C:20]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:21].CC[N:30](C(C)C)C(C)C.[Cl-].[NH4+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][C:12]([CH3:17])([CH3:18])[CH2:13][C:14]([NH2:30])=[O:16])[CH2:9][CH3:10])=[C:4]([F:19])[C:3]=1[C:20]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:21]
Reactant: CC[C@@H](NC(C)(C)CC(=O)O)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[C@@H](NC(C)(C)CC(N)=O)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Step 2 To a stirred solution of 3-{[(1R)-1-{4-chloro-2-fluoro-3-[(pyridin-3-yl)carbonyl]phenyl}-propyl]amino}-3-methylbutanoic acid (0.023 g, 0.0585 mmol), iPr2NEt (0.0714 mL, 0.41 mmol) and ammonium chloride (0.0157 g, 0.293 mmol) in DMF (0.351 mL) at 0° C. was added HATU (0.0334 g, 0.0878 mmol). The mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was poured into EtOAc and washed with water (×3). The organic extract was dried (Na2SO4), filtered and concentrated. The material was converted to the HCl salt and triturated with EtOAc providing 3-{[(1R)-1-{4-chloro-2-fluoro-3-[(pyridin-3-yl)carbonyl]phenyl}propyl]amino}-3-methylbutanamide, 0.013 g, 52%.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])([CH3:3])[CH3:2].[I:22]Cl.C([O-])(O)=O.[Na+]>CC(O)=O.O>[I:22][C:7]1[CH:6]=[C:5]([S:12]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:13])=[O:14])[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][C:8]=1[O:10][CH3:11]
Reactant: COc1ccc(S(=O)(=O)c2ccc(C)cc2)c(C(C)C)c1
Reactant: ClI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C(C)C)c(S(=O)(=O)c2ccc(C)cc2)cc1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
To a solution of 2-Isopropyl4-methoxy-1-(toluene4-sulfonyl)-benzene (10 g, 31.25 mmol) in HOAc (10 ml) was added a solution of ICl (9.6 g, 59.26 mmol) in HOAc (10 ml) and H2O (5 ml). The reaction mixture was stirred at room temperature for 16 hrs and basified by saturated NaHCO3 solution. The aqueous solution was extracted into EtOAc which was washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo to give 1-Iodo4-isopropyl-2-methoxy-5-(toluene4-sulfonyl)-benzene (12.35 g, 89%).
Reaction SMILES: O[C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH2:4][CH2:3]1.CCN(S(F)(F)F)CC>>[CH:5]1([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH2:6][CH2:7][CH:2]=[CH:3][CH2:4]1
Reactant: O=C1CCCN1[C@H]1CC[C@H](O)CC1
Agent: CCN(CC)S(F)(F)F
Product: O=C1CCCN1C1CC=CCC1
Yield: 26 %

Procedure:
Using trans-1-(4-hydroxy-cyclohexyl)-pyrrolidin-2-one (6.0 g, 0.03 mol Preparation 14)) and DAST (8.6 mL, 0.06 mol) and purification by chromatography on silica gel, obtain the title compound as a clear oil (1.29 g, 26%). MS (EI) m/z=165 (M+).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>ClCCl>[CH2:2]([O:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[S:32]([C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=1)(=[O:34])=[O:33])=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H]1CCCCN1S(=O)(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.5 %

Procedure:
To a mixture of (S)-piperidine-2-carboxylic acid benzyl ester hydrochloride (5.00 g, 19.5 mmol) and triethylamine (5.50 mL, 39.1 mmol) in dichloromethane (150 mL) was added 3-fluorobenzenesulfonyl chloride (3.80 g, 19.5 mmol). The mixture was stirred at room temperature for 5 h as it turned to a white suspension. The suspension was washed twice with distilled water. The organic layer was then dried over magnesium sulfate and concentrated to afford 9 g of crude oil. Flash column chromatography on silica gel (ethyl acetate/n-heptane) provided 6.51 g (88.3%) of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)N.Cl.N([O-])=O.[Na+].[C:18]([Cu])#[N:19].[C-]#N.[Na+]>CC(C)=O.O.CCOC(C)=O>[Cl:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[C:18]#[N:19]
Reactant: N#C[Cu]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1N
Agent: Cl
Agent: O=N[O-]
Agent: [C-]#N
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(Cl)cc1C#N
Yield: 77.5 %

Procedure:
To a suspension of 5-chloro-4-nitro-2-methylaniline (40.0 g, 0.21 mol) in acetone (140 mL) and H2O (150 mL) at 0° C. was added concentrated aqueous HCl (45 mL). The mixture was well stirred and a solution of NaNO2 (18.0 g, 0.26 mol) in H2O (60 mL) was added dropwise over a period of 15 min. The mixture was further stirred for 20 min. and then added portionwise to a vigorously stirred mixture of CuCN (30.0 g, 0.34 mol) and NaCN (44.0 g, 0.90 mol) in H2O (200 mL):EtOAc (100 mL). After stirring at room temperature for 30 min., the mixture was diluted with H2O and extracted with EtOAc. The EtOAc extract was washed successively with 1N NaOH and brine, dried over anhydrous MgSO4 and concentrated. The residue was suspended in hexanes:Et2O (1:1), stirred for 15 min., and filtered to provide the title compound (32 g, 76%) as yellow solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.Br[CH2:15][CH2:16]Br.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[C:5]([C:9]2([C:10]#[N:11])[CH2:16][CH2:15]2)[CH:6]=[CH:7][CH:8]=1
Reactant: N#CCc1cccc(C(F)(F)F)c1
Reactant: BrCCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: N#CC1(c2cccc(C(F)(F)F)c2)CC1
Reaction time: 8 h
Yield: 79.1 %

Procedure:
To a mixture of 3-(trifluoromethyl)phenylacetonitrile (18.5 g, 0.1 mole), 1,2-dibromoethane (56.4 g, 0.3 mole) and triethylbenzylammonium chloride (TEBA) (1.0 g), there was added 40 ml of 50% sodium hydroxide solution at room temperature. The exothermic reaction mixture was vigorously stirred overnight. The reaction mixture was diluted with water (100 ml) and extracted with ether (4×100 ml). The organic layer was washed with water (3×50 ml), brine (50 ml) and dried over magnesium sulfate. The solvent was removed and the product was distilled under reduced pressure (B.P. 92°-94° C. at 0.4 mm Hg) to give a 16.7 g of product (79% yield). ##STR4## where Xn is 4-chloro; 2-bromo; 3-bromo; 2-iodo; 3-iodo; 4-iodo; 3-carboxylic acid; 3-NO3 ; 2,3-benzo.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]3[CH:12]=[C:11]([C:13]([OH:15])=O)[O:10][C:8]3=[CH:9][C:4]=2[NH:3][C:2]1=[O:16].[CH2:17]([O:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)C>[CH2:17]([O:24][CH:25]1[CH2:30][CH2:29][N:28]([C:13]([C:11]2[O:10][C:8]3[C:7](=[CH:6][C:5]4[O:1][C:2](=[O:16])[NH:3][C:4]=4[CH:9]=3)[CH:12]=2)=[O:15])[CH2:27][CH2:26]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)c1cc2cc3oc(=O)[nH]c3cc2o1
Reactant: c1ccc(COC2CCNCC2)cc1
Solvent: CCOCC
Product: O=C(c1cc2cc3oc(=O)[nH]c3cc2o1)N1CCC(OCc2ccccc2)CC1

Procedure:
The title compound is prepared from 3H-furo[2,3-f]benzoxazole-2-one-6-carboxylic acid and 4-benzyloxypiperidine according to the method described in Example 1/c. Mp.: 217-219° C. (diethyl ether).
Reaction SMILES: NN1CCCC1.Cl[C:8]1[N:9]=[C:10]([N:17]([CH3:19])[CH3:18])[C:11]2[S:16][CH:15]=[CH:14][C:12]=2[N:13]=1.Cl.[NH2:21][C@H:22]1[CH2:26][CH2:25][N:24]([C:27](=[O:40])[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=2)[CH2:23]1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl.O.C(O)CO>[CH3:18][N:17]([CH3:19])[C:10]1[C:11]2[S:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:8]([NH:21][C@H:22]2[CH2:26][CH2:25][N:24]([C:27](=[O:40])[CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][C:36]([F:37])([F:38])[F:39])=[CH:33][CH:34]=3)[CH2:23]2)[N:9]=1
Reactant: N[C@H]1CCN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C1
Reactant: CN(C)c1nc(Cl)nc2ccsc12
Agent: Cl
Agent: NN1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN(C)c1nc(N[C@H]2CCN(C(=O)Cc3ccc(OC(F)(F)F)cc3)C2)nc2ccsc12
Temperature: 110 °C
Yield: 12.2 %

Procedure:
To a solution of 50% aqueous dimethyl amine (0.77 g) in ethanol (30 mL) was added 2,4-dichlorothieno[3,2-d]pyrimidine (1.00 g) with ice cooling, and the mixture was stirred for 12 h while heating to room temperature. The reaction mixture was concentrated under reduced pressure and diluted with chloroform and water, and then the aqueous layer was extracted with chloroform. The organic layer was washed with 1 M hydrochloric acid and saturated brine, then the organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was crystallized with diethyl ether to obtain 2-chloro-N,N-dimethylthieno[3,2-d]pyrimidin-4-amine (0.90 g). (2) A mixture of 2-chloro-N,N-dimethylthieno[3,2-d]pyrimidin-4-amine (0.60 g), (S)-1-(3-aminopyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone mono hydrochloride (2.70 g), N,N-diisopropylethylamine (1.80 g), and ethylene glycol (18 mL) was heated at 110° C. for 20 h with stirring. The reaction mixture was diluted with chloroform and water, and then the aqueous layer was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform/methanol, and NH silica gel, chloroform/methanol) and crystallized with diethyl ether to obtain white solid (S)-1-(3-(4-dimethylaminothieno[3,2-d]pyrimidin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.16 g).
Reaction SMILES: [OH:1][C:2]([CH:5]1[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7][CH2:6]1)([CH3:4])[CH3:3]>CO.[Pd]>[OH:1][C:2]([CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)([CH3:4])[CH3:3]
Reactant: CC(C)(O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(O)C1CCNCC1
Reaction time: 8 h
Yield: 100 %

Procedure:
Benzyl 4-(1-hydroxy-1-methylethyl)piperidine-1-carboxylate (1.786 g, 6.44 mmol) synthesized in Production example 42-2 was dissolved in methanol (100 ml) under nitrogen atmosphere; 10% palladium on carbon (50% wet, 1.37 g) was added; the reaction system was purged with hydrogen at atmospheric pressure; and the reaction mixture was stirred overnight. After the reaction system was purged with nitrogen, the catalyst was filtered out, and washed with methanol; the solvent, together with the filtrate and the washing solution, was distilled off; and the residue was dried under reduced pressure to yield the title compound (922 mg, 6.44 mmol, quantitative) as pale gray crystals.