Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:16][CH2:15]1)[CH2:10]2)=[O:5])[CH3:2].CCN(CC)CC.[CH:35]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.[OH-].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([N:14]1[CH2:15][CH2:16][CH:17]([N:20]([C:41]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[O:42])[C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH2:18][CH2:19]1)[CH2:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C2CCC1CC(N1CCC(Nc3ccc(F)cc3)CC1)C2
Reactant: O=C(Cl)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1C2CCC1CC(N1CCC(N(C(=O)C3CCCCC3)c3ccc(F)cc3)CC1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[4-(4-Fluoro-phenylamino)-piperidin-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid ethyl ester (50 mg; 0.13 mmol; 1 eq.) was dissolved in DCM (3 mL) and Et3N (0.056 mL; 0.39 mmol; 3 eq.) was added. Cyclohexylcarbonyl chloride (30 mg; 0.2 mmol; 2 eq.) was then added and the solution was stirred at room temperature for 18 hours (overnight). 1N NaOH (10 mL) was added and the solution was extracted with EtOAc (2×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified using reversed-phase HPLC (2-99% CH3CN/H2O gradient with 0.05% TFA). LC/MS M/Z=432.4, Retention time=2.12; 10-99% CH3CN/H2O gradient with 0.05% TFA over 5 minutes. H NMR (400 MHz, MeOD, TFA salt) δ 7.33-7.22 (m, 4H), 4.75 (tt, J=12.3 Hz, 3.8 Hz, 1H), 4.39 (s, 2H), 4.14 (q, J=7.1 Hz, 2H), 3.75-3.58 (m, 3H), 3.09 (t, J=11.9 Hz, 2H), 2.14-1.89 (m, 7H), 1.79-1.40 (m, 14H), 1.27 (t, J=7.1 Hz, 3H), 1.26-1.11 (m, 1H), 1.02-0.90 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[N:6]([C:17](=[O:18])[C:16]2[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:21][CH:20]=2)[CH:7]=1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Product: O=C(c1ccc([N+](=O)[O-])cc1)n1cc(F)c(=O)[nH]c1=O
Yield: 52.8 %

Procedure:
2.6 g (0.02 mole) of 5-fluorouracil was reacted with 9.28 g (0.05 mole) of p-nitrobenzoyl chloride in the same manner as in Example 1 and 2.95 g (52.9% yield) of 5-fluoro-1-(p-nitrobenzoyl)uracil was obtained. The product was recrystallized from ethanol and white needles melting at 182°-183°C. were obtained. The results of an elementary analysis of the above crystals were well in agreement with the calculated value as follows:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](F)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])=[CH:19][CH:18]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])=[CH:21][CH:22]=2)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(OCc2ccccc2)cn1
Reactant: CC(=O)NC(C)CCc1ccc(O)cc1
Product: CC(=O)NC(C)CCc1ccc(Oc2ccc(OCc3ccccc3)cn2)cc1

Procedure:
5-Benzyloxy-2-fluoropyridine (980 mg, 4.82 mmol) was reacted with N-[3-(4-hydroxy-phenyl)-1-methylpropyl]acetamide in analogy to example 1b.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17](/[CH:20]=[CH:21]/[CH2:22]Cl)[CH2:16][CH2:15]2)[CH3:11])=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([CH3:11])[CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17](/[CH:20]=[CH:21]/[CH2:22][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: CN(CC[C@H]1CC[C@H](/C=C/CCl)CC1)C(=O)Oc1ccc(Cl)cc1
Reactant: C1CCNCC1
Solvent: CC(=O)N(C)C
Product: CN(CC[C@H]1CC[C@H](/C=C/CN2CCCCC2)CC1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to the method described in example 12.1, trans-{2-[4-(3-chloro-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-carbamic acid 4-chloro-phenyl ester was reacted with piperidine in N,N-dimethylacetamide at room temperature to yield trans-methyl-{2-[4-(3-piperidin-1-yl-(E)-propenyl)-cyclohexyl]-ethyl}-carbamic acid 4-chloro-phenyl ester as colorless viscous oil, MS: 419 (MH+, 1Cl).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]1[NH:12][N:11]=[C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[N:14]=2)[N:9]=1.Br[CH2:30][C:31]1[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1>C1COCC1>[CH3:7][C:8]1[N:12]([CH2:30][C:31]2[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=2)[N:11]=[C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([F:28])([F:26])[F:27])=[CH:22][CH:23]=3)[N:14]=2)[N:9]=1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Reactant: Oc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(O)c1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of K2CO3 (2.63 g, 19.0 mmol), 5-(5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (Intermediate B, 3.70 g, 11.9 mmol) and 3-(bromomethyl)phenol (1.78 g, 9.52 mmol) was dissolved in THF (48 mL) and stirred at 50° C. for 16 h. The reaction mixture was filtered, the solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography (0% to 80% EtOAc in Hexanes) to afford the title compound. MS (ES+) C19H14F3N5O3 requires: 417. found 418 [M+H]+; 1H-NMR (600 MHz, CD3OD) δ ppm 8.22 (d, J=8.8 Hz, 2H), 7.61 (d, J=8.0 Hz, 2H), 7.19 (d, J=7.8 Hz 1H), 6.72 (m, 2H), 6.67 (s, 1H), 5.49 (s, 2H), 2.56 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1.Cl[CH2:11][C:12](=O)[CH3:13]>C(O)C>[NH2:9][C:6]1[CH:5]=[CH:4][N:3]2[CH:11]=[C:12]([CH3:13])[N:1]=[C:2]2[C:7]=1[Br:8]
Reactant: Nc1ccnc(N)c1Br
Reactant: CC(=O)CCl
Solvent: CCO
Product: Cc1cn2ccc(N)c(Br)c2n1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of 2,4-diamino-3-bromopyridine (17) (in Rauckman, B. S, and al. J. Med. Chem. 1980, 23, 384-391) (2.00 g, 10.6 mmol) in ethanol (40 mL) was added chloracetone (3.93 g, 42.5 mmol). The solution was stirred under reflux for 24 h. After cooling to room temperature, the solution was evaporated to dryness. The residue was diluted with water (40 mL) and the resulting solution made basic by the addition of Na2CO3. The solution was extracted with CH2Cl2 and the combinated extracts were dried (Na2SO4), filtered and evaporated under reduced pressure. The crude product was purified by chromatography using CH2Cl2/EtOAc (4/1, v/v) as eluent to afford compound 18 (yield: 90%); mp 158-160° C.; 1H NMR (200 MHz, DMSO-d6) δ 2.19 (s, 3H), 5.78 (brs, 2H), 6.41 (d, 1H, J=7 Hz), 7.36 (s, 1H), 8.07 (d, 1H, J=7 Hz); 13C NMR (100 MHz, DMSO-d6) δ 14.1, 86.2, 104.6, 109.1, 125.5, 140.8, 143.1, 144.0. Anal.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[N:18]=[C:17]2[CH:19]=[C:20]([F:24])[CH:21]=[C:22]([F:23])[C:16]2=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:23][C:22]1[C:16]2[C:17](=[N:18][N:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=3)[N:15]=2)[CH:19]=[C:20]([F:24])[CH:21]=1
Reactant: C#CCCn1nc2cc(F)cc(F)c2n1
Reactant: FCc1cccc(Br)n1
Product: FCc1cccc(C#CCCn2nc3cc(F)cc(F)c3n2)n1
Yield: 58333.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (50 mg, 0.27 mmol) and 2-(but-3-ynyl)-4,6-difluoro-2H-benzo[d][1,2,3]triazole (50 mg, 0.24 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 45 mg (0.14 mol, 53%) of 4,6-difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a brown oil.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[Br:24][C:25]1[CH:26]=[C:27]([F:32])[C:28](F)=[N:29][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O>[Br:24][C:25]1[CH:26]=[C:27]([F:32])[C:28]([N:21]2[CH2:22][CH2:23][CH:18]([N:4]([CH:1]3[CH2:3][CH2:2]3)[C:5](=[O:17])[C:6]3[CH:7]=[CH:8][C:9]([C:12]4[O:16][CH:15]=[N:14][CH:13]=4)=[CH:10][CH:11]=3)[CH2:19][CH2:20]2)=[N:29][CH:30]=1
Reactant: Fc1cc(Br)cnc1F
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2ncc(Br)cc2F)CC1

Procedure:
The title compound is prepared from N-Cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 5-bromo-2,3-difluoro-pyridine following a procedure analogous to that described in Example 61 using K2CO3 as base and N-methylpyrrolidinone as solvent. LC (method 1): tR=1.35 min; Mass spectrum (ESI+): m/z=507 [M+Na]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[F:49][C:50]1[CH:69]=[CH:68][C:53]([O:54][C:55]2[S:59][C:58]([NH2:60])=[N:57][C:56]=2[C:61]2[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=2)=[CH:52][CH:51]=1>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C:12]([C:13](=[O:15])[NH:60][C:58]1[S:59][C:55]([O:54][C:53]2[CH:68]=[CH:69][C:50]([F:49])=[CH:51][CH:52]=2)=[C:56]([C:61]2[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=2)[N:57]=1)([CH3:17])[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1nc(-c2ccc(F)cc2)c(Oc2ccc(F)cc2)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)Nc1nc(-c2ccc(F)cc2)c(Oc2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-benzyloxycarbonylamino-2-methyl-propionic acid (10.5 g, 44.2 mmol), HBTU (16.8 g, 44.3 mmol) and Et3N (6.2 mL, 45 mmol) in DMF (50 mL) was stirred at room temperature for 2 h. To this was added a solution of 5-(4-Fluoro-phenoxy)-4-(4-fluoro-phenyl)-thiazol-2-ylamine (9.62 g, ca. 32 mmol with some impurities present) in DMF (50 mL). The mixture was heated at 85° C. for 18 h and partitioned between EtOAc and, sequentially, 3M HCl and aqueous KOH. The organic extract was dried over MgSO4, concentrated and chromatographed to give the title compound. m/z 524.2 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:13]2[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][CH:20]=O)=[CH:17][C:12]=2[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]1=[O:22].[CH3:23][NH:24][CH3:25].C([BH3-])#N.[Na+].Cl>CO>[CH3:23][N:24]([CH3:25])[CH2:20][CH2:19][CH2:18][C:16]1[CH:15]=[CH:14][C:13]2[N:4]([CH2:3][O:2][CH3:1])[C:5](=[O:22])[C:6]3[CH:7]=[CH:8][CH:9]=[N:10][C:11]=3[C:12]=2[CH:17]=1
Reactant: CNC
Reactant: COCn1c(=O)c2cccnc2c2cc(CCC=O)ccc21
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COCn1c(=O)c2cccnc2c2cc(CCCN(C)C)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
The compound (151 mg, 0.51 mmol) prepared in step 7 was dissolved in methanol, sequentially added with 2 M dimethylamine (2.18 ml, 4.38 mmol), sodium cyanoborohydride (35 mg, 0.56 mmol), zinc chloride(II) (35 mg, 0.255 mmol), and 1.25 M hydrochloric acid (2.44 ml, 3.06 mmol) at 0° C. The resulting mixture was stirred for one hour at room temperature. The mixture was poured into ice water and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated to dryness. The residue was then purified by flash column chromatography (chloroform:methanol=15:1) to obtain the title compound (152 mg, yield: 92%, white solid).
Reaction SMILES: [I-].[CH3:2][S+](C)C.[H-].[Na+].[C:8]1([CH:20]2[CH2:25][CH2:24][C:23](=[CH:26][C:27]#[N:28])[CH2:22][CH2:21]2)[N:9]=[N:10][N:11]2[C:16]=1[C:15]1[CH:17]=[CH:18][NH:19][C:14]=1[N:13]=[CH:12]2.O>CS(C)=O>[C:8]1([CH:20]2[CH2:21][CH2:22][C:23]3([CH:26]([C:27]#[N:28])[CH2:2]3)[CH2:24][CH2:25]2)[N:9]=[N:10][N:11]2[C:16]=1[C:15]1[CH:17]=[CH:18][NH:19][C:14]=1[N:13]=[CH:12]2
Reactant: C[S+](C)C
Reactant: N#CC=C1CCC(c2nnn3cnc4[nH]ccc4c23)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC1CC12CCC(c1nnn3cnc4[nH]ccc4c13)CC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 36.8 %

Procedure:
Trimethylsulfonium iodide (59.0 μL, 0.269 mmol) in dimethyl sulfoxide (1 mL) was stirred with sodium hydride (55 wt % dispersion in mineral oil, 12.0 mg, 0.269 mmol) at room temperature for 30 minutes. The reaction mixture was mixed with 2-[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexylidene]acetonitrile (15.0 mg, 0.0539 mmol) obtained in Synthetic Examplea 434 and then stirred at room temperature for 15 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1 (v/v)) to give the title compound as a colorless solid (5.80 mg, yield 37%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1B(O)O>>[F:21][C:4]1[CH:3]=[C:2]([C:24]2[CH:23]=[N:22][C:31]3[C:26]([CH:25]=2)=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: OB(O)c1ccc2ccccc2n1
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Product: O=C(c1ccc(-c2cnc3ccccc3c2)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 2-Quinoline boronic acid. MS (M+H) 404.2
Reaction SMILES: [O:1]1CC[CH2:3][CH2:2]1.Cl.Cl.Cl.[NH2:9][N:10]1[O:22][C:21]2[C:20]3[CH2:19][CH2:18][NH:17][CH2:16][C:15]=3[S:14][C:13]=2[N:12]=[C:11]1[S:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)[CH2:29][CH2:28]1.C(Cl)(=O)C>C(N(CC)CC)C>[C:2]([N:17]1[CH2:16][C:15]2[S:14][C:13]3[N:12]=[C:11]([S:23][CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][N:30]([C:33]5[CH:42]=[CH:41][C:40]6[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=6)[N:34]=5)[CH2:29][CH2:28]4)[N:10]([NH2:9])[O:22][C:21]=3[C:20]=2[CH2:19][CH2:18]1)(=[O:1])[CH3:3]
Reactant: NN1Oc2c(sc3c2CCNC3)N=C1SCCCN1CCN(c2ccc3ccccc3n2)CC1
Reactant: C1CCOC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Product: CC(=O)N1CCc2c(sc3c2ON(N)C(SCCCN2CCN(c4ccc5ccccc5n4)CC2)=N3)C1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To 10 ml of tetrahydrofuran, 203 mg of 3-amino-2-[3-(4-quinolin-2-ylpiperazin-1-yl)-propylthio]-3,4,5,6,7,8-hexahydro-4-oxa-9-thia-1,3,7-triaza-9H-fluorene trihydrochloride as synthesized in Example 1-59 was added and into which 133 mg of triethylamine was dropped. Acetyl chloride was added to the mixture under cooling with ice, followed by 30 minutes stirring and distillation under reduced pressure. The residue was purified on silica gel column chromatography (chloroform:methanol=25:1) to provide 150 mg (83%) of 7-acetyl-3-amino-2-[3-(4-quinolin-2-ylpiperazin-1-yl)propylthio]-3,4,5,6,7,8-hexahydro-4-oxa-9-thia-1,3,7-triaza-9H-fluorene.
Reaction SMILES: S(=O)(=O)(O)O.C(Cl)(Cl)(Cl)Cl.[CH:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH:12]1O)[CH2:18]2.[CH:22]([OH:24])=[O:23]>>[CH:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH:12]1[C:22]([OH:24])=[O:23])[CH2:18]2
Reactant: O=CO
Reactant: OC1C2CC3CC(C2)CC1C3
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)C1C2CC3CC(C2)CC1C3
Temperature: 0 °C
Yield: 5 %

Procedure:
Concentrated sulfuric acid (50 mL) and carbon tetrachloride (100 mL) were combined, cooled to 0° C. and vigorously stirred. Adamantan-2-ol (451 mg) was dissolved in 96% formic acid (6 mL) and the solution was added to the sulfuric acid over 1 hour. The reaction continued to stir at 0° C. for 90 min after which it was added to 300 mL of ice. The layers were separated and the aqueous layer was extracted with 50 mL carbon tetrachloride (2×). The organic layers were combined and extracted with 1N NaOH. The aqueous portion was extracted with methylene chloride (4×) then acidified with 5N HCl. The solution turned white and was cooled on ice. Filtration provided the desired adamantane-2-carboxylic acid (contaminated with about 5% adamantane-1-carboxylic acid) as a white powder.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:9]=[C:10](O)[C:11]3[CH:16]=[CH:15][NH:14][C:12]=3[N:13]=2)[CH:4]=[N:3]1.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:10]1[C:11]2[CH:16]=[CH:15][NH:14][C:12]=2[N:13]=[C:8]([NH:7][C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[N:9]=1
Reactant: Cn1cc(Nc2nc(O)c3cc[nH]c3n2)cn1
Reactant: O=P(Cl)(Cl)Cl
Product: Cn1cc(Nc2nc(Cl)c3cc[nH]c3n2)cn1
Yield: 56 %

Procedure:
A solution of 2-((1-methyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-ol (5 g, 0.02 mol) in POCl3 (50 mL) was stirred at 120° C. for 4 hrs. After removal of POCl3 by rotary evaporation, water (37 mL) was added. The pH was adjusted to 10 by aq. NaOH (2 mol/L, 30 mL) and then extracted with EtOAc/THF (2:1, three×200 mL). The combined organic layers were concentrated to dryness to afford the title compound (2.8 g, 56% yield) as a brown solid, which was used as is in the next step.
Reaction SMILES: N[C:2]1C(=O)C2[C:9]([C:10](=[O:13])[C:11]=1N)=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:15]1([C:21](=O)[C:22](=[O:24])[CH3:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)(=O)C.O>[CH3:2][C:11]1[C:10](=[O:13])[C:9]2[C:23]([C:22](=[O:24])[C:21]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: CC(=O)C(=O)c1ccccc1
Reactant: NC1=C(N)C(=O)c2ccccc2C1=O
Solvent: CC(=O)O
Solvent: O
Product: CC1=C(c2ccccc2)C(=O)c2ccccc2C1=O
Reaction time: 0.08 h
Yield: 94.5 %

Procedure:
In a 200 ml of Erlenmeyer flask were placed 5.0 g (26.5 mmols) of 2,3-diaminonaphthoquinone and 75 ml of acetic acid/water (1/1), a solution composed of 5.9 g (39.8 mmols) of 1-phenyl-1,2-propanedione and 25 ml of acetic acid/water (1/1) was added dropwise to the mixture under ice-cooling over a period of about 10 minutes, and after stirring the mixture for 5 minutes, yellow precipitates thus formed were collected by filtration and washed with water. The precipitates were dissolved in methylene chloride, and after purifying the product with silica gel short column (eluted by methylene chloride), the product was recrystallized from methylene chloridemethanol to provide 6.22 g (78%) of 2-methyl-3-phenylnaphthoquinone (Compound Id-11) as a yellow powder. Melting point 235°-236° C. The infrared spectrum of the compound obtained is shown in FIG. 7.
Reaction SMILES: [C:1]1([C:7]2[CH:17]=[CH:16][C:10]([CH2:11][C:12](=[CH2:15])[CH2:13]Cl)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[OH-].[Na+]>CC1C=CC(C)=CC=1>[C:1]1([C:7]2[CH:17]=[CH:16][C:10]([CH2:11][C:12](=[CH2:15])[CH2:13][N:22]3[CH2:23][CH2:24][CH:19]([CH3:18])[CH2:20][CH2:21]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(CCl)Cc1ccc(-c2ccccc2)cc1
Reactant: CC1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccc(C)cc1
Product: C=C(Cc1ccc(-c2ccccc2)cc1)CN1CCC(C)CC1

Procedure:
A mixture of 2-[(4-phenyl)benzyl]-2-propenyl chloride (4 g.), formed in a manner analogous to that used in Example 1, and 4-methylpiperidine (3.3 g.) in p-xylene (15 ml.) was refluxed for five hours, cooled and neutralized with 25% aqueous sodium hydroxide (15 ml.). The mixture was extracted with toluene, dried over sodium sulfate and evaporated under reduced pressure to give an oil. The oil was distilled under vacuum and the fraction boiling at 195° C. to 200° C. at a pressure of 0.7 mm Hg. was collected and identified as 1-[2-[(4-phenyl)benzyl]-2-propenyl]-4-methylpiperidine. The compound, obtained in a yield of 3.5 g., solidified after being left at room temperature for a few hours. The solid was characterized by a melting point of 53° C.
Reaction SMILES: [C:1]1([CH2:10][C:11]([OH:13])=[O:12])[O:2][CH:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl.[CH3:15]O>>[C:1]1([CH2:10][C:11]([O:13][CH3:15])=[O:12])[O:2][CH:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C(O)Cc1occ2ccccc12
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1occ2ccccc12

Procedure:
Compound 7 (72 g) was dissolved in methanol (200 ml) and the solution saturated with dry HCl. The solution was refluxed for 2 hours and the solvent evaporated. The residue was dissolved in methylene chloride (200 ml) and the solution washed with 5% sodium bicarbonate, and then with water (100 ml). The residue was dried over magnesium sulfate and the solvent was evaporated. The product was distilled in vacuo. The yield was approximately 67.3 g.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[K+]>C(O)(C)C>[CH3:2][C@@H:1]([OH:3])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: C[C@@H](O)c1ccccc1
Reaction time: 12 h
Yield: 93.6 %

Procedure:
An autoclave was charged with acetophenone (1.03 Kg), isopropanol (300 g), and KOH (100 g, 10 M). Catalyst R-XylPPhos RuCl2 R-DAIPEN (150 mg) was then added, and the reaction mixture was hydrogenated at a pressure of 30 bar and a temperature of 70° C. for 12 hours. The resultant mixture was transferred into a separatory funnel. The aqueous layer was discarded. The organic layer was washed with water (200 ml) and distilled first at 100 mmHg to remove isopropanol, and then at 5-10 mmHg to provide (R)-alpha-methylbenzyl alcohol (980 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6](N)[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[I:19])=[O:11].Cl.O.[N+]([O-])([O-])=O.[Na+].[N-:27]=[N+:28]=[N-:29].[Na+]>>[OH:1][C:2]1[C:7]([N:27]=[N+:28]=[N-:29])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[I:19])=[O:11]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc(NC(=O)Nc2ccccc2I)c(O)c1
Agent: Cl
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1cccc(NC(=O)Nc2ccccc2I)c1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24.1 %

Procedure:
The N-(2-hydroxy-4-aminophenyl)-N′-(2-iodophenyl)urea(77 mg, 0.21 mmol) was added to HCl/H2O (0.21 mL/0.42 mL), and cooled to 0° C. Sodium nitrate (14.5 mg, 0.21 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0° C. for 30 minutes. Sodium azide (14 mg, 0.21 mmol) was added to reaction mixture and it was warmed to room temperature. The reaction mixture was stirred at room temperature for 18 hours. Then it was extracted with three times by ethyl acetate. The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure and chromatography of the resulting solid on silica gel (hexane : ethyl acetate; 5:1) gave product (20 mg, 24%). EI-MS m/z 396 (M+H)+.