Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(C2C3C(=CC=CC=3)C=CC=2)C2C(=CC=CC=2)C=CC=1>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:9]([CH:16]1[CH2:21][CH2:20][N:19]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: Brc1ccc(I)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc2c(-c3cccc4ccccc34)cccc2c1
Solvent: C1CCOC1
Product: Brc1ccc(N2CCC(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-bromo-4-iodo benzene (0.500 g), 4-benzylpiperidine (0.25 mL), sodium-tert-butylate (0.238 g), tris(dibenzylideneacetone)dipalladium (0.016 g) and 2,2′-bis/diphenylphosphino)-1,1′-binaphtyl racemate (0.018 g) is dissolved in tetrahydrofuran and stirred at room temperature overnight. The reaction mixture is concentrated and the resulting residue is loaded on Celite and purified by silica gel chromatography (4:1 hexanes/ethyl acetate) to give 4-benzyl-1-(4-bromo-phenyl)-piperidine as a light yellow syrup. MS (m/z): 331 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][OH:13].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][CH:12]=[O:13]
Reactant: O=[N+]([O-])c1ccc(CCO)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=CCc1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
To a stirred suspension of 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-N-benzodioxol-3(1H)-one (Dess-Martin periodinane) (25.24 g, 59 mmol) in DCM (92 mL) was added a solution of 2-(2-chloro 4-nitro-phenyl)ethanol (10 g, 49 mmol) in DCM (30 mL) at RT. The reaction mixture was stirred for 3 hours at RT. After completion of reaction, sodium bicarbonate solution was added and the mixture was stirred for 15 minutes. The separated organic layer was washed with water (2×50 mL), dried (Na2SO4) and the solvent removed under reduced pressure to afford the title compound (9.5 g, 95%).
Reaction SMILES: [CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)=[CH:12][CH:11]=3)[CH2:6][CH2:7]2)[CH2:3]1.Br[C:23]1[S:24][CH:25]=[CH:26][N:27]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:11]=[CH:12][C:13]([N:16]4[CH2:17][CH2:18][N:19]([C:23]5[S:24][CH:25]=[CH:26][N:27]=5)[CH2:20][CH2:21]4)=[CH:14][CH:15]=3)[CH2:6][CH2:7]2)[CH2:3]1
Reactant: CN1C[C@H]2CCN(c3ccc(N4CCNCC4)cc3)[C@H]2C1
Reactant: Brc1nccs1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CN1C[C@H]2CCN(c3ccc(N4CCN(c5nccs5)CC4)cc3)[C@H]2C1
Temperature: 80 °C

Procedure:
The product of Example 49B (50 mg, 0.175 mmole), 2-bromothiazole (35 mg, 0.21 mmole), tris(dibenzylideneacetone)dipalladium (3.2 mg, 0.0035 mmole), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (4.4 mg, 0.007 mmole) and sodium tert-butoxide (25.2 mg, 1.5 mmole) were dissolved in 1 ml of toluene and heated at 80° C. under N2 for 24 hours. The mixture was cooled to room temperature, diluted with water and extracted with dichloromethane (5×). The combined organics were dried over sodium sulfate, filtered, concentrated under reduced pressure and was purified by chromatography (eluting with a mixture of 5% methanol in dichloromethane) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.22 (d, J=3.73 Hz, 1H) 6.88-6.96 (m, 2H) 6.59 (d, J=3.73 Hz, 1H) 6.50-6.58 (m, 2H) 4.06-4.22 (m, 1H) 3.60-3.69 (m, 4H) 3.48-3.58 (m, 1H) 3.17-3.27 (m, 1H) 3.11-3.17 (m, 4H) 2.95-3.07 (m, 1H) 2.61-2.71 (m, 4H) 2.41(s, 3H) 2.10-2.22 (m, 1H) 1.93-1.97 (m, 1H); MS (M+H)+=370.
Reaction SMILES: [C:1]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:21][CH:20]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:19]2)=[C:14]([F:30])[CH:13]=1)([O:3]CC1C=CC=CC=1)=[O:2].[C:31](OC[C@@H]1OC1)(=[O:35])[CH2:32][CH2:33]C>O1CCCC1>[Si:23]([O:22][CH:20]1[CH2:19][N:18]([C:15]2[CH:16]=[CH:17][C:12]([N:11]3[CH2:33][C@H:32]([CH2:31][OH:35])[O:3][C:1]3=[O:2])=[CH:13][C:14]=2[F:30])[CH2:21]1)([C:26]([CH3:27])([CH3:29])[CH3:28])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OC1CN(c2ccc(NC(=O)OCc3ccccc3)cc2F)C1
Reactant: CCCC(=O)OC[C@H]1CO1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 75.3 %

Procedure:
A solution of N-(carbobenzyloxy)-4-[3-[(tert-butyldimethylsilyl)oxy]-1-azetidinyl]-3-fluoroaniline (6.30 g, 14.7 mmol) in dry tetrahydrofuran (100 mL) under a nitrogen atmosphere was cooled to -78° C. and treated with n-butylithium (9.16 mL of a 1.6M solution in hexanes, 14.7 mmol). When the addition was complete, the reaction mixture was stirred at -78° C. for 15 min and then treated with (R)-glycidyl butyrate (2.21 mL, 14.7 mmol). After completion of the addition, the cooling bath was removed and the reaction mixture allowed to stir at ambient temperature for 1.5 h. After this time, saturated aqueous ammonium chloride (20 mL) was added. After 3 min, saturated aqueous sodium bicarbonate (10 mL) was added to the reaction mixture and the organic solvent removed by rotary evaporation under reduced pressure. Dichloromethane (100 mL) was added and the mixture washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography over silica gel (200 g), eluting with a gradient of 1-3% methanol/chloroform, afforded, after concentration of appropriate fractions, 4.39 g (75%) of the title compound as an off-white solid with mp 183°-186° C. and MS(EI) 396 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][C:22]([F:25])([F:24])[F:23])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH2:10][CH2:9]1.[NH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32]>C(O)COCCO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][C:22]([F:25])([F:24])[F:23])[C:14]=3[N:13]=[C:12]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[C:11]=2[CH2:10][CH2:9]1
Reactant: NCCCCO
Reactant: Cc1ccccc1N1CCc2c(Cl)nc3c(OC(F)(F)F)cccc3c21
Solvent: OCCOCCO
Product: Cc1ccccc1N1CCc2c(NCCCCO)nc3c(OC(F)(F)F)cccc3c21

Procedure:
1-(2-Methylphenyl)-4-chloro-6-trifluoromethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(600 mg, 1.6 mmol) was dissolved in diethylene glycol(10 ml) and hereto was added 4-amino-1-butanol(1.0 ml), then reacted at the same condition of Step 5 in the Example 1 to obtain 510 mg of desired compound as solid in 73% of yield.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[CH2:24]([C:31]([OH:33])=O)[CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1.[NH2:34][C@H:35]([CH2:54][C:55]1[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=1)[C:36]([N:38]1[CH2:41][C:40]([CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:39]1)=[O:37].[OH-].[Na+]>CN(C)C=O.C(N(CC)CC)C>[F:48][C:45]1[CH:46]=[CH:47][C:42]([C:40]2([CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:39][N:38]([C:36](=[O:37])[C@H:35]([NH:34][C:31](=[O:33])[CH2:24][CH2:25][C:26]3[N:30]=[CH:29][NH:28][CH:27]=3)[CH2:54][C:55]3[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=3)[CH2:41]2)=[CH:43][CH:44]=1
Reactant: CCCCCC1(c2ccc(F)cc2)CN(C(=O)[C@H](N)Cc2ccc(OC)cc2)C1
Reactant: O=C(O)CCc1c[nH]cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCC1(c2ccc(F)cc2)CN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)CCc2c[nH]cn2)C1
Reaction time: 0.25 h
Yield: 60.7 %

Procedure:
600 mg (1.86 mmol) of TBTU and 0.45 ml of triethylamine are added to a solution containing 330 mg (1.86 mmol) of desamino-histidine hydrochloride in 5 ml of dimethylformamide. After stirring for 15 minutes, 590 mg (1.55 mmol) of (R)-2-amino-3-(4-methoxyphenyl)-1-(3-pentyl-3-(4-fluorophenyl)azetidin-1-yl)-propan-1-one dissolved in 5 ml of dimethylformamide are added. The reaction medium is stirred at ambient temperature for 3 days. The reaction is stopped by adding a 1N solution of sodium hydroxide and then extracted with a 1/1 heptane/ethyl acetate mixture. The organic phases are combined and dried over sodium sulphate. After filtration, the solvents are evaporated off and the residue is then purified by silica gel chromatography (eluent 85/15 dichloromethane/methanol). 490 mg of N-[(R)-2-[3-(4-fluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)-propionamide are obtained in the form of a white powder with a yield of 61%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([O:13][C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[C:16]([Cl:22])[CH:15]=2)[CH:12]=1)[O:5][CH2:6][C:7](O)=[O:8].S(Cl)([Cl:25])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([O:13][C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[C:16]([Cl:22])[CH:15]=2)[CH:12]=1)[O:5][CH2:6][C:7]([Cl:25])=[O:8]
Reactant: N#Cc1cc(Cl)cc(Oc2cc(Cl)cc(OCC(=O)O)c2)c1
Reactant: O=S(Cl)Cl
Product: N#Cc1cc(Cl)cc(Oc2cc(Cl)cc(OCC(=O)Cl)c2)c1

Procedure:
190 mg (0.562 mmol) of [3-chloro-5-(3-chloro-5-cyanophenoxy)phenoxy]acetic acid (5-3) was refluxed in an excess of thionyl chloride for 5 hours. After this time the reaction was cooled and the thionyl chloride was removed in vacuo and the resultant oil solidified upon storage under reduced pressure to yield the desired product 5-4. 1H NMR(CDCl3): 4.94 (s, 2H), 6.49 (m, 1H), 6.71 (m, 1H), 6.74 (m, 1H), 7.16 (m, 1H), 7.23 (m, 1H), 7.41 (m, 1H).
Reaction SMILES: [CH:1]1([C:7]2[S:19][C:10]3[N:11]=[C:12]([CH3:18])[N:13]=[C:14](/[CH:15]=[CH:16]\O)[C:9]=3[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(=O)(O)[O-].[Na+]>CC(O)=O>[CH:1]1([C:7]2[S:19][C:10]3[N:11]=[C:12]([CH3:18])[N:13]=[C:14]([CH2:15][CH2:16][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:9]=3[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: Cc1nc(/C=C\O)c2cc(C3CCCCC3)sc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nc(CCN2CCOCC2)c2cc(C3CCCCC3)sc2n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixture of (Z)-2-(6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)ethenol (120 mg) and AcOH (12 mL) were added morpholine (400 μL) and NaBH (OAc)3 (200 mg), followed by stirring at room temperature for 15 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate, followed by extraction with chloroform. The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by basic silica gel column (hexane/EtOAc) to obtain 6-cyclohexyl-2-methyl-4-[2-(morpholin-4-yl)ethyl]thieno[2,3-d]pyrimidine (53 mg).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F:20][C:21]([F:30])([F:29])[C:22]1[CH:23]=[CH:24][C:25]([OH:28])=[N:26][CH:27]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.[CH2:53]([N:60]1[CH2:64][CH:63]([C:65]2[CH:70]=[CH:69][C:68]([Cl:71])=[C:67]([Cl:72])[CH:66]=2)[CH:62]([CH:73](O)[CH3:74])[CH2:61]1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>C1COCC1>[CH2:53]([N:60]1[CH2:64][CH:63]([C:65]2[CH:70]=[CH:69][C:68]([Cl:71])=[C:67]([Cl:72])[CH:66]=2)[CH:62]([CH:73]([O:28][C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:29])[F:30])=[CH:27][N:26]=2)[CH3:74])[CH2:61]1)[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: CC(O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Reactant: Oc1ccc(C(F)(F)F)cn1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1ccc(C(F)(F)F)cn1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
To a suspension of PPh3 (PPh3 polymer bound, 3 mmol PPh3/g resin) (0.77 g) in THF (25 mL) at 0° C. were added 5-trifluoromethyl-pyridin-2-ol (0.28 g, 1.75 mmol) and then DBAD (0.43 g). After 5 minutes was added (RS)-1-[(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (0.41 g, 1.17 mmol, described herein above). The reaction mixture was stirred over night at RT, filtered on celite and concentrated under vacuo. Extraction with EtOAc/aq.NaOH 1M, followed by column chromatography (SiO2, EtOAc/H, 1:4) yielded 0.45 g (78%) of the title compound as a colorless oil. ES-MS m/e: 495.8 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[NH:7][C:6]([Si](C)(C)C)=[C:5]2[CH3:19].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:19]
Reactant: COC(=O)c1cc(Cl)cc2c(C)c([Si](C)(C)C)[nH]c12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)cc2c(C)c[nH]c12
Temperature: 0 °C
Reaction time: 3 h
Yield: 106 %

Procedure:
Methyl 5-chloro-3-methyl-2-(trimethylsilyl)-1H-indole-7-carboxylate (510 mg, 1.73 mmol) from Step A above and aluminum chloride (254 mg, 1.9 mmol) were added to methylene chloride (5 mL) and the reaction mixture was stirred for 3 h at 0° C. The reaction was quenched with water, extracted with ether, dried over sodium sulfate, filtered, and concentrated to afford methyl 5-chloro-3-methyl-1H-indole-7-carboxylate (410 mg, quantitative yield) as a dark green solid: 1H NMR (500 MHz, CDCl3) δ 8.09 (s, 1H), 8.01 (d, J=1.0 Hz, 1H), 7.87 (d, J=1.0 Hz, 1H), 4.01 (s, 3H), 3.40 (s, 3H); MS (ESI+) m/z 224 (M+H).
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])OCC.[CH3:11][N:12]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21](C=O)[C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CO.C(OCC)C>[CH2:9]([O:8][CH:1]([O:5][CH2:6][CH3:7])[C:21]1[C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:11])[C:25]=2[CH:24]=[CH:23][CH:22]=1)[CH3:10]
Reactant: CCOC(OCC)OCC
Reactant: CN1c2ccccc2Sc2c(C=O)cccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CCOC(OCC)c1cccc2c1Sc1ccccc1N2C
Temperature: 0 °C
Yield: 96.2 %

Procedure:
15.0 ml of triethyl orthoformate were added at room temperature to a solution of 4.90 g (20.3 mmol) of 10-methylphenothiazine-4-carbaldehyde and 50 mg of p-toluenesulphonic acid×1H2O in 15 ml of methanol. The reaction mixture was boiled at reflux for 45 minutes, cooled and poured into 30 g of ice, 30 ml of saturated aqueous sodium hydrogen carbonate solution and 100 ml of diethyl ether. The organic phase was washed with 50 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. The residue was chromatographed on 300 g of silica gel with diethyl ether/hexane (1:4), whereupon, after crystallization from diethyl ether/hexane in a refrigerator, 6.16 g (96.2%) of 4-diethoxymethyl-10-methyl-phenothiazine were obtained as a white solid of m.p. 44.6°-46.2°.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[C:7]([CH2:12][OH:13])[CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:14][CH3:15])[CH2:4][CH2:3]1.[CH:16]1([NH2:19])[CH2:18][CH2:17]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH:16]1([NH:19][CH:2]2[C:11]3[C:6](=[C:7]([CH2:12][OH:13])[CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:14][CH3:15])[CH2:4][CH2:3]2)[CH2:18][CH2:17]1
Reactant: CCN1CCC(=O)c2cccc(CO)c21
Reactant: NC1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CCN1CCC(NC2CC2)c2cccc(CO)c21
Temperature: 65 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
To a solution of 4-oxo-1-ethyl-8-hydroxymethyl-1,2,3,4-tetrahydroquinoline (3.80 g) in methanol (40 ml), molecular sieve 3A (4 g), cyclopropylamine (11.42 g) and p-toluenesulfonic acid (catalytic amount) were added and the mixture was stirred for 8 hours at 65° C. After ice-cooling the reaction mixture, molecular sieve 3A was filtered off, then sodium borohydride (1.05 g) was added thereto, and the mixture was stirred for 1 hour at room temperature. A small amount of water was added to the reaction mixture, and methanol was distilled off. The residue was extracted with dichloromethane and dried over anhydrous magnesium sulfate. The solvent was distilled off and the resulting residue was purified by silica gel column chromatography [eluent: n-hexane-ethyl acetate (3:1)]to give 4-cyclopropylamino-8-hydroxymethyl-1-ethyl-1,2,3,4-tetrahydroquinoline (3.69 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][C:43]1[CH:44]=[C:45]([S:50](Cl)(=[O:52])=[O:51])[CH:46]=[CH:47][C:48]=1[CH3:49]>C(#N)C>[CH3:42][C:43]1[CH:44]=[C:45]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:52])[CH:46]=[CH:47][C:48]=1[CH3:49]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1C
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)cc1C
Yield: 36.4 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0300 g, 0.0650 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 3,4-dimethylbenzenesulfonyl chloride (0.0400 g, 0.195 mmol) to obtain 4-(3,4-dimethylbenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0149 g. yield 36%).
Reaction SMILES: [ClH:1].Cl.C1(CCC2C=CC([CH:17]([C:25]3([OH:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:18][N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=CC=2)C=CC=CC=1.OC1(C([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[CH2:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)CN2CCN(C(OC(C)(C)C)=O)CC2)CCCCC1>>[ClH:1].[ClH:1].[C:55]1([CH2:60][CH2:61][C:62]2[CH:63]=[CH:64][C:65]([CH:18]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:17][C:25]3([OH:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)=[CH:66][CH:67]=2)[CH:56]=[CH:57][CH:58]=[CH:59][CH:54]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(c2ccccc2CCc2ccccc2)C2(O)CCCCC2)CC1
Reactant: OC1(C(CN2CCNCC2)c2ccc(CCc3ccccc3)cc2)CCCCC1
Agent: Cl
Product: OC1(CC(c2ccc(CCc3ccccc3)cc2)N2CCNCC2)CCCCC1

Procedure:
In an analogous manner to Example 135, step 4 1-{1-[4-(2-phenylethyl)phenyl]-2-piperazin-1-ylethyl]cyclohexanol dihydrochloride was prepared from tert-butyl 4-[(1-hydroxycyclohexyl)(2-phenylethyl phenyl)ethyl]piperazine-1-carboxylate. MS (ESI) m/z 393; HRMS: calcd for C26H36N2O+H+, 393.29004; found (ESI, [M+H]+), 393.2904.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=2)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:26]#[C:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)CCC>>[F:20][C:15]1[CH:14]=[C:13]([C:4]2[CH:3]=[C:2]([C:26]#[C:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=2)[CH:18]=[CH:17][C:16]=1[OH:19]
Reactant: CCCC[Sn](C#Cc1ccccc1)(CCCC)CCCC
Reactant: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Product: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(C#Cc3ccccc3)c2c1
Yield: 92 %

Procedure:
This compound was prepared from 6b and tributyl(phenylethynyl)tin according to method J. Orange powder; Yield: 92%; mp 125-129° C.; 1H-NMR (300 MHz, DMSO-d6) δ 7.08 (dd, J=8.8, 8.8 Hz, 1H), 7.36 (dd, J=9.0, 2.6 Hz, 1H), 7.53 (m, 3H), 7.59 (d, J=2.6 Hz, 1H), 7.74 (m, 2H), 7.94 (d, J=9.1 Hz, 2H), 8.05 (dd, J=13.0, 1.8 Hz, 1H), 8.18 (s, 1H), 10.23 (s, 1H), 10.26 (s, 1H); 19F-NMR (300 MHz, DMSO-d6) δ −136.48 (dd, J=13.7, 9.2 Hz); MS (ESI) m/z 354 ([M−H]−), 356 ([M+H]+); Anal. Calcd for C23H14FNO2: C, 77.74; H, 3.97; N, 3.94. Found: C, 76.45; H, 3.88; N, 3.77.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([NH2:14])=[C:12]([CH3:15])[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([NH:14][C:16](=[O:18])[CH3:17])=[C:12]([CH3:15])[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccnc(-c2ccc(F)cc2)c1N
Solvent: O
Product: CC(=O)Nc1c(C)ccnc1-c1ccc(F)cc1

Procedure:
10.44 g of the product of Step 3, above, and 40 ml of acetic anhydride are warmed slowly to 40° for 2 hours. The mixture is added to water, extracted with ethyl acetate, dried and reduced in volume. Petroleum ether is added to achieve the title product (mp 165° to 167°)
Reaction SMILES: [NH:1]([C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]3([NH:23]C(=O)OC(C)(C)C)[CH2:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=1)[C:9]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:8]2)[NH2:2].C1N=CN([C:42](N2C=NC=C2)=[O:43])C=1>O1CCOCC1.CCOC(C)=O>[NH2:23][C:19]1([C:16]2[CH:15]=[CH:14][C:13]([C:10]3[C:9]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:8][C:7]4[CH:6]=[CH:5][N:4]5[C:42](=[O:43])[NH:2][N:1]=[C:3]5[C:12]=4[N:11]=3)=[CH:18][CH:17]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(NN)nccc4cc3-c3ccccc3)cc2)CCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: NC1(c2ccc(-c3nc4c(ccn5c(=O)[nH]nc45)cc3-c3ccccc3)cc2)CCC1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
A mixture of tert-butyl {1-[4-(8-hydrazino-3-phenyl-1,7-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (7-5) (30.0 mg, 0.0620 mmol) and CDI (40.4 mg, 0.249 mmol) in 1,4-dioxane (2 mL) was stirred at 100° C. for 15 h and then cooled to room temperature. The mixture was diluted with EtOAc, washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel. The residue was treated with HCl in MeOH and the mixture was heated in a microwave reactor at 80° C. for 5 min. The solvent was evaporated and the residue was purified by reverse phase (H2O/0.1% TFAaq.-MeCN/0.1% TFAaq.) HPLC to give 9-[4-(1-aminocyclobutyl)phenyl]-8-phenyl[1,2,4]triazolo[4,3-h]-1,7-naphthyridin-3(2H)-one (7-6) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[C:4]([Cl:16])[C:3]=1[CH:17]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:18](Cl)=[O:19].[BH4-].[Na+].Cl>O1CCOCC1>[Cl:16][C:4]1[CH:5]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:7]=[C:2]([Cl:1])[C:3]=1[CH:17]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[CH2:18][OH:19]
Reactant: O=C(Cl)C(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=c1cnn(-c2cc(Cl)c(C(CO)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29 %

Procedure:
A solution of 2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetyl chloride (0.188 mol) in 1,4-dioxane (900 ml) was stirred at RT. NaBH4 (36.25 g) was added portionwise over 2.5 hours. The resulting reaction mixture was stirred for 3 hours at RT. The reaction mixture was cooled and acidified till pH 6 with 1 N HCl. The precipitated salts were removed by filtration. The filtrate was washed with water, and the precipitate was filtered off, stirred in DIPE, filtered off and dried, yielding 22.5 g of (±)-2-[3,5-dichloro-4-[1-(4-chlorophenyl)-2-hydroxyethyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (comp. 420). The biphasic filtrate was separated into its layers. The organic layer was dried, filtered and the solvent was evaporated. The residue was purified by HPLC over silica gel (eluent: CH2Cl2/CH3OH 98.5/1.5 and 97/3). The pure fractions were collected and the solvent was evaporated. The residue was stirred in DIPE, filtered off, washed, and dried, yielding 24 g of (±)-2-[3,5-dichloro-4-[1-(4-chlorophenyl)-2-hydroxyethyl]phenyl]-1,2,4-triazin-3,5(2H,4H)-dione (comp. 420).