Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][C@@H:9]1[CH2:24][O:25][C:26]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:49]=[N+:50]=[N-:51].[Na+]>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:49]=[N+:50]=[N-:51])[CH2:10][C@@H:9]1[CH2:24][O:25][C:26]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:35]1[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1)[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(C(OC[C@H]2C[C@@H](OS(=O)(=O)c3ccc(C)cc3)CN2C(=O)OC(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(OC[C@H]2C[C@H](N=[N+]=[N-])CN2C(=O)OC(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 80 °C
Yield: 92 %

Procedure:
(2R,4R)-1-(tert-Butyloxycarbonyl)-2-(4,4'-Dimethoxytrityl)oxymethyl-4-[(p-toluenesulfonyl)oxy]pyrrolidine 39 (5.1 g, 7.58 mmol) was dissolved in dimethylformamide (50 ml) and diluted with water (5 ml ). To this stirred solution was added sodium azide (0.65 g, 10 mmol) and heated at 80° C. for 8 h. It was cooled and evaporated to dryness. The residue was partitioned between CH2Cl2 (200 ml) and water (100 ml), and extracted in CH2Cl2. The organic extract was washed with brine (50 ml), dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography over silica gel using hexane→EtOAc as the eluent. The pure fractions were pooled together and evaporated to give 3.8 g (92%) of a clear oil. 1HNMR (CDCl3): 1.45 (s, 9H, Boc), 1.90 (dd, 1H), 2.34 (m, 1H), 3.40-3.62 (m, 3H), 3.74 (s, 6H, 2.0CH3), 4.00 (m, 2H), 4.28 (bs, 1H), 4.44 (m, 1H), 6.82 (d, 4H, Ph), and 7.26-7.80 (m, 9H, Ph).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:13]=[CH:12][C:11]2[C:10]([CH3:15])([CH3:14])[CH2:9][CH:8]=[C:7]([CH:16]([CH3:18])[CH3:17])[C:6]=2[CH:5]=1)[CH3:2].F[C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=1.CCOCC>C1(C)C=CC=CC=1>[CH2:1]([N:3]([C:4]1[CH:13]=[CH:12][C:11]2[C:10]([CH3:15])([CH3:14])[CH2:9][CH:8]=[C:7]([CH:16]([CH3:17])[CH3:18])[C:6]=2[CH:5]=1)[C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=1)[CH3:2]
Reactant: O=C(O)c1ccc(F)nc1
Reactant: CCNc1ccc2c(c1)C(C(C)C)=CCC2(C)C
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCN(c1ccc2c(c1)C(C(C)C)=CCC2(C)C)c1ccc(C(=O)O)cn1
Temperature: 125 °C
Yield: 20.4 %

Procedure:
To a mixture of 85 mg (0.35 mmol) of ethyl-(8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-amine (Compound 168) and 0.10 g (0.71 mmol) of 6-fluoro-nicotinic acid was added a small amount of ether and toluene to help stirring. The resulting mixture was heated at 100-150° C. for 1 h. The mixture was cooled. Purification was done using flash chromatography (silica, 50% ethyl acetate in hexanes) followed by recrystallization using ethyl acetate:hexane (1:1) to give the title compound as white crystals (26 mg).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:28](O)=[O:29])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38](=[N:40]O)[NH2:39]>>[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1[N:40]=[C:28]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:19][CH:18]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]3)=[O:10])[CH2:12]2)[O:29][N:39]=1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1
Reactant: NC(=NO)c1ccccc1F
Product: N#CC1CCN(C(=O)N2CC(c3ccc(OC(F)(F)F)cc3)CC(c3nc(-c4ccccc4F)no3)C2)CC1

Procedure:
85 mg (0.2 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethoxy)phenyl]-piperidine-3-carboxylic acid (Example 108A) and 46 mg (0.3 mmol) of 2-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 69 mg (63% of theory).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([O:18][C@H:19]2[CH2:23][CH2:22][N:21]([CH3:24])[C:20]2=[O:25])[CH:17]=1)[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].[N:26]1([C:30]([C:32]2[N:33]=[CH:34][C:35](Cl)=[N:36][CH:37]=2)=[O:31])[CH2:29]C[CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:27][N:26]([CH3:29])[C:30]([C:32]1[CH:37]=[N:36][C:35]([O:1][C:2]2[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]3[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=3)[CH:15]=[C:16]([O:18][C@H:19]3[CH2:23][CH2:22][N:21]([CH3:24])[C:20]3=[O:25])[CH:17]=2)=[CH:34][N:33]=1)=[O:31]
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Reactant: O=C(c1cnc(Cl)cn1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cnc(NC(=O)c2cc(Oc3cnc(C(=O)N(C)C)cn3)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Yield: 78 %

Procedure:
A mixture of 3-hydroxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)benzamide (Intermediate 18) (188 mg, 0.55 mmol), 5-(azetidin-1-ylcarbonyl)-2-chloropyrazine (CAS no. 915949-00-7) (712 mg, 3.6 mmol) and potassium carbonate (152 mg, 0.55 mmol) in acetonitrile (5 mL) was stirred at 120° C. for 2 hours. The solution was evaporated to dryness then diluted with ethyl acetate (30 mL), washed with water (2×10 mL) and brine (20 mL), dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was purified by flash chromatography on silica eluting with 50-100% ethyl acetate in isohexane to afford the product (210 mg, 78%). 1H NMR δ (300 MHz, CDCL3) 2.15-2.31 (m, 1H), 2.52-2.68 (m, 1H), 2.56 (s, 3H), 2.95 (s, 3H), 3.17 (d, 6H), 3.35-3.59 (m, 2H), 4.95 (t, 1H), 7.15 (s, 1H), 7.37 (s, 1H), 7.56 (s, 1H), 8.14 (s, 1H), 8.39 (s, 1H), 8.52 (s, 2H), 9.54 (s, 1H); m/z 492 (M+H)+.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:31])[CH2:11][C:12]1([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:13]1=[O:26])C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CCO>[OH:8][NH:9][C:10](=[O:31])[CH2:11][C:12]1([CH2:27][CH:28]([CH3:29])[CH3:30])[CH2:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:13]1=[O:26]
Reactant: CC(C)CC1(CC(=O)NOCc2ccccc2)CC(=O)N(CCc2ccccc2)C1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)CC1(CC(=O)NO)CC(=O)N(CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.1 %

Procedure:
A mixture of N-benzyloxy-3-(2-methylpropyl)-2,5-dioxo-1-(2-phenylethyl)-3-pyrrolidineacetamide (80 mg, 0.19 mmol), Pd/C (10%, 5 mg), ammonium formate (59 mg, 0.95 mmol) and EtOH (2.5 mL) is stirred at room temperature. After 2 hours, a second portion of ammonium formate (35 mg, 0.56 mmol) is added and the mixture is allowed to stir overnight at room temperature. The mixture is filtered, and the filter cake washed with MeOH (3×15 mL) and CHCl3 (3×15 mL). The filtrate is concentrated, reconstituted in 100 mL of 5% MeOH/CHCl3, dried (MgSO4), filtered and concentrated to an oil. Crystallization from CH2Cl2 /Et2 O/hexane gives 19 mg (31%) of the title compound as a white solid (mp 136°-137° C.).
Reaction SMILES: [CH2:1]([C:9]1[N:10]=[C:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[NH:15][C:14]3[N:22]=[CH:23][CH:24]=[CH:25][C:13]=3[N:12]2[C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([C:33]2([NH:37]C(=O)OC(C)(C)C)[CH2:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>ClCCl.O1CCOCC1>[CH2:1]([C:9]1[N:10]=[C:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[NH:15][C:14]3[N:22]=[CH:23][CH:24]=[CH:25][C:13]=3[N:12]2[C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([C:33]2([NH2:37])[CH2:34][CH2:35][CH2:36]2)=[CH:29][CH:28]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(CCc4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3c(CCc4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (1-(4-(2-phenethyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutyl)carbamate (0.042 g) in dichloromethane (2 mL) was added 4.0 M HCl in dioxane (0.18 mL). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was treated with aq. saturated sodium bicarbonate (10 mL). The mixture was extracted with dichloromethane (2×10 mL). The combined extracts were concentrated under reduced pressure and the crude product was purified by preparative HPLC (YMC PACK ODS-AM; AM12S05-1020WT; 100×20 mm ID; CAN/0.1% TFA, 30 mL/min) The product, 1-(4-(2-phenethyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutanamine was obtained as a yellow solid (0.010 g, 29%). M.p.: 158-160° C.; 1H NMR (DMSO-d6) 400 MHz δ 8.62 (br. s, 1 H), 8.56 (br. s, 3H), 8.12 (dd, JA=4.8 Hz, JB=1.6 Hz, 1H), 7.91 (dd, JA=7.6 Hz, JB=1.6 Hz, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.40-7.36 (m, 1H), 7.32-7.22 (m, 3H), 7.21-7.05 (m, 6H), 6.82 (dd, JA=8.0 Hz, JB=1.6 Hz, 1H), 6.76 (dd, JA=7.6 Hz, JB=4.0 Hz, 1H), 3.05-2.97 (m, 2H), 2.91-2.83 (m, 2H), 2.64-2.46 (m, 4H), 2.22-2.10 (m, 1H), 1.87-1.75 (m, 1H); LCMS: 484 [M+H].
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH:10](=O)/[CH:11]=[CH:12]/[CH3:13]>>[O:8]=[C:5]1[NH:6][C:7]2[CH:10]=[CH:11][C:12]([CH3:13])=[N:1][C:2]=2[C:3](=[O:9])[NH:4]1
Reactant: C/C=C/C=O
Reactant: Nc1c[nH]c(=O)[nH]c1=O
Product: Cc1ccc2[nH]c(=O)[nH]c(=O)c2n1
Reaction time: 0.17 h
Yield: 248.1 %

Procedure:
20 g of 5-aminouracil (40 mmol), 80 ml of 20% HCI and 4 ml of crotonaldehyde (50 mmol) were heated together under reflux for 1 hour. The solution was evaporated to dryness under rotarary evaporation. Water was added to the residue so as to make the mixture just stirrable and then it was triturated with ammonium hydroxide with strong stirring until the pH increased to 10-11. Stirring was continued for another 10 minutes. The precipitate was filtered and was washed with minimal methanol and then chloroform and dried to give 17.58 g (63%) of 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C@@H:14]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)[C:15]([F:18])([F:17])[F:16])[CH2:11][O:10][C:9]1([CH3:30])[CH3:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C@@H:14]([O:19][C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[C:15]([F:18])([F:16])[F:17])[CH2:11][O:10][C:9]1([CH3:30])[CH3:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](Oc2ccc([N+](=O)[O-])cc2)C(F)(F)F)COC1(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](Oc2ccc(N)cc2)C(F)(F)F)COC1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.7 %

Procedure:
To a stirred suspension of (S)-2,2-dimethyl-4-[(R)-3,3,3-trifluoro-2-(4-nitro-phenoxy)-propyl]-oxazolidine-3-carboxylic acid tert-butyl ester (2.66 g) in methanol (20 ml) was added 10% palladium on charcoal (326 mg) and the mixture was then stirred under an atmosphere of hydrogen at room temperature for 3 hours. The mixture was then filtered through celite and the filtrate was concentrated in vacuo to afford (S)-4-[(R)-2-(4-amino-phenoxy)-3,3,3-trifluoro-propyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.80 g, 73%) as a yellow viscous oil. MS (ISP): 405.4 ([M+H]+), 349.3 ([M+H—C4H8]+), 305.3 ([M+H—C4H8—CO2]+).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:15][C:12]1[CH:11]=[CH:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(-c2ccc(C)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
To a solution of 4′-methoxy-4-methylbiphenyl (10.5 g, 53 mmol) in CH2Cl2 (300 mL) at 0° C. was added a solution of 1M BBr3 in CH2Cl2 (65 mL, 65 mmol). The mixture was slowly warmed to r.t. and stirred overnight. After cooling to 0° C. again, the mixture was quenched with H2O. The CH2Cl2 layer was separated, washed with H2O, dried (MgSO4) and concentrated to give the title compound as a white solid (9.5 g, 97% yield).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[NH:13][N:12]=[C:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:10]=1[C:23]#[N:24]>C1COCC1>[C:5]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][NH:14][C:11]2[C:10]([C:23]#[N:24])=[C:9]([NH2:8])[NH:13][N:12]=2)=[CH:21][CH:20]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1c(NCc2ccc(N)cc2)n[nH]c1N
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(CNc2n[nH]c(N)c2C#N)cc1

Procedure:
With stirring, a solution of 1.087 ml (11.5 mmol) of acetic anhydride in 20 ml of THF is added dropwise over a period of 15 minutes, to a suspension, cooled to 0° C., of 2.5 g (10.95 mmol) of 5-amino-3-(4-amino-benzylamino)-4-cyano-pyrazole in 50 ml of THF. The reaction mixture is stirred for a further 2 hours at RT, there initially being formed a solution from which crystalline product gradually precipitates. The reaction mixture is filtered and the filter residue is washed with THF and diethyl ether. Drying under a HV (8 hours, 110° C.) yields the title compound containing 21.06% THF; m.p. 124-126° C. (decomp.); FAB-MS: (M+H)+ 271 (C13H14N6O).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:22]1([C:27](O)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NC(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C.O>[CH:22]1([C:27]([NH:1][C:2]2[S:3][C:4]3[CH:10]=[C:9]([O:11][S:12]([C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)(=[O:13])=[O:14])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Reactant: O=C(O)C1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1)C1CCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 68 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-aminobenzothiazol-6-yl ester (intermediate 16) (101.2 mg, 0.312 mmol), cyclopentanecarboxylic acid (53.4 mg, 0.936 mmol), HBTU (355 mg, 0.936 mmol) and N,N-diisopropyl-amine (326 μl, 1.872 mmol) in 5 ml of dimethylformamide in a test tube, equipped with a magnetic bar, is stirred for 20 hours at room temperature. 100 ml of water are added and the reaction medium is extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated. The residue obtained is taken up in ethyl acetate and purified on a Varian flash cartridge containing 5 g of silica of porosity 15-35μ, with a mixture of 1% methanol in dichloromethane. After evaporating off the solvent, 90 mg of 4-fluorobenzenesulfonic acid 2-(cyclopentane carbonylamino)benzothiazol-6-yl ester are obtained (yellow oil) in a yield of 68%. LC/MS (method A1): [M+H]+: 421.13, retention time: 4.05 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([OH:30])=O)=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([N:35]5[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]5)=[O:30])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)nc4CCC3C2C2CCCC2)cc1Cl
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc3c(n2)CCC2C3=NN(c3ccc(C#N)c(Cl)c3)C2C2CCCC2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50.3 %

Procedure:
In a dried reaction flask, 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid (0.421 g, 1.0 mmol), 1-methylpiperazine (144 mg, 1.437 mmol), DIEA (0.2 mL, 1.15 mmol), and HATU (0.418 g, 1.1 mmol) were added to a mixed solvent of DMF (4 mL) and dichloromethane (8 mL). The mixture was stirred at room temperature for 1.5 hr and was concentrated under reduced pressure. Water was added to the residue. The mixture was filtered to produce a crude yellow solid, which was washed with methanol to obtain a purified product (0.253 g) in 50.3% yield.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:20]3[N:21]=[CH:22][C:23]([OH:25])=[CH:24][C:19]3=[C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]=2[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=2[CH3:40])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[F:39][C:35]1[C:34]([CH3:40])=[C:33]([CH:38]=[CH:37][CH:36]=1)[CH2:32][C:17]1[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:19]2[CH:24]=[C:23]([OH:25])[CH:22]=[N:21][N:20]2[C:16]=1[C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15]
Reactant: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2cc(O)cnn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2cc(O)cnn2c1C(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
The compound of step 3 (0.109 g, 0.20 mmol) was dissolved in 3 ml of anhydrous DCM and a 4 M solution of hydrogen chloride in dioxane (1.0 ml, 4.0 mmol) was added. After stirring at room temperature overnight, the mixture was evaporated to dryness under reduced pressure. The obtained solid was triturated several times with diethyl ether and dried in vacuo at 55° C. to give 0.073 g of the title compound in the form of [6-(3-fluoro-2-methyl-benzyl)-3-hydroxy-5-phenyl-pyrrolo[1,2-b]pyridazin-7-yl]-piperazin-1-yl-methanone hydrochloride as a greenish-yellow solid with the following characteristics:
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]([O:11][C:12]([C:14]1([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[CH2:18][CH2:17][NH:16][CH2:15]1)=[O:13])[CH3:10]>>[CH2:9]([O:11][C:12]([C:14]1([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)[CH2:18][CH2:17][N:16]([C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:7])[CH2:15]1)=[O:13])[CH3:10]
Reactant: O=C(Cl)C1CCCC1
Reactant: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCNC1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCN(C(=O)C2CCCC2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 76 using cyclopentanecarbonyl chloride and 3-(4′-fluoro-biphenyl-4-yloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 65) to afford the racemate as a white solid (120 mg, 94%)
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8]C)=[C:6]([Br:10])[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH3:17])[C:3]=1[C:18]#[N:19].BrB(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Br:10])[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH3:17])[C:3]=1[C:18]#[N:19]
Reactant: COc1c(N)c(C#N)c(C)c(-c2ccccc2)c1Br
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1c(C#N)c(N)c(O)c(Br)c1-c1ccccc1
Temperature: -70 °C
Reaction time: 1.5 h

Procedure:
4-Amino-6-bromo-5-methoxy-2-methylbiphenyl-3-carbonitrile (I-40) (44.5 mg, 0.14 mmol) was dissolved in dichloromethane (dewatered, 1.4 ml) under nitrogen atmosphere, and cooled in a dry ice-methanol bath at −70° C. 1 M Tribromoborane (dichloromethane solution, 0.42 ml) was dropwise added to it at −70 to −68° C., followed by stirring for 1.5 hours with heating up to 0° C. The reaction liquid was diluted with cold water, and controlled to have a pH of 6 to 7 with aqueous 10% sodium carbonate solution added thereto. The organic matter was extracted with ethyl acetate, washed with saturated brine, then dried on anhydrous magnesium sulfate, the solvent was evaporated away under reduced pressure to obtain the entitled compound (42.4 mg, quant.) as a pale brown solid.
Reaction SMILES: Cl.[CH3:2][S:3]([N:6]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:7]1)(=[O:5])=[O:4].[OH-].[Na+].[CH2:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH:23]1[NH:31][C:32](=O)[O:33]C1C=CC=CC=1.O>CS(C)=O>[CH2:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:22][CH:23]1[NH:31][C:32]([N:11]1[CH2:10][CH2:9][C:8]2([C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:6]([S:3]([CH3:2])(=[O:4])=[O:5])[CH2:7]2)[CH2:13][CH2:12]1)=[O:33]
Reactant: CS(=O)(=O)N1CC2(CCNCC2)c2ccccc21
Reactant: O=C(NC1Cc2ccccc2C1)Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)N1CC2(CCN(C(=O)NC3Cc4ccccc4C3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
1-Methanesulfonylspiro[indoline-3,4′-piperidine]hydrochloride (60 mg) and 10M aqueous sodium hydroxide (33 μL) were added to a solution of phenyl N-(2-indanyl)carbamate (50 mg) in dimethyl sulfoxide (2 mL), and the mixture was stirred at room temperature for one hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was washed with ethyl acetate to give the title compound (65 mg) as a colorless crystal.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=O)[NH:10][C:4]=2[CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:29]2)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=[S:29])[NH:10][C:4]=2[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Solvent: Cc1ccccc1
Product: S=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Yield: 63.4 %

Procedure:
To 9-bromo-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin-6-one (9 g) in toluene (175 ml), under nitrogen, was added 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (12.6 g). The mixture was refluxed for 1 hr and concentrated under reduced pressure. Recrystallization of the residue from chloroform: hexane afforded 6 g (63%) of product, mp 196°-197° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:9]1[CH2:14][NH:13][C:12](=[O:15])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23]C(C)([O-])C.[K+].CI.[Na+].[Cl-]>O1CCCC1.C(OCC)(=O)C>[CH2:16]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]1[CH2:14][N:13]([CH3:23])[C:12](=[O:15])[CH2:11][CH2:10]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CN1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: C1CCOC1
Product: CN1C[C@@H](N(Cc2ccccc2)Cc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
500 mg (S)-5-dibenzylamino-piperidin-2-one are suspended in 15 ml of tetrahydrofuran. While cooling with the ice bath 175 mg potassium-tert-butoxide are added. The reaction mixture is then stirred for 30 minutes at ambient temperature. While cooling with the ice bath 95 μl methyliodide are added. The reaction mixture is then stirred for 48 hours at ambient temperature and then combined with a saturated NaCl solution and ethyl acetate. The organic phase is dried and evaporated to dryness. 450 mg of the product are obtained as an oil. Analytical HPLC-MS (method D): RT=−1.07 min.