Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[Na+].[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[CH:20]=[C:19]2[C:14]([C:15](=O)[CH:16]([CH3:21])[CH2:17][O:18]2)=[CH:13][CH:12]=1.Cl.[NH2:24][OH:25]>CO>[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[N:24][OH:25])[CH:16]([CH3:21])[CH2:17][O:18]2)=[CH:13][CH:12]=1
Reactant: CC1COc2cc(-c3ccco3)ccc2C1=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1COc2cc(-c3ccco3)ccc2C1=NO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium acetate (395 mg, 4.82 mmol) was added portionwise to a solution of 7-furyl-3-methyl-4-chromanone (60) (500 mg, 2.19 mmol) and hydroxylamine hydrochloride (167 mg, 2.41 mmol) in methanol (5 mL), and stirred overnight at room temperature. The reaction was quenched with H2O and extracted with ether (2×25 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to give 7-furyl-3-methyl-4-chromanone oxime (61) as a white solid, m.p. 175-177° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CCCCCC.O.P(Cl)(C(C)(C)C)C(C)(C)C>[C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccccc1
Reactant: OB(O)c1ccccc1
Agent: CC(C)(C)P(Cl)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 57 %

Procedure:
A 30 mL of reactor equipped with magnetic stir bar was charged with 24 mg (0.044 mmol) of (t-Bu)2PCl)2PdCl2,, 1.0 (8.8 mmol) of chlorobenzene, 1.3 g (10.66 mmol) of Ph—B(OH)2, 3.7 g (26.77 mmol) of K2CO3 in 5 mL of THF. The reaction mixture was refluxed for 4 hours. The reaction mixture was cooled to room temperature, transferred to a separatory funnel, and diluted with 220 mL of hexane and 150 mL of H2O. The layers were separated, and organic layer was washed with H2O (50 mL), brine (100 mL), and dried over MgSO4, filtered, and solvents removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel. The eluate was concentrated by rotary evaporation followed by high vacuum to give 0.78 g (57% yield) of biphenyl.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:26](=[O:27])[C:22]3([CH2:25][CH2:24][CH2:23]3)[N:21]([C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][C:37]([NH2:39])=O)=[CH:30][CH:29]=3)[C:20]2=[S:40])=[CH:15][C:14]=1[C:41]([F:44])([F:43])[F:42])#[N:12]>ClCCl>[C:37]([CH2:36][CH2:35][CH2:34][C:31]1[CH:30]=[CH:29][C:28]([N:21]2[C:20](=[S:40])[N:19]([C:16]3[CH:17]=[CH:18][C:13]([C:11]#[N:12])=[C:14]([C:41]([F:44])([F:42])[F:43])[CH:15]=3)[C:26](=[O:27])[C:22]32[CH2:23][CH2:24][CH2:25]3)=[CH:33][CH:32]=1)#[N:39]
Reactant: N#Cc1ccc(N2C(=O)C3(CCC3)N(c3ccc(CCCC(N)=O)cc3)C2=S)cc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: N#CCCCc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of DMSO (0.01 mL, 0.12 mmol) in dry dichloromethane (1 mL) was added to a stirred solution of oxalyl chloride (0.01 mL, 0.09 mmol) in dry dichloromethane (2 mL) at −78° C. After 15 min, a dichloromethane solution of 4-(4-(7-(4-Cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenyl)butanamide, RD130 (Formula 52) (35 mg, 0.07 mmol) was added to the reaction mixture. Stirring was continued for 20 min at −78° C., and then biethylamine (0.03 mL, 0.22 mmol) was added. After 30 min at −78° C., the reaction mixture was warmed to room temperature and then reaction was quenched with saturated aq. NH4Cl solution. The reaction mixture was diluted with dichloromethane, and extracted with dichloromethane. The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane:acetone, 95:5) to yield 4-(5-(4-(3-Cyanopropyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-2-(trifluoromethyl)benzonitrile, RD170 (Formula 53) (29 mg, 87%) as a viscous oil. 1H NMR δ 7.98 (d, 1H, J=1.8 Hz), 7.98 (d, 1H, J=8.3 Hz), 7.86 (dd, 1H, J=8.3, 1.8 Hz), 7.43 (d, 2H, J=8.4 Hz), 7.27 (d, 2H, J=8.4 Hz), 2.90 (t, 2H, J=7.3 Hz), 2.63-2.73 (m, 2H), 2.52-2.62 (m, 2H), 2.42 (t, 2H, J=7.3 Hz), 2.18-2.30 (m, 1H), 2.07 (p, 2H, J=7.3 Hz), 1.63-1.73 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][CH2:6][C:7]1[C:8]2[CH2:29][NH:28][CH2:27][CH2:26][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])=[CH:16][CH:15]=2)[N:12]=1.[CH2:33]=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][CH2:6][C:7]1[C:8]2[CH2:29][N:28]([CH3:33])[CH2:27][CH2:26][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])=[CH:18][CH:19]=2)[N:12]=1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(CCc4cccc(F)c4)n2)CNCC3)cc1
Reactant: C=O
Product: Cc1nccn1-c1ccc(Nc2nc(CCc3cccc(F)c3)c3c(n2)CCN(C)C3)cc1
Yield: 4.7 %

Procedure:
4-(3-Fluorophenethyl)-6-methyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (5.92 mg, 4.7%, Example 49a) was synthesised from 4-(3-fluorophenethyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and formaldehyde according to the general procedure for reductive amination. MS (ES+) m/z 443.3 (M+H)+
Reaction SMILES: C([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1O)[N:10](CC1C=CC=CC=1)[CH:9]=[CH:8][C:7]2=O)(=O)C.C(=O)([O-])[O-:24].[K+].[K+].BrCC=C.O>CN(C)C=O>[NH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:13][CH:12]=2)[CH:7]=[CH:8][C:9]1=[O:24]
Reactant: CC(=O)c1cc2c(=O)ccn(Cc3ccccc3)c2cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C=CCBr
Solvent: CN(C)C=O
Product: O=c1ccc2ccccc2[nH]1
Reaction time: 1 h
Yield: 198.7 %

Procedure:
A mixture of 6-acetyl-7-hydroxy-1-phenylmethyl-4(1H)-quinolinone (6.3 g, 21.5 mmol), anhydrous potassium carbon- ate (2.97 g, 21.5 mmol) and 3-bromopropene (2.86 g, 2.36 mmol) was stirred at room temperature in dry dimethylformamide (100 ml) for 18 hours. The mixture was poured into a large excess of water and was stirred rapidly for 1 hour. The solid produced was filtered off and washed well with water. The yellow solid was dried to give the required quino- lone as a yellow powder 6.2 g (87%) mp 139°-140°.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li]CCCC.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C1CCCCC1>[CH2:37]([CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: [Li]CCCC
Solvent: C1CCCCC1
Product: CCCCCCCCCCCCCCCCCCC1c2ccccc2-c2ccccc21
Yield: 87.9 %

Procedure:
Fluorene (7.0 g, 42.1 mmol), n-BuLi (17.35 ml, 43.4 mmol, 2.5 M in hexane), RX=1-bromooctadecane (14.53 g, 43.6 mmol). Following the usual workup 44 was isolated as a white solid (15.5 g, 88%), Rf 0.73 (cyclohexane).
Reaction SMILES: Br[C:2]1[C:3]([O:23][CH3:24])=[C:4]([CH:10]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([NH2:21])=[C:15]3[C:14]([CH3:22])=[N:13]2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[CH3:25][N:26]([CH3:43])[CH2:27][CH2:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl.N#N>C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Cl:9][C:6]1[C:7]([CH3:8])=[C:2]([C:32]2[CH:31]=[N:30][N:29]([CH2:28][CH2:27][N:26]([CH3:43])[CH3:25])[CH:33]=2)[C:3]([O:23][CH3:24])=[C:4]([CH:10]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([NH2:21])=[C:15]3[C:14]([CH3:22])=[N:13]2)[CH3:11])[CH:5]=1
Reactant: CN(C)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1cnn(CCN(C)C)c1
Temperature: 95 °C
Reaction time: 2 h
Yield: 27.5 %

Procedure:
A mixture of 1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Peak 1 from Example 167, step 4, 10 mg, 0.024 mmol), N,N-dimethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]-ethanamine (8.6 mg, 0.036 mmol), sodium carbonate (5.2 mg, 0.049 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (4.0 mg, 0.0049 mmol) in acetonitrile (0.5 mL)/water (0.1 mL) was vacuumed and the refilled with N2 and the stirred at 95° C. for 2 h. The crude was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (3.1 mg, 28%). The product was isolated as a single enantiomer. LCMS calculated for C23H30ClN8O (M+H)+: m/z=469.2; Found: 469.2.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:32][N:33]1[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34]1.O[C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1>C1COCC1>[CH3:32][N:33]1[CH2:37][CH2:36][CH:35]([O:38][C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)[CH2:34]1
Reactant: Oc1cccnc1
Reactant: CN1CCC(O)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC(Oc2cccnc2)C1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 72.9 %

Procedure:
To 629 mg (2.4 mmol) of PPh3 in 13 mL of dry THF at −20° C. was added 378 μL (2.4 mmol) of DEAD dropwise. The solution was allowed to stir 10 min. at −20° C. After 10 min, a solution containing 220 μL (2.0 mmol) of 1-methyl-3-hydroxypyrrolidine and 2 mL of dry THF was added dropwise. The solution was again allowed to stir 10 min at −20° C. After 10 min, to the solution was added 190 mg (2.0 mmol) of 3-hydroxypyridine at once. The solution was allowed to stir at room temperature overnight. Next day, solvent was removed under reduced pressure. The crude product was purified by flash chromatography (9:1, CHCl3:MeOH) to obtain 260 mg (72.9%) of a clear oil: 1H NMR (300 MHz, CDCl3) δ 8.26 (1H, d, J=2.6 Hz), 8.20 (1H, d, J=4.2 Hz), 7.22-7.13 (2H, m), 4.85 (1H, m), 2.89-2.76 (3H, m), 2.48-1.95 (3H, m), 2.40 (3H, s); Mass spectrum (ESI) m/z 179.6 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[OH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:26]4[CH:27]=[CH:28][C:23]([CH2:22][OH:21])=[CH:24][CH:25]=4)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Reactant: OCc1ccc(B(O)O)cc1
Product: O=C1NC(=O)c2c1c(-c1ccc(CO)cc1)cc1[nH]c3ccc(O)cc3c21
Yield: 34 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione, prepared as in example 7, with 4-hydroxymethylbenzeneboronic acid according to the procedure described in example 8 gave 9-hydroxy-4-(4-hydroxymethylphenyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (21) (I, Ar=4-hydroxymethylphenyl) in a 34% yield; mp 266–271° C. 1H NMR δ [(CD3)2SO] 11.74 (br s, 1H), 11.00 (br s, 1H), 9.25 (br s, 1H), 8.34 (d, J=2.4 Hz, 1H), 7.56 (d, J=8.3 Hz, 2H), 7.56 (s, 1H), 7.43 (d, J=8.7 Hz, 1H), 7.40 (d, J=8.3 Hz, 1H), 7.06 (dd, J=8.7, 2.4 Hz, 1H), 5.27 (t, J=5.7 Hz, 1H), 4.59 (d, J=5.7 Hz, 2H). Found: C, 69.74; H, 4.04; N, 7.57. C21H14N2O4,1/4H2O requires C, 69.51; H, 4.02; N, 7.72.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:12](O)[CH:13]=[CH2:14].C[Si](Cl)(C)C>>[CH2:14]([O:6][C:5](=[O:7])[C:4]1[CH:3]=[C:2]([OH:1])[CH:10]=[C:9]([OH:11])[CH:8]=1)[CH:13]=[CH2:12]
Reactant: C=CCO
Reactant: O=C(O)c1cc(O)cc(O)c1
Agent: C[Si](C)(C)Cl
Product: C=CCOC(=O)c1cc(O)cc(O)c1
Temperature: -20 °C
Reaction time: 16 h

Procedure:
To 1.5 g of 3,5-dihydroxybenzoic acid in screw-capped vial was added 10 g of allyl alcohol and the vial was closed and cooled to −20° C. To the cold contents of the reaction vial was added 5 mL of trimethylsilyl chloride via syringe through a septum. The reaction vial was allowed to warm to room temperature and agitated for 16 hours. The vial was opened carefully and its contents transferred to a round-bottomed flask. The solvent was removed under reduced pressure and the residual solid was dried under reduced pressure over potassium hydroxide pellets for 12 h. The semisolid product was used in the subsequent synthetic steps without further purification. The product was analyzed by HPLC and had a retention time of 3.65 on 5 cm C18 reversed phase column with flow rate of 2.5 mL/min of pure acetonitrile (for solvent A) and 0.1% aqueous trifluroacetic acid (for solvent B). The product was characterized by 1H NMR (DMSO-d6, 350 MHz): δ=6.87 (s, 2H, aromatic); 6.44 (s, 1H, aromatic); 5.85-5.96 (m, 1H); 5.16-5.33 (m, 2H); 4.65-4.67(dd, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2.[C:14]1([C:20]2[CH:21]=[CH:22][C:23](=[O:26])[NH:24][N:25]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[K+].O>C1C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:14]1([C:20]2[CH:21]=[CH:22][C:23](=[O:26])[N:24]([CH2:2][CH2:3][C:4]3[CH:5]=[C:6]4[C:11](=[CH:12][CH:13]=3)[N:10]=[CH:9][CH:8]=[CH:7]4)[N:25]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=c1ccc(-c2ccccc2)n[nH]1
Reactant: BrCCc1ccc2ncccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: O=c1ccc(-c2ccccc2)nn1CCc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.5 %

Procedure:
(reference: Synthesis 1981, 631). To a solution containing 6-(2-bromoethyl)quinoline (0.13 g, 0.56 mmol) in benzene (6.0 mL) was added 6-phenyl-3(2H)-pyridazinone (0.096 g, 0.56 mmol, Aldrich), tetrabutylammonium bromide (0.036 g, 0.11 mmol) and potassium hydroxide (0.094 g, 1.7 mmol). The mixture was stirred at 25° C. for 20 h, then poured into water (100 mL) and extracted with EtOAc (3×50 mL). The combined extracts were washed with brine (50 mL), dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (0 to 3.0% MeOH (2 M in NH3)/CH2Cl2) afforded the title compound as a white solid (0.12 g, 63% yield). MS (ESI pos. ion) m/z (MH+): 328. Calc'd exact mass for C21H17N3O: 327. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.83 (dd, J=4.2, 1.7 Hz, 1 H), 8.25 (dd, J=8.3, 0.9 Hz, 1 H), 7.98 (d, J=9.8 Hz, 1 H), 7.94 (d, J=8.6 Hz, 1 H), 7.78 (d, J=1.4 Hz, 1 H), 7.65-7.71 (m, 3H), 7.47 (dd, J=8.3, 4.2 Hz, 1 H), 7.36-7.42 (m, 3 H), 7.02 (d, J=9.8 Hz, 1 H), 4.51 (t, J=7.2 Hz, 2 H), 3.31 (t, J=7.0 Hz, 2 H).
Reaction SMILES: [NH:1]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:14].P(Cl)(Cl)(Cl)(Cl)Cl.II.[Br:23]Br>C(Cl)(Cl)Cl>[Br:23][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:1][C:2]1=[O:14]
Reactant: O=C1CCCCCc2ccccc2N1
Reactant: BrBr
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: II
Solvent: ClC(Cl)Cl
Product: O=C1Nc2ccccc2CCCCC1Br

Procedure:
To a solution of 1,3,4,5,6,7-hexahydro-1-benzazonin-2-one (4.7 g) in chloroform (75 ml), phosphorus pentachloride (5.9 g) is added in portions, while maintaining the temperature at 0°-5° C. When addition is complete, iodine (60 mg) is added, followed by bromine (4.5 g), which is added dropwise over five minutes. The mixture is then refluxed for 4 hours. The chloroform solution is evaporated and the residue partitioned between ice/water (60 ml) and dichloromethane (100 ml). The organic phase is dried over magnesium sulfate and evaporated under reduced pressure. The crude residue is purified by chromatography on silica gel, eluting with ether/hexane mixtures. Concentration of the appropriate fractions yields 3-bromo-1,3,4,5,6,7-hexahydro-1-benzazonin-2-one.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13](=[O:25])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.C(O)(=O)C.[Pd]>[C:21]([O:20][C:18](=[O:19])[CH2:17][N:14]1[CH2:15][CH2:16][NH:11][CH2:12][C:13]1=[O:25])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)CN1CCN(C(=O)OCc2ccccc2)CC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)CN1CCNCC1=O
Yield: 99 %

Procedure:
4-tert-Butoxycarbonylmethyl-3-oxopiperazine-1-carboxylic acid benzyl ester (2.0 g, 5.75 mmol) is dissolved in 20 mL of methanol and 2 mL of acetic acid. Palladium (5%) on carbon (100 mg) is added, and the reaction mixture is stirred in an atmosphere of hydrogen overnight. The mixture is filtered and concentrated. Ethyl acetate is added, and the mixture is neutralized to pH 7 using 1N NaOH. The organic layer is concentrated to give (2-oxo-piperazin-1-yl)acetic acid tert-butyl ester (1.22 g).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CN1CCOCC1.Cl.[CH3:27][N:28]([CH3:45])[C:29]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:34][CH2:33][C:32](=[CH:35][C:36](O)=[O:37])[CH2:31][CH2:30]1.C1(N=C=NC2CCCCC2)CCCCC1.[OH-].[Na+]>CN(C)C=O.O>[CH2:11]([NH:18][C:36](=[O:37])[CH:35]=[C:32]1[CH2:31][CH2:30][C:29]([N:28]([CH3:45])[CH3:27])([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:34][CH2:33]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: CN(C)C1(c2ccccc2)CCC(=CC(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: CN(C)C1(c2ccccc2)CCC(=CC(=O)NCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 288 h
Yield: 65 %

Procedure:
1-Hydroxybenzotriazole (273 mg, 2.0 mmol), benzylamine (0.109 ml, 1.0 mmol) and N-methylmorpholine (0.222 ml, 2.0 mmol) were added to a solution of (4-dimethylamino-4-phenylcyclohexylidene)acetic acid hydrochloride (296 mg, 1.0 mmol) in dry dimethylformamide (10 ml) under argon. The solution was cooled to 0° C. and dicyclohexylcarbodiimide (417 mg, 2.0 mmol) was added. The reaction mixture was stirred at RT for 12 d. Working up of the mixture was carried out by separating off the urea which had precipitated out and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). Still further urea thereby precipitated out and was separated off. 5 M sodium hydroxide solution (4 ml, 20 mmol) was added to the aqueous phase and the mixture was diluted with water (300 ml) and stored at 5° C. for 3 d. The product thereby precipitated out as a colourless solid in a yield of 65% (227 mg) and with an m.p. of 145-148° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][CH2:15][CH2:16][C:17]#[N:18])[N:8]=1.C[N:23](C=O)C>N.CCO.CCOC(C)=O.O>[F:1][C:2]([F:21])([F:20])[CH2:3][N:4]=[C:5]([NH2:23])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][CH2:15][CH2:16][C:17]#[N:18])[N:8]=1
Reactant: CN(C)C=O
Reactant: N#CCCSCc1nccc(NC(=S)NCC(F)(F)F)n1
Agent: N
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: N#CCCSCc1nccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 0.67 h

Procedure:
The above thiourea (1 g.) in DMF (10 ml.) and 8 M ammonia in EtOH (10 ml.) was treated with mercuric oxide (3 g.). The mixture was stirred for 40 minutes, diluted with EtOAc/water 1:1 v/v (100 ml.) and filtered through diatomaceous earth. The EtOAc extract was dried (MgSO4) and evaporated in vacuo to give 3-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylmethylthio]propionitrile as an oil, which was used without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[NH:14][N:13]=2)[CH2:9]1)=O)(C)(C)C.[ClH:23]>O1CCOCC1.C(OCC)C.CO>[ClH:23].[NH:8]1[CH2:11][CH:10]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[NH:14][N:13]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(c2n[nH]c(-c3ccccn3)n2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOCC
Product: c1ccc(-c2nc(C3CNC3)n[nH]2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(5-pyridin-2-yl-1H-[1,2,4]triazol-3-yl)-azetidine-1-carboxylic acid tert-butyl ester (3.13 g, 10.39 mmol) was suspended in a solution of HCl in dioxane (4M, 80 mL) and stirred at rt overnight. The reaction mixture was diluted with diethyl ether, filtered and the residue suspended in acetonitrile and stirred for 45 min at rt. The solid (hydroscopic) was isolated by filtration, partially dissolved in warm methanol and addition of diethyl ether resulted in precipitation of a yellow sticky solid which could not be filtered. The mixture was concentrated in vacuo and dried in a vacuum oven (40° C.) to obtain the desired compound as a light-yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Br[CH2:18][CH2:19][O:20][CH3:21].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:18][CH2:19][O:20][CH3:21])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1F
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COCCOc1ccc(-c2ccc(C#N)c(F)c2)cc1

Procedure:
A mixture of 3-fluoro-4′-hydroxy-1,1′-biphenyl-4-carbonitrile (0.50 g, 2.35×10−3 mol), 1-bromo-2-methoxyethane (0.33 g, 2.35×10−3 mol), potassium iodide (0.04 g, 2.35×10−4 mol) and potassium carbonate (1.30 g, 9.40×10−3 mol) in butanone (20 cm3) was reacted, worked up and purified as described for compound 3 in Example 2. Yield 0.40 g (63%), GC purity (99.86%).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[OH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].[F:14][C:15]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:25]=[C:26]3[CH2:37][CH2:36][NH:35][CH2:34][C:27]3=[N:28][C:29]=2[NH:30][CH:31]([CH3:33])[CH3:32])[CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[F:14][C:15]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:16]=1[O:17][CH:18]1[CH2:19][CH2:20][N:21]([C:24]2[N:25]=[C:26]3[CH2:37][CH2:36][N:35]([C:3]([N:2]([CH3:6])[CH3:1])=[O:4])[CH2:34][C:27]3=[N:28][C:29]=2[NH:30][CH:31]([CH3:33])[CH3:32])[CH2:22][CH2:23]1.[C:8]([OH:9])([C:10]([F:13])([F:12])[F:11])=[O:7]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(C(=O)N(C)C)C2
Reaction time: 1 h

Procedure:
Dimethylcarbamic chloride (5.2 mg, 0.049 mmol) was added to a solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (12.6 mg, 0.024 mmol) and triethylamine (10 μL, 0.073 mmol) in DCM (240 μL) at rt. After 1 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (8.0 mg, 55.8%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.28 (d, J=6.6 Hz, 6H), 1.90-2.00 (m, 2H), 2.08-2.17 (m, 2H), 2.77-2.84 (m, 2H), 2.91 (s, 6H), 2.99-3.08 (m, 2H), 3.35-3.44 (m, 2H), 3.55 (t, J=5.8 Hz, 2H), 4.09-4.17 (m, 1H), 4.29 (s, 2H), 4.44-4.51 (m, 1H), 6.84-6.91 (m, 1H), 6.99 (s, 1H), 7.18 (td, J=9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 475.4.