Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[CH:23]1([NH:26][C:27]([C:29]2[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=2)=[O:28])[CH2:25][CH2:24]1>>[CH:23]1([NH:26][C:27](=[O:28])[C:29]2[CH:36]=[CH:35][C:32]([C:33]3[NH:10][C:9]4[CH:8]=[CH:7][C:6]([NH:13][C:14](=[O:22])[C:15]5[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:31][CH:30]=2)[CH2:24][CH2:25]1
Reactant: O=Cc1ccc(C(=O)NC2CC2)cc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(F)cc1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(C(=O)NC4CC4)cc3)nc2c1)c1ccc(F)cc1

Procedure:
Compound 234 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-fluorobenzamide and 4-cyclopropylaminocarbonylbenzaldehyde. [M+H]+ calcd for C24H19FN4O2: 415.16; found: 415.53.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[F:13][C:14]1[CH:15]=[C:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH2:28])[CH:17]=[C:18]([F:21])[C:19]=1[F:20]>C1(C)C=CC=CC=1>[F:13][C:14]1[CH:15]=[C:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH:28][C:8]([C:7]2[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=2)=[O:9])[CH:17]=[C:18]([F:21])[C:19]=1[F:20]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: Nc1ccccc1-c1cc(F)c(F)c(F)c1
Solvent: Cc1ccccc1
Product: Cn1cc(C(=O)Nc2ccccc2-c2cc(F)c(F)c(F)c2)c(C(F)F)n1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
100.0 g (0.504 mol, 98% pure) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride were dissolved at 25° C. in 257.2 g of toluene. The solution was evacuated to 400 mbar and heated to 85° C. Subsequently, within 3 hours, 492.8 g (0.499 mol, 23% strength) of toluenic 3′,4′,5′-trifluorobiphenyl-2-ylamine solution were metered in, after which stirring was continued for another 1 hour. After venting and cooling to 25° C. with a ramp of 10° C./h, the mixture was stirred overnight. Subsequently, the mixture was cooled to 0° C., and the solid constituents were filtered off, washed with cold toluene and dried at 80° C. under reduced pressure. The yield (without further processing of the mother liquor) was 177.7 g (92%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([N:13]([CH3:15])[CH3:14])[CH2:9]2)[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][C:3]=1[C:22]#[N:23].[I:24]N1C(=O)CCC1=O.C(Cl)(Cl)Cl.[OH-].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[C:7]([I:24])=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([N:13]([CH3:14])[CH3:15])[CH2:9]2)[C:5]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:4][C:3]=1[C:22]#[N:23]
Reactant: O=C1CCC(=O)N1I
Reactant: CN(C)[C@H]1CCN(c2cc(N)c(C#N)cc2-c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CN(C)[C@H]1CCN(c2c(-c3ccccc3)cc(C#N)c(N)c2I)C1
Reaction time: 6 h
Yield: 62 %

Procedure:
4-Amino-6-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]biphenyl-3-carbonitrile (I-243) (75 mg, 0.25 mmol) was dissolved in acetic acid (1 ml), and at room temperature, N-iodosuccinimide (66 mg, 0.29 mmol) was added. After stirring under nitrogen atmosphere at the same temperature for 6 hours, the reaction liquid was fractionated with chloroform and aqueous 1 M sodium hydroxide solution. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=9:1) to obtain the entitled compound (67 mg, 63%) as a brown gel.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2].FC(F)(F)S(O)(=O)=O.ClC(Cl)(Cl)C(=N)O[CH2:68][CH:69]=[CH2:70]>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:70][CH:69]=[CH2:68])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: C=CCOC1CCC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CC1OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (400 mg in 6 ml 33% methylene chloride in cyclohexane), allyl trichloroacetimidate (209 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (9 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 6 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×10 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:3)+1% methanol) gave the title compound (320 mg). (1H NMR was consistent with the desired structure).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:7]=[C:8]([CH2:17][N:18]2[N:22]=[CH:21][N:20]=[CH:19]2)[CH:9]=[C:10]([C:12]([C:15]#[N:16])([CH3:14])[CH3:13])[CH:11]=1)([C:4]#[N:5])[CH3:3].[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25]>CO.C(#N)C>[CH3:3][C:2]([C:6]1[CH:7]=[C:8]([CH2:17][N:18]2[N:22]=[CH:21][N:20]=[CH:19]2)[CH:9]=[C:10]([C:12]([C:15]#[N:16])([CH3:13])[CH3:14])[CH:11]=1)([C:4]#[N:5])[CH3:1].[C:23]([O-:28])(=[O:27])[C:24]([O-:26])=[O:25]
Reactant: O=C(O)C(=O)O
Agent: CC(C)(C#N)c1cc(Cn2cncn2)cc(C(C)(C)C#N)c1
Solvent: CO
Solvent: CC#N
Product: O=C([O-])C(=O)[O-]

Procedure:
Anastrozole (28.3 mg, 0.096 mmol) and oxalic acid (8.9 mg, 0.099 mmol) were dissolved in 1 mL methanol:acetonitrile (1:1 v/v) solution. Crystals of anastrozole oxalate were obtained from slow evaporation at room temperature in an ambient atmosphere. Crystals of anastrozole oxalate were also obtained via crystallization of anastrozole (38.3 mg, 0.131 mmol) and oxalic acid (10.7 mg, 0.119 mmol) in 1.5 mL methanol:ethyl acetate (1:0.5 v/v) solution. The crystalline form of anastrozole oxalate was characterized by single crystal x-ray diffraction and melting point. (See FIGS. 14 and 15)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].C(OCC)(=O)C>CO.[C].[Pd]>[NH2:15][C:12]1[N:11]=[CH:10][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:4]=2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])nc2)ccc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc(N)nc2)ccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.3 %

Procedure:
To a solution of tert-butyl {2-fluoro-5-[(6-nitropyridin-3-yl)oxy]phenyl}carbamate (14.2 g, 49.5 mmol) in methanol (200 mL)/ethyl acetate (200 mL) was added palladium carbon (50% water-containing product, 1.50 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 12 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate) to give the title compound (9.69 g, 75%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16][N:15]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:14][CH2:13][N:12]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:38][C:39]([NH:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]([CH3:52])([CH3:51])[CH3:50])=[CH:45][CH:44]=1)=[O:40].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([CH2:8][N:9]1[CH2:20][CH2:19][N:18]([CH2:38][C:39]([NH:41][CH2:42][C:43]2[CH:44]=[CH:45][C:46]([C:49]([CH3:52])([CH3:51])[CH3:50])=[CH:47][CH:48]=2)=[O:40])[CH2:17][CH2:16][N:15]([CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:14][CH2:13][N:12]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CNC(=O)CCl)cc1
Reactant: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN1CCN(CC(=O)NCc2ccc(C(C)(C)C)cc2)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 1,4,7-tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraaza-cyclododecane (7.57 g, 12.7 mmol), 2-chloro-N-(4-tert-butylphenylmethyl)-acetamide (3.60 g, 15 mmol) obtained from Example 2a and potassium carbonate (5.53 g, 40 mmol) in acetonitrile (100 ml) was heated to 75° C. and stirred under nitrogen-atmosphere overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated in vacuo and the residue was submitted to flash-chromatography (silica, MeOH/CHCl3). The fractions containing the product were combined and evaporated in vacuo resulting in the title compound being a yellow oil that crystallised upon storage.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=O)=[CH:14][N:13]=1.N>>[Cl:11][C:12]1[N:13]=[CH:14][C:15]([C:16]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)=[CH:19][CH:20]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: N
Product: Clc1ccc(-c2nc(-c3cccnc3)no2)cn1

Procedure:
The title compound was prepared according to the procedure of Example 1 using N′-hydroxynicotinimidamide (Tyger) and 6-chloronicotinoyl chloride (Aldrich). 1H NMR (300 MHz, CDCl3) δ 7.48 (dd, J=7.6, 5.3 Hz, 1 H), 7.57 (d, J=8.5 Hz, 1 H), 8.40-8.48 (m, 2 H), 8.80 (dd, J=4.7, 1.7 Hz, 1 H), 9.24 (d, J=2.4 Hz, 1 H), 9.40 (d, J=2.4 Hz, 1 H) ppm; MS (DCI/NH3) m/z 259 (M+H)+, 261 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][N:10]=[CH:11][C:12]1[C:17](Br)=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[Br:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.ClCCl.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].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[Br:20][C:13]1[CH:14]=[C:15]([CH3:19])[CH:16]=[C:17]2[C:12]=1[CH:11]=[N:10][N:9]2[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: Cc1cc(Br)c(C=NNc2ccc(F)cc2F)c(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc(Br)c2cnn(-c3ccc(F)cc3F)c2c1
Yield: 33 %

Procedure:
2,6-Dibromo-4-methylbenzaldehyde (2,4-difluorophenyl)hydrazone (Intermediate 12, 67.4 g, 0.167 mol), tripotassium phosphate (88.8 g, 0.418 mol), tris(dibenzylideneacetone)dipalladium(0) (3.4 g, 3.71 mmol) and racemic BINAP (2.09 g, 3.27 mmol) were heated in degassed 1,4-dioxane (1.125 L) under reflux for 4 days. The mixture was filtered through Celite, washing through with dichloromethane. The filtrate was evaporated under reduced pressure to give a dark brown residue which was dissolved in dichloromethane, absorbed onto silica gel, applied to a silica gel column (1 kg) and eluted with a gradient of 10 to 35% dichloromethane in hexane. Product containing fractions were combined and evaporated to give the title compound as a red solid (17.8 g).
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]#[N:14])=[CH:5][CH:4]=1)=O.[CH3:15][C:16](=[O:21])[CH2:17][C:18](=[O:20])[CH3:19].C(O)(=O)C.N1CCCCC1>ClCCl>[C:18]([C:17]([C:16](=[O:21])[CH3:15])=[CH:1][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]#[N:14])=[CH:5][CH:4]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)CC(C)=O
Reactant: N#Cc1ccc(C=O)c2ccccc12
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1ccc(C#N)c2ccccc12)C(C)=O

Procedure:
240 mg (1.33 mmol) of 4-formyl-1-naphthonitrile, 132.6 mg (1.33 mmol) of 2,4-pentanedione, 119.3 mg (1.99 mmol) of acetic acid and 22.6 mg (0.27 mmol) of piperidine are dissolved in 20 ml of dichloromethane and heated under reflux with an inverse water trap overnight. Cooling is followed by washing twice with water, and the organic phase is dried with magnesium sulfate. The solvent is removed in a rotary evaporator and the residue is purified by column chromatography (silica gel, mobile phase: initially dichloromethane, then isohexane/ethyl acetate 3:1). The residue after concentration of the product fractions is crystallized from diethyl ether and dried under high vacuum. 340 mg (97.5% of theory) of the title compound are obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]([O:13]C)=[O:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[OH-].[Na+]>CO.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]([OH:13])=[O:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: COC(=O)Cc1ccc2occc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1ccc2occc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
Methyl benzofuran-5-ylacetate (1.2 gm, 6.3 mmol) was dissolved in methanol (10 mL) and 2N sodium hydroxide (6.5 mL) was added under nitrogen and the mixture was stirred at rt for 3 hr. It was then diluted with water and extracted with ether. The aqueous layer was acidified with 2N hydrochloric acid and again extracted twice with ethyl acetate. The organic layers were washed with brine, combined, dried over sodium sulfate and evaporated to give 1.1 gm of title compound suitable for the next step.
Reaction SMILES: [OH-].[Na+].C(O)C[OH:5].[Cl:7][C:8]1[C:9]([Cl:21])=[C:10]([Cl:20])[C:11]([Cl:19])=[C:12]2[C:17](=[O:18])[O:16][C:14](=[O:15])[C:13]=12>O>[Cl:7][C:8]1[C:9]([Cl:21])=[C:10]([Cl:20])[C:11]([Cl:19])=[C:12]([C:17]([OH:16])=[O:18])[C:13]=1[C:14]([OH:5])=[O:15]
Reactant: OCCO
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(=O)O
Reaction time: 0.33 h

Procedure:
A 20 g quantity of sodium hydroxide was dissolved in 1000 g of water, and 200 g of ethylene glycol was added to the solution. Subsequently, 143 g of tetrachlorophthalic anhydride was added to the mixture, and the resulting mixture was heated to 95° to 98° C. to obtain a solution. A 122.5 g quantity of 40% aqueous solution of Cr2 (SO4)3 was diluted with 200 g of water and then added dropwise to the obtained solution at the same temperature, over a period of 40 minutes. The resulting mixture was thereafter stirred for 20 minutes, and provided a grayish green precipitate. Subsequently, 10% aqueous solution of sodium hydroxide was added dropwise to the reaction mixture to adjust the pH thereof to about 3. About 13 g of sodium hydroxide was so used. The mixture was further stirred for 2 hours, then cooled and filtered at about 50° C. The resulting reaction product was washed with water and dried, giving 140 g of Cr complex compound of tetrachlorophthalic acid. This complex compound was found to have good thermal stability (as tested at temperatures of below 350° C. in the same manner as described in Example 1).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][C:5]1[C:6]2[CH2:27][NH:26][CH2:25][CH2:24][C:7]=2[N:8]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])=[CH:14][CH:13]=2)[N:10]=1.[CH:32](=O)[CH2:33][OH:34]>>[F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][C:5]1[C:6]2[CH2:27][N:26]([CH2:32][CH2:33][OH:34])[CH2:25][CH2:24][C:7]=2[N:8]=[C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])=[CH:16][CH:17]=2)[N:10]=1
Reactant: O=CCO
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4F)n2)CNCC3)cc1
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4F)n2)CN(CCO)CC3)cc1
Yield: 4.5 %

Procedure:
2-(4-(2-Fluorobenzyl)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanol (4.7 mg, 4.5%) was synthesised from 4-(2-fluorobenzyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (Example 52a) and glycolaldehyde according to the general procedure for reductive amination. MS (ES+) m/z 459.3 (M+H)+
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[C:7](/[CH:24]=[CH:25]\[CH3:26])[CH:6]=1)=[O:4].[OH-].[Na+].Cl>CO>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2/[CH:24]=[CH:25]\[CH3:26])[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: C/C=C\c1cc(C(=O)OC)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C/C=C\c1cc(C(=O)O)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 116.8 %

Procedure:
tert-Butyl (Z)-4-[4-(methoxycarbonyl)-2-(prop-1-en-1-yl)phenyl]piperazine-1-carboxylate (96 mg, 0.267 mmol) was dissolved in methanol (3.0 mL). Under ice-cold conditions, 4N aqueous solution of sodium hydroxide (334 μL) was added, and the mixture was stirred at 50° C. overnight. Subsequently, 4N aqueous solution of sodium hydroxide (668 μL) was further added under ice-cold conditions, and stirred at 50° C. overnight. The reaction solution was added 4N aqueous solution of hydrochloric acid under ice-cold conditions, and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (108 mg (yield >99%)) was obtained as a white crystal.
Reaction SMILES: C1(O[C:8](=[O:22])[NH:9][C:10]2[N:11]([O:20][CH3:21])[CH2:12][C:13]3[CH2:14][CH2:15][CH2:16][CH2:17][C:18]=3[CH:19]=2)C=CC=CC=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH3:21][O:20][N:11]1[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[F:23])[CH2:35][CH2:34]2)=[O:22])=[CH:19][C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH2:12]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CON1CC2=C(C=C1NC(=O)Oc1ccccc1)CCCC2
Product: CON1CC2=C(C=C1NC(=O)N1CCN(c3ccccc3F)CC1)CCCC2
Yield: 70 %

Procedure:
Phenyl-N-(2-methoxy-5,6,7,8-tetrahydroisoquinolin-3-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.Cl.[NH2:18][CH2:19][C:20]1[CH:21]=[C:22]([O:31][CH2:32][CH2:33][CH3:34])[C:23]([O:27][CH2:28][CH2:29][CH3:30])=[C:24]([OH:26])[CH:25]=1.CCN(CC)CC.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:18][CH2:19][C:20]1[CH:21]=[C:22]([O:31][CH2:32][CH2:33][CH3:34])[C:23]([O:27][CH2:28][CH2:29][CH3:30])=[C:24]([OH:26])[CH:25]=1
Reactant: CCCOc1cc(CN)cc(O)c1OCCC
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCOc1cc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc(O)c1OCCC
Yield: 89.1 %

Procedure:
6-Bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (110 mg, 0.39 mmol), 5-aminomethyl-2,3-dipropoxy-phenol hydrochloride salt (93 mg, 0.39 mmol) and Et3N (112 μL, 0.8 mmol) in N,N-dimethylformamide (DMF) (2 mL) is stirred at 25° C. for 24 hours. H2O (10 mL) is added to the reaction mixture. The resulting precipitate is filtered, washed with H2O and dried in vacuo to give 170 mg (91%) of the title compound as a tan powder. HRMS (ESI) m/z calcd for C23H25BrN2O5 (M+H)+1 489.10196. found: 489.10078.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH2:18][CH2:19]Cl)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:22][NH:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C.[I-].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH2:18][CH2:19][N:23]([CH3:24])[CH3:22])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)CCCCl)CC1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C)CCCS(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 111.6 %

Procedure:
A mixture of 4-(3-chloro-propane-1-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (152.6 mg, 0.47 mmol), dimethylamine hydrochloride (403.5 mg, 4.95 mmol, 10.6 eq.), potassium carbonate (72.7 mg, 0.53 mmol, 1.13 eq.) and triethylamine (690 μL, 4.95 mmol, 10.6 eq) in acetonitrile (10 mL) plus a catalytic amount of potassium iodide was heated at 80° C. in a sealed tube overnight. The solvent was then removed in vacuo. The residue diluted with water and extracted with CH2Cl2 (3×20 mL). The combined fractions were dried (Na2SO4) to yield 4-(3-dimethylamino-propane-1-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester as an orange solid (176 mg).
Reaction SMILES: C(OC([N:11]1[CH:16]2[CH2:17][N:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH2:19][CH:12]1[CH2:13][O:14][CH2:15]2)=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:23][S:20]([N:18]1[CH2:17][CH:16]2[NH:11][CH:12]([CH2:13][O:14][CH2:15]2)[CH2:19]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)N1CC2COCC(C1)N2C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)N1CC2COCC(C1)N2
Yield: 78 %

Procedure:
To a solution of the crude Compound Y in MeOH (20 mL) was added 10% Pd on carbon (20 mg). The mixture was stirred under one atmosphere pressure of hydrogen at room temperature. After the reaction was completed, the mixture was filtered and concentrated to give 7-methanesulfonyl-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane (Compound W) (50 mg, 78%) which was directly used for next step. MS: calc'd (MH+) 207, measured (MH+) 207.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17]C)=[CH:16][C:11]=3[O:10][CH:9]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:11]=3[O:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(-c3ccc(Br)cc3)coc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc2c(-c3ccc(Br)cc3)coc2c1
Yield: 101.4 %

Procedure:
3.0 g of 3-(4-bromo-phenyl)-6-methoxy-benzofuran are treated at 0° C. with 100 ml of 1M boron tribromide solution in methylene chloride. The ice bath is removed and the reaction mixture is stirred, subsequently poured into saturated sodium carbonate solution and extracted with methylene chloride. The organic phases are washed with saturated sodium chloride solution, dried and evaporated. There are obtained 2.9 g of 3-(4-bromo-phenyl)-benzofuran-6-ol, MS: m/e 288 (M+, 1 Br).