Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([OH:9])=[O:8])([C:4](O)=[O:5])[CH2:3][CH2:2]1.[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1.CCOC(C)=O>[CH3:10][N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]([C:1]1([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)=[O:5]
Reactant: O=C(O)C1(C(=O)O)CC1
Reactant: CNc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C(=O)C1(C(=O)O)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
To a solution of cyclopropane-1,1-dicarboxylic acid (1.5 g, 11.53 mmol) in THF (24 mL) TEA (1.6 mL, 11.53 mmol) was added dropwise and under stirring thionyl chloride (0.83 mL, 11.53 mmol) and the mixture stirred 30 min at room temperature. A solution of N-methylaniline (1.3 mL, 11.53 mmol) in THF (14 mL) was added dropwise at 0° C. and the mixture was stirred for 2 h. The mixture was diluted with EtOAc, extracted with 2N NaOH, acidified to pH˜2 by addition of 2N HCl and extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated under reduced pressure affording 246 (1.24 g, 5.66 mmol, 49%) as a white solid. MS (m/z): (M+1) 220.0 (100%).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[C:13]([OH:15])=[O:14])=[O:6])[CH:2]=[CH2:3].S(=O)(=O)(O)O.[CH2:21](N(CC)CC)C>CO>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[C:13]([O:15][CH3:21])=[O:14])=[O:6])[CH:2]=[CH2:3]
Reactant: CCN(CC)CC
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: O=S(=O)(O)O
Solvent: CO
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Temperature: 25 °C

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-2-carboxy-4-hydroxypyrrolidine (426 g) in methanol (3 l) was added 36N sulfuric acid (45 ml) at 10° C., and the mixture was allowed to heat to reflux for 2 hours. After cooling to ambient temperature, to this mixture was added triethylamine (430 ml) and the mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate (3 l) and the solution was washed with brine, dried over magnesium sulfate and evaporated to give (2S,4R)-1-allyloxycarbonyl-2-methoxycarbonyl-4-hydroxypyrrolidine (385.6 g).
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17](O)=[O:18])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH:21][C:22]1[C:31]([CH3:32])=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][CH2:25][NH:26][CH2:27]2>>[C:1]1([C:7]2[N:16]=[C:15]([C:17]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[C:31]([CH3:32])[C:22]=4[OH:21])[CH2:27]3)=[O:18])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc2c(c1O)CCNC2
Reactant: O=C(O)c1nc(-c2ccccc2)nc2ccccc12
Agent: Cl
Product: Cc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccccc3)nc3ccccc13)C2
Yield: 14 %

Procedure:
Reaction of 2-phenylquinazolin-4-carboxylic acid with 5-hydroxy-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 21 (14% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.13 and 2.17 (2s, 3H), 2.66 and 2.92 (2t, 2H), 3.50 and 4.05 (2t, 2H), 4.41 and 4.93 (2s, 2H), 6.29-7.00 (4d, 2H), 7.56-7.80 (m, 4H), 7.86-7.98 (2d, 1H), 8.10-8.19 (m, 2H), 8.37 and 8.44 (2s, 1H), 8.49-8.57 (m, 2H); MS (ESI) m/z 396 ([M+H]+).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH2:12])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl-].[CH3:14][C:15]1[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=1[CH:17]=[N+:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>>[N:18]1([CH:17]([C:16]2[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=2[CH3:14])[C:5]2[N:1]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH2:12])[CH:2]=[CH:3][CH:4]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1ccccc1C=[N+]1CCCC1
Reactant: Nc1ccccc1-n1cccc1
Agent: [Cl-]
Product: Cc1ccccc1C(c1cccn1-c1ccccc1N)N1CCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-pyrrol-1-yl-phenylamine and 1-(2-methyl-benzylidene)-pyrrolidinium chloride.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][CH2:13][CH2:14]OS(C)(=O)=O)=[CH:8][C:7]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:6]2)[CH2:3][CH2:2]1.[N:29]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][CH2:13][CH2:14][N:32]3[CH2:33][CH2:34][N:29]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30][CH2:31]3)=[CH:8][C:7]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:6]2)[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2cc(CCCOS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: COc1ccc(-c2cc(CCCN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(CC3CC3)n2)cc1F
Yield: 76.9 %

Procedure:
Following the procedure of Example 1(10), 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 76.9%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH2:12][OH:13])[NH:8][CH2:9]2)=[CH:4][CH:3]=1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1>CN(C)C=O.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[NH:8][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC1Cc2ccc(Br)cc2CN1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC1Cc2ccc(Br)cc2CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (7-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl)methanol (620 mg, 2.6 mmol) in N,N-dimethylformamide (5 mL) was added tert-butyldimethylsilyl chloride (580 mg, 3.8 mmol, Aldrich, Cat. No. 190550) and 1H-imidazole (260 mg, 3.8 mmol). The solution was stirred at r.t. overnight. The reaction solution was diluted with water, and extracted with AcOEt. The organic layer was washed with brine, dried over MgSO4. After filtration, the filtrate was concentrated to afford the desired compound which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=356.3.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[OH:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[NH:14][C:13](=[O:16])[CH:12]=[CH:11]2.[C:17](OC(=O)C)(=[O:19])[CH3:18]>ClC1C=CC=CC=1Cl>[C:17]([C:9]1[CH:8]=[CH:7][C:6]([OH:5])=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13](=[O:16])[NH:14]2)(=[O:19])[CH3:18]
Reactant: O=c1ccc2cccc(O)c2[nH]1
Reactant: CC(=O)OC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: CC(=O)c1ccc(O)c2[nH]c(=O)ccc12
Temperature: 22.5 °C
Reaction time: 0.5 h

Procedure:
Aluminium chloride (93.3 g, 700 mmol, 3.5 eq.) is suspended in 1,2-dichlorobenzene (320 mL). The suspension is maintained at 20-25° C. and 8-hydroxy-(1H)-quinolin-2-one (32.24 g, 200 mmol, 1.0 eq.) is added in 5 portions (40 minutes, IT max. 25° C.). Acetic anhydride (21.4 g, 210 mmol, 1.05 eq.) is slowly added (30 minutes, IT max. 20° C.) and the addition funnel is rinsed with a small amount of 1,2-dichlorobenzene. The suspension is stirred for 30 minutes at 20-25° C. HPLC control reveals complete conversion to 8-acetoxy-(1H)-quinolin-2-one. The mixture is heated to IT=80° C. while purging the head-space with a stream of nitrogen. HCl evolution is noticed upon reaching IT=40° C. The reaction mixture is stirred for 1 hour at IT=80° C. HPLC control reveals almost complete conversion to 5-acetyl-8-hydroxy-(1H)-quinolin-2-one (3.1% O-acetyl intermediate, 10.8% ortho-isomer). The reaction mixture is poured hot (80° C.) over water (800 mL). Water (100 mL) is added in the reaction vessel and brought to reflux temperature. After 15 minutes at reflux temperature, the suspension is added to the previous quench suspension. The mixture is maintained for 15 minutes at IT=80° C. and then hot filtered. The yellow product is rinsed with water (2×200 mL, 50° C.), rinsed with acetone (50 mL) and then dried overnight under vacuum at 70° C. Yield: 33.32 g (82.0%). Purity: 95-97%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17](Br)[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:29]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C(Cl)Cl.CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2].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]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([C:31]3[CH:32]=[CH:33][S:29][CH:30]=3)[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Br)ccc2OCc2cccc(Cl)c2)C1
Reactant: OB(O)c1ccsc1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(-c3ccsc3)ccc2OCc2cccc(Cl)c2)C1
Temperature: 80 °C

Procedure:
3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester (188 mg, 0.4 mmol), 3-thiophene boronic acid (53 mg, 0.41 mmol), Q-Phos (23 mg, 0.032 mmol), Pd(dba)2 (9.2 mg, 0.016 mmol) and K3PO4 (255 mg, 1.2 mmol) were taken into toluene (3 mL) and heated at 80° C. After the reaction was complete it was cooled to rt, diluted with CH2Cl2 (20 mL), filtered, washed with H2O (2×25 mL) and concentrated to give 3-[2-(3-chloro-benzyloxy)-5-thiophen-3-yl-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester. To this compound was added MeOH (10 mL) followed by 4M HCl in dioxane (4 mL). After 4 h the reaction was concentrated and purified on RP HPLC (basic) to yield the title compound (12 mg). MS (ESI): mass calcd. for C20H18ClNO2S, 371.9; m/z found, 372.2 [M+H]+. 1H NMR (CDCl3): 10.30-9.57 (m, 1H), 7.43 (s, 1H), 7.40-7.28 (m, 6H), 7.24 (dd, J=8.4, 2.1 Hz, 1H), 7.01 (d, J=2.1 Hz, 1H), 6.96 (d, J=8.5 Hz, 1H), 5.24-4.99 (m, 3H), 4.40-4.11 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:11]([C:20]([C:22]3[CH:23]=[N:24][C:25](Cl)=[CH:26][CH:27]=3)=[O:21])=[CH:10]2)[CH:5]=[CH:4][CH:3]=1.[N-:29]=[N+]=[N-].[Na+].C(N(CC)CC)C.Cl.C(CCP(CCC(O)=O)CCC(O)=O)(O)=O>CN(C=O)C.O>[NH2:29][C:25]1[N:24]=[CH:23][C:22]([C:20]([C:11]2[C:12](=[O:19])[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:9]([CH2:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=3)[CH:10]=2)=[O:21])=[CH:27][CH:26]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(c1ccc(Cl)nc1)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Agent: Cl
Agent: O=C(O)CCP(CCC(=O)O)CCC(=O)O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cn1
Yield: 62.7 %

Procedure:
100 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-3-(6-chloro-pyridine-3-carbonyl)-1H-quinolin-4-one and 72 mg (1.1 mmol) of sodium azide were heated at 100° C. in 1 mL of DMF for 1 h. The temperature of the solution was lowered to 70° C. and 1 mL of water was added, followed by 214 uL (155 mg, 1.54 mmol) of triethylamine and 378 mg (1.32 mmol) of tris(2-carboxyethyl)phosphine hydrochloride. After 1 h of reaction time the mixture was purified on reverse-phase HPLC, followed by flash chromatography to give 60 mg of a yellow powder. LC-MSD, m/z for C21H15BrN4O2 [M+H]+=435.0, 437.0; HPLC retention time: 0.6 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[Cl:9].[C:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[Cl:9])[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1ccc(Br)c(Cl)c1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(F)cc2Cl)CC1

Procedure:
The title compound was prepared according to the procedure described for example AX from 1-bromo-2-chloro-4-fluorobenzene and N-Boc-piperazine (10%, off white solid, MS (m/e): 315.1(M+H, 100%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[NH:12][CH2:13][CH2:14][O:15][Si](C)(C)C.[H-].[Na+].[CH2:29]([N:31]([CH2:45][CH3:46])[C:32](=[O:44])[NH:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1)[CH3:30].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:40]([C:37]1[CH:36]=[CH:35][C:34]([NH:33][C:32]([N:31]([CH2:45][CH3:46])[CH2:29][CH3:30])=[O:44])=[CH:39][CH:38]=1)(=[O:42])=[O:41])[C:6](=[O:11])[C:5]2([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[NH:12][CH2:13][CH2:14][OH:15]
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[Si](C)(C)OCCNC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)N2C(=O)C(NCCO)(c3ccccc3Cl)c3cc(Cl)ccc32)cc1
Reaction time: 0.42 h
Yield: 32.2 %

Procedure:
A solution of 1.084 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-[[2-(trimethylsilyloxy)ethyl]amino]indol-2-one in 20 ml of DMF is cooled to 0° C. under an argon atmosphere and 0.111 g of sodium hydride as a 60% dispersion in oil is added. After stirring for 25 minutes, 0.78 g of 4-(N',N'-diethylureido)benzenesulfonyl chloride is added and the reaction mixture is stirred for 3 hours at RT. It is poured into water and extracted with AcOEt, the organic phase is washed with water and with a saturated solution of NaCl and dried over sodium sulfate and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (70/30; v/v) as the eluent to give 0.505 g of the expected product after crystallization and then recrystallization from a DCM/iso ether mixture. M.p.=192°-193° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[NH2:9][CH2:10][C@H:11]1[C@H:16]([CH3:17])[CH2:15][CH2:14][CH2:13][N:12]1[C:18]([C:20]1[N:21]=[C:22]([CH3:32])[S:23][C:24]=1[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)=[O:19]>>[Cl:8][C:5]1[CH:4]=[N:3][C:2]([NH:9][CH2:10][C@H:11]2[C@H:16]([CH3:17])[CH2:15][CH2:14][CH2:13][N:12]2[C:18]([C:20]2[N:21]=[C:22]([CH3:32])[S:23][C:24]=2[C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[O:19])=[N:7][CH:6]=1
Reactant: Cc1nc(C(=O)N2CCC[C@@H](C)[C@@H]2CN)c(-c2ccc(F)cc2)s1
Reactant: Clc1cnc(Cl)nc1
Product: Cc1nc(C(=O)N2CCC[C@@H](C)[C@@H]2CNc2ncc(Cl)cn2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound was prepared following the same general protocol as described for Example 16 using 2,5-dichloropyrimidine and rac-trans-(2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone. MS (ESI) 460.4 (M+H).
Reaction SMILES: [OH:1][C@@H:2]([C:24]1[CH:33]=[CH:32][C:27]2[C:28](=[O:31])[O:29][CH2:30][C:26]=2[C:25]=1[CH3:34])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([C:13]2[CH:22]=[CH:21][C:16]3[C:17](=[O:20])[O:18][CH2:19][C:15]=3[C:14]=2[CH3:23])=[O:12])[CH2:6][CH2:5]1.[CH3:35][Li]>C1COCC1>[OH:12][C:11]([C:13]1[CH:22]=[CH:21][C:16]2[C:17](=[O:20])[O:18][CH2:19][C:15]=2[C:14]=1[CH3:23])([CH3:35])[CH2:10][N:7]1[CH2:6][CH2:5][N:4]([CH2:3][C@@H:2]([OH:1])[C:24]2[CH:33]=[CH:32][C:27]3[C:28](=[O:31])[O:29][CH2:30][C:26]=3[C:25]=2[CH3:34])[CH2:9][CH2:8]1
Reactant: [Li]C
Reactant: Cc1c(C(=O)CN2CCN(C[C@@H](O)c3ccc4c(c3C)COC4=O)CC2)ccc2c1COC2=O
Solvent: C1CCOC1
Product: Cc1c([C@H](O)CN2CCN(CC(C)(O)c3ccc4c(c3C)COC4=O)CC2)ccc2c1COC2=O
Reaction time: 0.33 h

Procedure:
To a solution of 5-({4-[(2S)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}acetyl)-4-methyl-2-benzofuran-1(3H)-one (50 mg, 0.108 mmol) in THF (2 mL) in a 25 mL flask was added methyl lithium (2 mg, 0.1 mmol) at 0° C. The reaction mixture was stirred for 20 min.; LC analysis indicated formation of the desired product. The solution was concentrated to dryness, dissolved in MeOH (3.5 mL), filtered and was then purified by mass-directed HPLC to give 5-(1-hydroxy-2-{4-[(2S)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}-1-methylethyl)-4-methyl-2-benzofuran-1(3H)-one. LC-MS (IE, m/z): 481 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2I)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](=O)([O-:27])[O-:26].[K+].[K+].[OH-].[Na+]>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[C:25]([OH:27])=[O:26])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(Cl)cc2I)CC1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(Cl)cc2C(=O)O)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 47.5 %

Procedure:
To a stirring solution of 2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-5-chloro-1-iodobenzene (10 g, 21.5 mmol) in acetonitrile (350 mL) was added potassium carbonate (14.9 g, 107.5 mmol), followed by Pd(PPh3)4 (1.24 g, 1.1 mmol), and copper iodide (0.21 g, 1.1 mmol). The mixture was placed under an atmosphere of carbon monoxide and heated to 80° C. After 3 h, 1 N aqueous sodium hydroxide (50 mL) was added to the hot reaction solution. The solution was stirred for 10 min and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The aqueous phase was filtered, acidified to pH 3 with citric acid, and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 3.91 g (48%) of a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[N:10][C:11]([N+:14]([O-])=O)=[CH:12][CH:13]=2)[CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[N:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2ccc(N)nc2)CC1
Yield: 98.2 %

Procedure:
1-Methyl-4-(6-nitro-pyridin-3-yl)-piperazine (1.748 g, 7.865 mmol) was stirred in 30 mL methanol with 175 mg 10% palladium on carbon under an atmosphere of hydrogen gas for 5 hours. This was filtered and concentrated in vacuo to yield 5-(4-Methyl-piperazin-1-yl)-pyridin-2-ylamine (1.485 g, 7.724 mmol). MS (ESI) 193.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[CH:19]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])O.[Na+]>ClCCl>[CH:19]1([NH:24][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: NC1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc2c(NC3CCCC3)nnc(Cc3ccncc3)c2c1
Temperature: 15 °C
Reaction time: 6 h

Procedure:
A mixture of 0.3 g (1.173 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine and 0.4 g (4.692 mmol) cyclopentylamine is stirred for 6 h at 1 15° C. The cooled reaction mixture is then distributed between dichloromethane and saturated aqueous sodium hydrogen carbonate solution. The organic solution washed with brine and dried over anhydrous sodium sulfate is evaporated and the residue purified on silica gel by flash chromatography using acetate/methanol (9:1). Title compound is obtained after crystallization of the product-containing fractions from acetonitrile/water and drying under HV (8 h, 100° C.); m.p. 163-165° C.; ESI-MS: (M+H)+=305.
Reaction SMILES: [Pb](Br)Br.[Al].[CH3:5][O:6][C:7]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:8]=1[CH:9]=[O:10].Cl.[C:20](Cl)([Cl:23])([Cl:22])[Cl:21]>CN(C)C=O>[OH:10][CH:9]([C:8]1[CH:11]=[C:12]([O:17][CH3:18])[C:13]([O:15][CH3:16])=[CH:14][C:7]=1[O:6][CH3:5])[C:20]([Cl:23])([Cl:22])[Cl:21]
Reactant: ClC(Cl)(Cl)Cl
Reactant: COc1cc(OC)c(OC)cc1C=O
Agent: Br[Pb]Br
Agent: Cl
Agent: [Al]
Solvent: CN(C)C=O
Product: COc1cc(OC)c(C(O)C(Cl)(Cl)Cl)cc1OC
Reaction time: 1 h
Yield: 79 %

Procedure:
In 50 ml of dimethylformamide, 0.37 g of lead bromide, 0.41 g of aluminum foil and 1.96 g of 2,4,5-trimethoxybenzaldehyde were added, followed by the addition of 1.9 ml of carbon tetrachloride at room temperature. The resulting mixture was stirred for one hour. After the completion of the reaction, 2N hydrochloric acid was added to the reaction mixture under ice cooling, followed by extraction with ethyl acetate. The extract was washed successively with a saturated aqueous solution of sodium bicarbonate, water and saturated saline, followed by drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the crude product so obtained was washed with methanol, whereby 2.49 g of 1-(1-hydroxy-2,2,2-trichloroethyl)-2,4,5-trimethoxybenzene were obtained (yield: 79%). The physical properties of the product were equal to those of the product obtained in Referential Example 2.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:7]([C:16]2[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([C:5]1[O:9][C:8]2[C:7](=[C:16]3[C:17](=[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]4=2)[C:18](=[O:22])[NH:19][CH:20]=[CH:21]3)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(-c2cc[nH]c(=O)c2)c(-c2ccccc2)o1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc2c3cc[nH]c(=O)c3c3ccccc3c2o1

Procedure:
A solution of 4-(5-tert-butyl-2-phenyl-3-furyl)pyridin-2(1H)-one (50 mg, 0.2 mmol) in THF (50 mL) was irradiated with a sun lamp for 5 h. The solution was then concentrated in vacuo and the product purified by flash chromatography using EtOAc-Pet. Spirit (80:20) as eluant, to separate the pure product as a cream solid (26 mg, 52%).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][C:11]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:20][OH:21].[C:22](Cl)(=[O:24])[CH3:23]>ClCCl>[F:1][C:2]1[C:3]([CH2:20][OH:21])=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([CH:14]2[CH2:15][CH2:16][N:17]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:19]2)=[N:12][CH:13]=1
Reactant: CC(=O)Cl
Reactant: OCc1cccc(-c2cnc(C3CCNCC3)nc2)c1F
Solvent: ClCCl
Product: CC(=O)N1CCC(c2ncc(-c3cccc(CO)c3F)cn2)CC1
Reaction time: 3 h
Yield: 98.1 %

Procedure:
{2-Fluoro-3-[2-(piperidin-4-yl)pyrimidin-5-yl]phenyl}methanol (80 mg) was mixed with dichloromethane (1.6 ml), and TEA (85 mg) and acetyl chloride (48 mg) were added thereto at 0° C. The reaction mixture was concentrated under reduced pressure, the residue was mixed with MeOH, and a 1 M aqueous NaOH solution (0.8 ml) was added thereto, followed by stirring for 3 hours. 1 M hydrochloric acid was added to the reaction mixture, and CHCl3/water was added to the reaction liquid. The aqueous layer was extracted with CHCl3, and the prepared organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 1-(4-{5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}piperidin-1-yl)ethanone (90 mg).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](S(C)(=O)=O)=[CH:6][CH:5]=1)=[O:3].BrBr>C(O)(=O)C.Cl.O>[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(S(C)(=O)=O)cc1
Agent: BrBr
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1ccccc1

Procedure:
To a stirred solution of the acetophenone prepared in Step 2 (11.91 g, 60.5 mmol) in glacial acetic acid (133 ml) and hydrochloric acid (0.11 ml) at ambient temperature, was added a solution of bromine (8.22 g, 51.4 mmol) in glacial acetic acid (9.3 ml) over a period of three hours. The reaction mixture was diluted with water (500 ml) and extracted with chloroform. The combined chloroform extracts were dried (MgSO4) and concentrated in vacuo to give 15.66 g of crude 2-bromo-4′-methylsulfonyl)acetophenone: 1H NMR (CDCl3) δ3.10 (s, 3H), 4.45 (s, 2H), 8.08 (d, J=9 Hz, 2H), 8.17 (d, J=9 Hz, 2H). The sample was used without further purification.