Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][C:11]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][C:11]([CH2:15][C:16]([OH:18])=[O:17])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)Cc1cnc(-c2ccnc(F)c2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cc1cnc(-c2ccnc(F)c2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of tert-butyl 2-(2′,3-difluoro-2,4′-bipyridin-5-yl)acetate 205-5 (248 mg, 0.81 mmol) and TFA (0.8 mL) in DCM (0.8 mL) was stirred at room temperature for 3 hours. The solution was adjusted to pH around 12 by Na2CO3 and extracted with dichloromethane. The aqueous phase was acidified to pH 3 by 1N HCl aqueous solution and stirred for 15 minutes. The solvents were evaporated and the remaining solid was extracted with 20% methanol in ethyl acetate and filtered to remove the insoluble. The filtrate was concentrated to dryness by rotary evaporation to give 2-(2′,3-difluoro-2,4′-bipyridin-5-yl)acetic acid 205-6, which was used directly for next step. MS m/z 251.1 (M+1).
Reaction SMILES: C[O:2][CH2:3][C@H:4]([CH3:33])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][CH2:30][CH2:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.ClCCl.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>ClCCl>[O:29]1[CH2:30][CH2:31][N:32]=[C:28]1[C:26]1[NH:27][C:23]([C:8]2[CH:7]=[C:6]([CH:11]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[CH:9]=2)[O:5][C@@H:4]([CH3:33])[CH2:3][OH:2])=[CH:24][CH:25]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NCCO3)[nH]2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](CO)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NCCO3)[nH]2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazole (3.17 g, 6.74 mmol) synthesized in Example 20 was dissolved in dichloromethane (100 mL), and cooled to −78° C., and a 1.0 mol/l boron tribromide dichloromethane solution (7.07 mL, 7.07 mmol) was added under nitrogen atmosphere. The temperature was raised naturally, followed by stirring at room temperature for 30 minutes, subsequently a saturated aqueous sodium hydrogencarbonate solution was added to neutralize the reaction solution, and extraction was carried out with dichloromethane (200 mL). The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was washed with ethyl acetate (100 mL) and ethanol (50 mL) to afford the desired product (1.96 g, yield 64%) as a white solid.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][N:11]=2)[CH2:6][CH2:5]1)([OH:3])=O.Cl.[NH:19]1[CH2:24][CH2:23][CH:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:21][CH2:20]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([N:7]2[CH2:8][CH2:9][CH:4]([C:1]([N:19]3[CH2:24][CH2:23][CH:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:21][CH2:20]3)=[O:3])[CH2:5][CH2:6]2)=[N:11][CH:12]=1)#[N:17]
Reactant: COC(=O)CC1CCNCC1
Reactant: N#Cc1ccc(N2CCC(C(=O)O)CC2)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CC1CCN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)CC1

Procedure:
2.3 g of 4-carboxy-1-(5-cyanopyrid-2-yl)-piperidine, 2.0 g of methyl 4-piperidylacetate hydrochloride, 4.8 g of 2-[(1H)-benzotriazol-1-yl]-1,1,3,3-tetramethyl-uronium tetrafluoroborate and 5 ml of triethylamine in 75 ml of dimethylformamide is stirred at ambient temperature for 16 hours. The solvent is removed under reduced pressure. The residue is diluted with water and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water and saturated saline solution and dried over sodium sulphate. The solvent is removed under reduced pressure and the residue is chromatographed over silica gel. Yield: 2.75 g (74% of theory), Melting point: 112°-115° C. Rf value: 0.40 (silica gel; methylene chloride/methanol=15:1)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1.[NH2:13][C:14]1[CH:15]=[C:16]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[NH:24][N:23]=[N:22][N:21]=3)[CH:15]=2)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)cc1F
Yield: 52.2 %

Procedure:
The product was synthesized according to General Procedure 1, described in Example 1, starting with 4-bromo-2-fluorobenzene sulfonyl chloride (17.8 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8 mg, 0.05 mmol) affording 10.4 mg (52%) of the title compound. MS (ESI+) calcd for C13H9BrFN5O2S 396.964436, found 396.963956.
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[F:25][C:26]([F:36])([F:35])C1C=CC(CN)=NC=1>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:26]([F:36])([F:35])[F:25])=[CH:21][N:20]=3)[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Reactant: NCc1ccc(C(F)(F)F)cn1
Agent: Cl
Product: Cc1nc(NCc2ccc(C(F)(F)F)cn2)nc(NC2CCCCC2)c1C

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using {[5-(trifluoromethyl)pyridin-2-yl]methyl}amine instead of (pyridin-2-ylmethyl)amine. The product was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-grey solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04-1.16 (m, 3H), 1.16-1.19 (m, 2H), 1.38 (d, J=10.21 Hz, 2H), 1.55 (s, 3H), 1.86 (s, 3H), 2.26 (bs, 3H) 3.53 (d, J=5.37 Hz, 1H), 4.73 (s, 2H), 7.53 (d, J=7.52 Hz, 2H), 8.15 (d, J=7.79 Hz, 2H), 8.89 (s, 1H), 12.98 (bs, 1H); MS (ESI) m/z 380.0 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C@H:15]([CH:16]([CH3:18])[CH3:17])[C@@H:14]3[C@H:19]([O:22][Si](C(C)(C)C)(C)C)[CH2:20][CH2:21][N:13]3[C:12]2=[O:30])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl-].[NH4+].CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C@H:15]([CH:16]([CH3:18])[CH3:17])[C@@H:14]3[C@H:19]([OH:22])[CH2:20][CH2:21][N:13]3[C:12]2=[O:30])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(N2C(=O)N3CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3[C@H]2C(C)C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(N2C(=O)N3CC[C@@H](O)[C@H]3[C@H]2C(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 91.1 %

Procedure:
To 71C (2.00 g, 4.47 mmol) in THF (45 mL) was added a 1 M THF solution of TBAF (4.47 mL, 4.47 mmol). After stirring at rt for 45 min, saturated aqueous ammonium chloride and EtOAc were added and the layers were separated. The organic layer was washed with brine then dried (MgSO4), filtered and concentrated. The resulting residue was purified via flash chromatography eluting with 75-100% EtOAc/hexane to provide the title compound (1.36 g) which contained a minor impurity (6.76%). To obtain an analytically pure sample, a portion of the product (ca. 250 mg) was purified via preparative HPLC (YMC ODS C-18, 30×100 mm, eluting with 25% solvent B (solvent B=10% H2O-90% CH3CN-0.1% TFA) for 25 min; Flow rate at 40 mL/min; UV detection at 220 nm) to provide, after recrystallization from MeOH/water, the title compound (106 mg) as white needles. MS: m/z 665 [2M−H]−
Reaction SMILES: [C:1]([C:4]1[CH2:9][CH2:8][CH2:7][NH:6][CH:5]=1)(=[O:3])[CH3:2].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC(N1CCCC(C(C)=O)=C1)C>>[C:10]([N:6]1[CH2:7][CH2:8][CH2:9][C:4]([C:1]([CH3:2])=[O:3])=[CH:5]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)C1=CNCCC1
Agent: CC(=O)C1=CN(C(C)C)CCC1
Product: CC(=O)C1=CN(C(=O)c2ccccc2)CCC1

Procedure:
Methyl 1-benzoyl-1,4,5,6-tetrahydro-3-pyridyl ketone was prepared from 3-acetyl-1,4,5,6-tetrahydropyridine and benzoyl chloride according to the procedure of Part (b) of Example 1. The product was recrystallised from ethanol/water m.pt. 93-95°C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]2[C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:28])[C:22]=3[C:21]3=[N:29][O:30][C:31]([CH3:32])=[C:20]3[C:19]2=[O:33])[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(#N)C.O>[CH2:1]([O:8][C:9](=[O:34])[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]2[C:27]3[C:22](=[C:23]([Cl:28])[CH:24]=[CH:25][CH:26]=3)[C:21]([NH2:29])=[C:20]([C:31](=[O:30])[CH3:32])[C:19]2=[O:33])[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)OCc3ccccc3)C1)c1cccc(Cl)c21
Solvent: CC#N
Solvent: O
Product: CC(=O)c1c(N)c2c(Cl)cccc2n(C2CCCC(CNC(=O)OCc3ccccc3)C2)c1=O
Reaction time: 8 h

Procedure:
A solution of [3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-carbamic acid benzyl ester (0.5 g, 1.04 mmol) and Mo(CO)6 (3.0 g, 0.01 mmol) in Acetonitrile (50 mL) and water (5 mL) was heated to 60° C. and stirred overnight. The reaction was concentrated to a solid, diluted in CH2Cl2 and filtered through Celite to remove the black insoluble material. The filtrate was concentrated to a solid and purified using silica gel column chromatography. The product was eluted with 10% EtOAc in CH2Cl2. The solvent was removed to afford 0.520 g (quantitative) of product as a light brown oil. MS (ES+) m/z 482.0 (M+H)+,(ES−) m/z 479.9 (M−H)−, 540.0 (M+CH3COO−)−.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:35]=[N:34][N:33]([CH:36]([CH3:38])[CH3:37])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([C:26]([CH:28]3[CH2:31][N:30]([CH3:32])[CH2:29]3)=[O:27])[CH2:24][CH:25]=2)[CH:19]=1)=[O:13]>CCO.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:35]=[N:34][N:33]([CH:36]([CH3:38])[CH3:37])[C:16]=2[N:17]=[C:18]([CH:20]2[CH2:21][CH2:22][N:23]([C:26]([CH:28]3[CH2:29][N:30]([CH3:32])[CH2:31]3)=[O:27])[CH2:24][CH2:25]2)[CH:19]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)C4CN(C)C4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CCN(C(=O)C4CN(C)C4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 9.5 h
Yield: 62 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1-(1-methylazetidine-3-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) in EtOH, 10% Pd/C in catalytic amount was added and stirred it at room temperature under hydrogen pressure (bladder pressure) for 3-16 h hr. On completion of reaction, reaction mass was filtered through celite bed, then filtrate was concentrated under reduced pressure to give the desired product 62% yield). LCMS: 520.35 (M+1)+; HPLC: 93.45% (@ 254 nm) (Rt; 6.931); 1H NMR (DMSO-d6, 400 MHz) δ 11.54 (s, 1H), 8.75 (t, 1H, J=4.8 Hz), 8.27 (s, 1H), 7.51 (s, 1H), 5.88 (s, 1H), 5.20-5.17 (m, 1H), 4.50 (d, 1H, J=12.4 Hz), 4.36 (d, 2H, J=4.8 Hz), 3.69 (d, 1H, J=13.2 Hz), 3.43 (s, 3H), 3.13-3.06 (m, 4H), 2.69 (t, 1H, J=12 & 11.6 Hz), 2.20 (s, 3H), 2.17 (s, 3H), 2.12 (s, 3H), 1.93 (d, 2H, J=12 Hz), 1.65 (m, 2H), 1.48 (d, 6H, J=7.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([N:14]=[C:15]([NH:17][C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[CH2:24][NH:23][CH2:22][CH2:21]5)[N:16]=3)[CH:11]=[CH:12][CH:13]=2)=[C:4]([O:28][CH3:29])[CH:3]=1.Cl[CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([N:14]=[C:15]([NH:17][C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[CH2:24][N:23]([CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:22][CH2:21]5)[N:16]=3)[CH:11]=[CH:12][CH:13]=2)=[C:4]([O:28][CH3:29])[CH:3]=1
Reactant: CN(C)C(=O)CCl
Reactant: COc1cc(Cl)ccc1-c1cccn2nc(Nc3ccc4c(c3)CCNC4)nc12
Product: COc1cc(Cl)ccc1-c1cccn2nc(Nc3ccc4c(c3)CCN(CC(=O)N(C)C)C4)nc12

Procedure:
2-{6-[8-(4-Chloro-2-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-3,4-dihydro-1H-isoquinolin-2-yl}-N,N-dimethyl-acetamide was prepared from [8-(4-chloro-2-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]-(1,2,3,4-tetrahydro-isoquinolin-6-yl)-amine (0.077 g, 0.190 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.029 mL, 0.284 mmol) in a manner analogous to Example 313 to give product (0.015 g, 16%). MP=103-106° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.53 (s, 1H), 8.78 (d, 1H), 7.58 (m, 2H), 7.42 (m, 2H), 7.25 (s, 1H), 7.15 (d, 1H), 7.05 (t, 1H), 6.92 (d, 1H), 3.78 (s, 3H), 3.54 (s, 2H), 3.28 (s, 2H), 3.05 (s, 3H), 2.85 (s, 3H), 2.78 (m, 2H), 2.70 (m, 2H): MS=491 (MH)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[C:14]3[NH:21][CH:20]=[C:19]([C:22]([OH:24])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[C:25]([O:29][C:30](=[O:39])[NH:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([NH2:38])[CH2:34][CH2:33]1)([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30](=[O:39])[NH:31][C@H:32]1[CH2:33][CH2:34][C@H:35]([NH:38][C:22]([C:19]2[C:15]3[N:16]=[CH:17][N:18]=[C:13]([C:7]4[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:14]=3[NH:21][CH:20]=2)=[O:24])[CH2:36][CH2:37]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: O=C(O)c1c[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc12
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A76) and trans-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]([C:4]1([CH3:19])[NH:8][C:7]([C:9]2[N:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[N:6][C:5]1=[O:18])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Ca+2:24]>O>[CH:1]([C:4]1([CH3:19])[NH:8][C:7]([C:9]2[N:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([O-:13])=[O:12])=[N:6][C:5]1=[O:18])([CH3:3])[CH3:2].[Ca+2:24].[CH:1]([C:4]1([CH3:19])[NH:8][C:7]([C:9]2[N:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([O-:13])=[O:12])=[N:6][C:5]1=[O:18])([CH3:3])[CH3:2]
Reactant: CC(C)C1(C)NC(c2ncccc2C(=O)O)=NC1=O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: CC(C)C1(C)NC(c2ncccc2C(=O)[O-])=NC1=O
Reaction time: 0.17 h
Yield: 87.3 %

Procedure:
To 0.98 g of the acid of Example 9 partially dissolved in 10 ml water is added, with stirring 0.18 g calcium carbonate. After 10 minutes, the solution is filtered, the filtrate concentrated and the residue treated with ether to give a crystalline product which is dried at 40° C. and 25 mm pressure to give 0.88 g of the calcium salt mp 265° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][OH:8])([O-:3])=[O:2].[C:12]([Si:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)Cl)([CH3:15])([CH3:14])[CH3:13].N1C=CN=C1>CN(C)C=O.CN(C)C1C=CN=CC=1>[Si:16]([O:8][CH2:7][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=[CH:10][CH:9]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1cccc(CO)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1cccc([N+](=O)[O-])c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.8 %

Procedure:
A solution of 5 g (33 mmol) of 3-nitrobenzyl alcohol in 100 ml of dimethylformamide was treated with 10.8 g (40 mmol) of tert-butyldiphenylchlorosilane, 6.7 g (99 mmol) of imidazole and 100 mg (0.9 mmol) of 4-(dimethylamino)pyridine and the mixture stirred at ambient temperature for 4 hours. The solvent was evaporated and the residue partitioned between 100 ml of ethyl acetate and 100 ml of 2M aqueous hydrochloric acid. The organic phase was washed with a further 50 ml of 2M aqueous hydrochloric acid, dried over magnesium sulfate, filtered and evaporated to afford 12.9 g (100%) of 3-(tert-butyldiphenylsilyloxymethyl)nitrobenzene as a colorless oil. [Mass spectrum (ESI) MH+ =392].
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[S:7]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>C(OCC)(=O)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][CH:6]3[C:11](=[O:12])[NH:10][C:9]4[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=4[S:7]3)[CH2:26][CH2:25]2)=[CH:22][CH:23]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=C1Nc2ccccc2SC1CCCCCl
Solvent: CCOC(C)=O
Product: O=C1Nc2ccccc2SC1CCCCN1CCN(c2ccc(F)cc2)CC1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
In 10 ml of ethyl acetate were dissolved 435 mg of 2-(4-chlorobutyl)-2H-1,4-benzothiazin-3(4H)-one and 613 mg of 1-(4-fluorophenyl)piperazine. The solvent was evaporated off, and the residue was stirred at 110° C. for one hour. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water and dried (MgSO4). After removal of the solvent, the residue was subjected to a column chromatography on silica-gel (40 g). From the eluate with hexane-ethyl acetate (1:1, v/v) was obtained 2-[4-[4-(4-fluorophenyl)-1-piperazinyl]butyl]-2H-1,4-benzothiazin-3(4H)-one. The yield was 293 mg (43.2%). Recrystallization from methanol gave prisms, m.p. 150°-151° C.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[C:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1>O>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[O:2][C:3](=[O:19])[C:4]3[C:5]([CH:10]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccccc1C#Cc1ccc(Br)cc1
Solvent: O
Product: O=c1oc(-c2ccc(Br)cc2)cc2ccccc12
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A mixture of 2-(4-bromo-phenylethynyl)-benzoic acid methyl ester (1.24 g, 3.95 mmol) and polyphosphoric acid (16 g) is heated to 80° C. and stirred at this temperature for 20 hours. The reaction mixture is allowed to cool to room temperature and water is added. The resulting precipitate is filtered off, washed with water and dried under vacuum to afford 3-(4-bromo-phenyl)-isochromen-1-one as brown powder; HPLC/MS 2.18 min (A), [M+H] 301/303.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[C:8]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:7]2=1.[CH3:19][O-:20].[Na+]>CO.O>[Cl:18][C:15]1[CH:16]=[CH:17][C:7]2[C:6]3[C:11](=[C:2]([O:20][CH3:19])[N:3]=[CH:4][CH:5]=3)[C:10](=[O:12])[N:9]([CH3:13])[C:8]=2[CH:14]=1
Reactant: C[O-]
Reactant: Cn1c(=O)c2c(Cl)nccc2c2ccc(Cl)cc21
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nccc2c1c(=O)n(C)c1cc(Cl)ccc21
Yield: 38.9 %

Procedure:
To a solution of 4,8-dichloro-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (1.0 g, 3.58 mmol) in MeOH (1 mL) was added sodium methoxide (0.806 mL, 3.58 mmol). The resultant mixture was heated in a microwave at 80° C. for 25 min. The reaction mixture was then diluted with water (20 mL) and extracted with ethyl acetate (30 mL). The organic layer was separated, dried over sodium sulphate and evaporated to dryness to afford 8-chloro-4-methoxy-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (0.4 g, 1.391 mmol, 39% crude yield) as a brown solid. The material was carried on without further purification. LC/MS (ESI) m/e 274.8 [(M+H)+, calcd for C14H12ClN2O2, 275.0]; LC/MS retention time (method C): tR=2.06 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18]CC3C=CC=CC=3)[CH:13]=2)[C:8]([C:26]([NH2:28])=[O:27])=[CH:7][N:6]=1.C1COCC1.CO.[H][H]>[C].[Pd].CN(C=O)C>[NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[C:8]([C:26]([NH2:28])=[O:27])=[CH:7][N:6]=1
Reactant: NCCNc1ncc(C(N)=O)c(Nc2cccc(OCc3ccccc3)c2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CO
Product: NCCNc1ncc(C(N)=O)c(Nc2cccc(O)c2)n1
Yield: 32.8 %

Procedure:
A 100 mg portion of 10% palladium-carbon powder was added to a mixture of 869 mg of 2-(2-aminoethylamino)-4-(3-benzyloxyanilino)pyrimidine-5-carboxamide with THF, methanol and DMF, followed by stirring at room temperature for 3 days in an atmosphere of hydrogen under ordinary pressure. The reaction mixture was filtered, and the filtrate was concentrated under a reduced pressure. By Ad:. recrystallizing the resulting residue from an ethyl acetate-methanol mixed solvent, 217 mg of 2-(2-aminoethylamino)-4-(3-hydroxyanilino)pyrimidine-5-carboxamide was obtained (light brown solid).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[NH:9]1[CH2:19][CH2:18][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].N1CCC[C@H]1C(O)=O>CS(C)=O.[Cu](I)I.O>[CH2:16]([O:15][C:13]([CH:12]1[CH2:18][CH2:19][N:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:10][CH2:11]1)=[O:14])[CH3:17]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Fc1ccccc1I
Agent: I[Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1CCN(c2ccccc2F)CC1
Temperature: 90 °C
Reaction time: 48 h
Yield: 25.9 %

Procedure:
1-Fluoro-2-iodobenzene (0.58 mL, 5.0 mmol) was added to a mixture of ethyl isonipecotate (1.2 mL, 7.5 mmol), potassium carbonate (1.4 g, 10 mmol), L-proline (0.12 g, 1 mmol) and copper iodide (0.095 g, 0.5 mmol) in 4 mL of dimethyl sulfoxide. Reaction stirred at 90° C. for 48 hours. The mixture was poured into a water (40 mL) solution and extracted with ethyl acetate (EtOAc) (4×10 mL). The combined organic layers were washed with brine (40 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography, using EtOAc/hexane (gradient system), to obtain 1-(2-fluorophenyl)piperidine-4-carboxylic acid ethyl ester (0.325 g, 26% yield).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5](OC2C=CC=CC=2)[C:4]=1[C:16]([C:18]1[C:23]([O:24]C2C=CC=CC=2)=[CH:22][CH:21]=[CH:20][C:19]=1[O:31]C)=O.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C1(C)C=CC=CC=1>[C:19]1([OH:31])[C:18]2[C:16]3([C:4]4[C:3]([OH:2])=[CH:8][CH:7]=[CH:6][C:5]=4[O:2][C:3]4[C:4]3=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:19]3[C:20](=[CH:21][CH:22]=[CH:23][CH:18]=3)[O:24][C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cccc(Oc2ccccc2)c1C(=O)c1c(OC)cccc1Oc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Oc1cccc2c1C1(c3ccccc3O2)c2ccccc2Oc2cccc(O)c21
Temperature: 0 °C
Yield: 146.3 %

Procedure:
To a solution of 2 (1.0 g, 2.3 mmol) in dry toluene (20 mL) was added AlCl3 (1.9 g, 14.3 mmol). The solution was warmed slowly and refluxed for 30 minutes. Then it was cooled to 0° C. and concentrated aqueous HCl (20 mL) was introduced with vigorous stirring. After refluxing for 1 hour, the reaction mixture was extracted with EtOAc, washed with concentrated HCl, water, aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated. Flash chromatography (eluting with CH2Cl2) gave 3 as light-yellow powder (0.64 g, yield 72%).