Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)=O.[F:17][C:18]([F:26])([F:25])[C:19](=[O:24])[CH2:20][C:21](=O)[CH3:22]>C(O)(=O)C.S(=O)(=O)(O)O>[F:17][C:18]([F:26])([F:25])[C:19]([C:20]1[C:10]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[C:3]2[C:4]3[CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:21]=1[CH3:22])=[O:24]
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: Nc1sc2c(c1C(=O)c1ccco1)CCC2
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc3c(c2c(-c2ccco2)c1C(=O)C(F)(F)F)CCC3
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 25.8 %

Procedure:
To a stirred solution of 50 mg (0.21 mmol) (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-furan-2-yl-methanone (the preparation of which is described in example 18) in 2 ml acetic acid was added 0.027 ml (0.21 mmol) of 1,1,1-trifluoro-pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 19 mg (25%) 2,2,2-trifluoro-1-(4-furan-2-yl-2-methyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl)-ethanone as a yellow solid. ES-MS m/e (%): 352 (M+H+, 72).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO.O>[OH:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:3][C:2]=2[C:32]2[CH:33]=[N:28][CH:29]=[N:30][CH:31]=2)[CH2:23]1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2CC[C@H](O)C2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2CC[C@H](O)C2)c(-c2cncnc2)c1
Temperature: 25 °C

Procedure:
(S)-3-Bromo-4-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.1, 80 mg, 0.180 mmol), pyrimidin-5-ylboronic acid (66.8 mg, 0.539 mmol), Pd(PPh3)2Cl2 (7.57 mg, 10.78 μmol) and Na2CO3 (57.1 mg, 0.539 mmol) were added to a MW vial and was treated with a mixture of DME (762 μL), water (218 μL) and EtOH (109 μL). The vial was sealed, evacuated/purged with argon and the RM was subjected to MW irradiation at 80° C. for 2 h. The RM was cooled to RT, diluted with THF (1 mL) and treated with Si-Thiol (Silicycle, 1.27 mmol/g, 70.7 mg, 0.090 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 4 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (8:2), from 30% to 80% EtOAc-EtOH+0.1% NH4OH (8:2) to yield the title compound as a yellow solid. UPLC-MS (condition 1) tR 2.36 min, m/z=445.0 [M+H]+, m/z=443.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.70-1.80 (m, 1H) 1.82-1.94 (m, 1H) 2.68 (dd, 1H) 2.99-3.09 (m, 2H) 3.18-3.26 (m, 1H) 4.17-4.24 (m, 1H) 4.87 (d, J=3.67 Hz, 1H) 6.98 (d, J=8.80 Hz, 1H) 7.33 (d, J=8.31 Hz, 2H) 7.82-7.88 (m, 3H) 7.94 (dd, J=8.80, 2.45 Hz, 1H) 8.86 (s, 2H) 9.16 (s, 1H) 10.09 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([OH:13])=O)=[CH:8][C:9]=1[CH3:10])=[O:4].[NH2:14][CH:15]([C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1)[CH3:16].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11](=[O:13])[NH:14][CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)[CH3:16])=[CH:8][C:9]=1[CH3:10])=[O:4]
Reactant: COC(=O)c1sc(C(=O)O)cc1C
Reactant: CC(N)c1cccc(O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C(=O)NC(C)c2cccc(O)c2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
To a solution of 3-methyl-thiophene-2,5-dicarboxylic acid 2-methyl ester (0.1 g, 0.5 mmol) and 3-(1-amino-ethyl)-phenol (82 mg, 0.6 mmol) in DMF (4 ml) was added at rt triethylamine (0.1 ml, 0.75 mmol), HOBT (81 mg, 0.6 mmol) and HBTU (228 mg, 0.6 mmol). The mixture was stirred at rt for 30 min, then quenched with 1NHCl and extracted with EtOAc. The layers were separated. The organic layer was washed with brine, then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 30-70% EtOAc in hexane to afford the desired product (121 mg, 75% yield).
Reaction SMILES: [O-:1]Cl=O.[Na+].[CH2:5]([O:12][C:13]1[C:14](=[O:33])[CH:15]=[C:16]([CH:31]=[O:32])[N:17]([C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:22]=[CH:23][CH:24]=2)[CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CC(C)=O.O>[CH2:5]([O:12][C:13]1[C:14](=[O:33])[CH:15]=[C:16]([C:31]([OH:1])=[O:32])[N:17]([C:19]2[CH:20]=[C:21]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:22]=[CH:23][CH:24]=2)[CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=Cc1cc(=O)c(OCc2ccccc2)cn1-c1cccc(-c2ccccc2)c1
Reactant: [O-][Cl+][O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1cc(=O)c(OCc2ccccc2)cn1-c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
NaClO2 (28.3 g, 315 mmol) was added portion-wise to a mixture of 5-(benzyloxy)-1-(biphenyl-3-yl)-4-oxo-1,4-dihydropyridine-2-carbaldehyde (80 g, 210 mmol) in 800 mL of acetone and 800 mL of water at room temperature. The resulting mixture was stirred at room temperature for 3 h. The solvent was removed to give a residue which was washed with water and MeOH and dried to give 5-(benzyloxy)-1-(biphenyl-3-yl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid. ′H NMR δ (400 MHz, d6-OMSO): 7.79 (s, 1H), 7.77-7.68 (m, 4H), 7.57 (t, J=8.0 Hz, 1H), 7.48 (t, =7.6 Hz, 2H), 7.42-7.31 (m, 7H), 6.66 (s, 1H), 5.04 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:26]#[C:27][CH2:28][N:29]([CH3:31])[CH3:30])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=1)[CH2:7]2.[H][H].C(Cl)(Cl)Cl.CO>C(O)C.[C].[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:17][CH:18]=1)[CH2:7]2
Reactant: CN(C)CC#Cc1cc(Cl)c2c(c1)CN(Cc1ccc(Oc3ccccc3)cc1)C2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN(C)CCCc1cc(Cl)c2c(c1)CN(Cc1ccc(Oc3ccccc3)cc1)C2=O
Yield: 41.8 %

Procedure:
A mixture of 7-chloro-5-(3-dimethylamino-prop-1-ynyl)-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.047 g, 0.11 mmol) and 10% palladium-carbon (0.015 g) in ethanol (25 mL) was reduced under 45 p.s.i. hydrogen. Workup and silica gel column chromatography using 5:1 CHCl3-MeOH afforded 7-chloro-5-(3-dimethylamino-propyl)-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.020 g, 42%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.78 (m, 2H), 2.2 (m, 6H), 2.31 (t, 2H), 2.66 (t, 2H), 4.22 (s, 2H), 4.74 (s, 2H), 6.88-7.38 (m, 11H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17](O)=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N+:23]([O-:25])=[O:24])[C:13]([CH:20]4[CH2:22][CH2:21]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:26][NH2:27].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:27][CH3:26])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N+:23]([O-:25])=[O:24])[C:13]([CH:20]4[CH2:22][CH2:21]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=C(O)c1c2cc(C3CC3)c([N+](=O)[O-])cc2nn1-c1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CNC(=O)c1c2cc(C3CC3)c([N+](=O)[O-])cc2nn1-c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.7 %

Procedure:
To a stirred solution of compound (vii) (2.2 g, 5.5 mmol) in pyridine (45 mL) was added methyl amine (8.2 mL, 2 M solution in THF, 16 mmol). The reaction mixture was cooled to 0° C. and POCl3 (2.88 g, 19 mmol) was added dropwise at the same temperature. After 1 h TLC and LCMS showed the absence of SM and formation of product. The reaction mixture was quenched in ice water and the precipitate was filtered and crystallized from MeOH to give 2-(4-bromophenyl)-5-cyclopropyl-N-methyl-6-nitro-2H-indazole-3-carboxamide (viii) (1.25 g, 55%). ESI-MS m/z calculated for [M+H]+: 415.04/417.04; found: 415.15/417.15.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:38]([O:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)=[O:39]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:38]([O:40][CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]4)=[O:39])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: O=C(Cl)OC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OC3CCCCC3)cc1)n2C)c1ccccn1
Yield: 40 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-methoxycarbonylmethyl-amide-hydrochloride and cyclohexyl chloroformate. Yield: 40% of theory, C32H35N7O5 (597.7) Rf value: 0.26 (silica gel; dichloromethane/ethanol=19:1) ##EQU85##
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>CN(C)C=O>[C:17]([Si:14]([CH3:16])([CH3:15])[O:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([CH3:8])[CH:7]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1csc(CO)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc(CO[Si](C)(C)C(C)(C)C)c1
Yield: 74 %

Procedure:
To a solution of 2-hydroxymethyl-4-methylthiophene (1.8 g, 14 mmol) (reference literature: J. Heterocycl. Chem., vol. 19, 1125 (1982)) and imidazole (1.9 g, 28 mmol) in N,N-dimethylformamide (20 ml) was added t-butyldimethylsilyl chloride (2.3 g, 15 mmol) with stirring, and the resulting mixture was stirred at room temperature for 2 hours. After stirring, the reaction mixture was poured into water (20 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (0:10 to 1:19) as the eluent to afford the title compound (2.5 g) in a yield of 74% as a colourless oily product.
Reaction SMILES: C([O:3][C:4]1[C:7](=[O:8])[C:6](=[O:9])[C:5]=1[NH:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=2)=[O:20])[CH2:15][CH2:14]1)C.Cl>C1COCC1>[OH:9][C:6]1[C:7](=[O:8])[C:4](=[O:3])[C:5]=1[NH:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=2)=[O:20])[CH2:15][CH2:14]1
Reactant: CCOc1c(NCCC2CCN(C(=O)OCc3cc(Cl)cc(Cl)c3)CC2)c(=O)c1=O
Agent: Cl
Solvent: C1CCOC1
Product: O=C(OCc1cc(Cl)cc(Cl)c1)N1CCC(CCNc2c(O)c(=O)c2=O)CC1

Procedure:
A mixture comprising 3,5-dichlorobenzyl 4-(2-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)ethyl)piperidine-1-carboxylate (Example 3) (35 mg, 0.077 mmol) and 6M HCl (aq) (38.4 μl, 0.077 mmol) in THF (256 μl) was stirred overnight at room temperature. The reaction mixture was concentrated under pressure to give an aqueous suspension. The suspension was filtered, air dried and partitioned between EtOAc and water. The organic portion was separated, dried over MgSO4, filtered and concentrated under reduced pressure. Further purification was carried out using preparative LC-MS. The resulting product fractions were concentrated under reduced pressure to give an aqueous solution and then extracted with EtOAc. The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[S:10]1[CH2:14][C:13](=[O:15])[NH:12][C:11]1=[O:16].[C:17]([O-])(=[O:19])[CH3:18].[Na+].C(OC(=O)C)(=O)C>O.CC(N(C)C)=O>[C:17]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:14]2[S:10][C:11](=[O:16])[NH:12][C:13]2=[O:15])=[CH:4][CH:3]=1)(=[O:19])[CH3:18]
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C1CSC(=O)N1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Oc1ccc(C=C2SC(=O)NC2=O)cc1
Reaction time: 1 h
Yield: 90.5 %

Procedure:
A mixture comprising 200 g of p-hydroxybenzaldehyde, 229 g of thiazolidine-2,4-dione, 280 g of sodium acetate and 660 ml of dimethylacetamide was stirred at 150° for 1 hour. It was then cooled, and 540 ml of dimethylacetamide and 370 ml of acetic anhydride were added to the reaction mixture. The resulting mixture was then stirred at 50° C. for 1.5 hours, after which it was poured into water. The solid which precipitated was collected by filtration, washed with water, and dried in vacuo, to give 390 g of the title compound.
Reaction SMILES: N1C2=NC=CC=C2C=N1.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=1.ClC1N=CC=CC=1C(Cl)=O.NN.[C:31]1([NH:37][NH2:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl.C(N(CC)CC)C>[C:31]1([N:37]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10]([OH:17])=[N:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NNc1ccccc1
Reactant: O=C(Cl)c1cccnc1
Agent: NN
Agent: O=C(Cl)c1cccnc1Cl
Agent: c1cnc2[nH]ncc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Oc1nn(-c2ccccc2)c2ncccc12

Procedure:
Scheme 4 depicts the synthesis of the 1H-pyrazolo[3,4-b]pyridine q. A nicotinoylchloride k (e.g., 2-chloronicotinoyl chloride) is reacted with a hydrazine m (e.g., phenylhydrazine) and a base such as triethylamine in a solvent such as anhydrous methylene chloride to give o (e.g., 1-phenyl-1H-pyrazolo[3,4-b]pyridin-3-ol). The compound o is then cyclized by heating at 175° C. to provide p. p is reacted as in the transformation of d to g in Scheme 1 to provide q.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[F:18][C:19]1[CH:33]=[CH:32][C:22]([O:23][C:24]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=2)=[CH:21][CH:20]=1.[Na]>C(Cl)Cl>[F:18][C:19]1[CH:33]=[CH:32][C:22]([O:23][C:24]2[CH:31]=[CH:30][C:27]([CH2:28][NH:1][CH2:2][C:3]3[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=3)[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[CH:26][CH:25]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CN)c1
Reactant: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Agent: [Na]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1cccc(CNCc2ccc(Oc3ccc(F)cc3)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.2 %

Procedure:
A solution of tert-butyl 3-(aminomethyl)benzylcarbamate (0.70 g, 2.94 mmol) and 4-(4-fluorophenoxy)benzaldehyde (0.6 g, 2.78 mmol) in CH2Cl2 (15 mL) was stirred at rt under nitrogen for 40 min, and then treated with sodium triacetoxyhydroborate (1.24 g, 5.83 mmol). The resulting mixture was stirred at rt. for 3 h. The reaction mixture was concentrated and the residue was partitioned between saturated NaHCO3 solution and ethyl acetate. The organic layer (clear solution) was washed with brine, dried over MgSO4. The filtrate was concentrated and the residue was dissolved in CH2Cl2 and ethyl acetate. The solution was loaded into solid sample cartridge, vacuum dried. The sample was purified by silica gel flash chromatography. Elution with 0-30% of ethyl acetate in CH2Cl2 gave the desired product as viscous oil (0.73 g, 59%). 1H NMR (DMSO-d6): δ 7.33-7.28 (m, 2H), 7.24-7.19 (m, 5H), 7.13 (m, 1H), 7.08-7.02 (m, 2H), 6.95 (m, 2H), 4.12 (m, 2H), 3.76 (s, 4H), 1.39 (s, 9H); MS (ESI): (M+H)+=437.3.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:17])[C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[CH:11][C:10](Br)=[CH:9][CH:8]=3.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=3)=[CH:11][C:12]=2[S:13][C:14]2[C:5]1=[CH:4][CH:3]=[C:2]([C:20]1[CH:19]=[CH:18][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=1)[CH:15]=2
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: CN1c2ccc(Br)cc2Sc2cc(Br)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CN1c2ccc(-c3ccc4ccccc4c3)cc2Sc2cc(-c3ccc4ccccc4c3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
9.30 g (25.1 mmol) of 3,7-dibromo-10-methylphenothiazine, 9.50 g (55.2 mmol) of 2-naphthylboronic acid, 0.407 g (0.50 mmol) of bis(triphenylphosphine)palladium dichloride and 3.80 g (27.5 mmol) of potassium carbonate were heated to boiling under reflux under nitrogen for 5 hours in 204 ml of dimethoxyethane and 101 ml of water. The reaction mixture was cooled to room temperature, stirred further overnight and then filtered. The residue was washed with 470 ml of ethanol and hot water, and then dried at 70° C. under reduced pressure. The solid was dissolved in 200 ml of methylene chloride and filtered through silica gel. After the solvent had been removed under reduced pressure, 9.6 g of greenish-yellow solid were obtained (melting point 276-281° C.) and were recrystallized from 500 ml of toluene. 7.10 g (81% of theory) of analytically pure, shiny yellow microcrystals having a melting point of 285-289° C. were obtained, whose solution in chloroform fluoresced at λ=402 nm.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].Br[CH2:12][C:13]#[N:14]>>[NH2:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][CH2:7]1
Reactant: N#CCBr
Reactant: CC(C)CN1CCNCC1
Product: CC(C)CN1CCN(CCN)CC1
Yield: 32.2 %

Procedure:
By using 1-isobutylpiperazine (2.84 g) and bromoacetonitrile(2.40 g), as in the case of Reference Example 28, 1.19 g (15%) of 4-(2-aminoethyl)-1-isobutylpiperazine was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH2:27][CH2:28][CH3:29])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1.[CH:30]([S:33](Cl)(=[O:35])=[O:34])([CH3:32])[CH3:31].C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][S:33]([CH:30]([CH3:32])[CH3:31])(=[O:35])=[O:34])=[CH:13][CH:14]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH2:27][CH2:28][CH3:29])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(O)cc3)ccnc2n1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(OS(=O)(=O)C(C)C)cc3)ccnc2n1

Procedure:
The product from Example 6 (120 mg, 0.274 mmol) was reacted with isopropyl sulfonyl chloride (43 mg, 0.30 mmol), N,N-diisopropylethylamine (43 mg, 0.33 mmol), and catalytic DMAP in CH2Cl2 for 18 h giving the crude title compound which was purified by HPLC with TFA providing the product as the trifluoroacetic acid (40 mg, 23%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.75 (d, J=8.54 Hz, 1H) 8.20 (d, J=6.71 Hz, 1H) 7.58 (d, J=8.54 Hz, 1H) 7.26 (d, J=7.93 Hz, 1H) 7.17-7.21 (m, 2H) 7.08 (d, J=9.16 Hz, 2H) 6.95 (d, J=8.54 Hz, 2H) 6.15 (d, J=6.71 Hz, 1H) 3.43-3.51 (m, J=13.43, 1H) 2.79 (t, J=7.63, 7.63 Hz, 2H) 2.20 (s, 3H) 1.61-1.67 (m, 2H) 1.21 (d, J=6.71 Hz, 6H) 0.78 (t, J=7.32 Hz, 3H); MS (ESI+) m/z 508 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[N:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH3:26])[CH:20]=1>>[Br-:1].[C:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N+:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH3:26])[CH:20]=2)=[CH:8][CH:9]=1
Reactant: Cc1ccncc1C
Reactant: BrCCCCCc1ccc(-c2ccccc2)cc1
Product: Cc1cc[n+](CCCCCc2ccc(-c3ccccc3)cc2)cc1C
Product: [Br-]
Temperature: 65 °C
Yield: 87 %

Procedure:
A mixture of 4-(5-bromopentyl)-1,1′-biphenyl (322 mg, 1.06 mmol) and 3,4-lutidine (1 mL) was heated at 60-70° C. for 12 hrs. The resulted mixture was washed with diethyl ether and then dissolved in water (15 mL). The aqueous solution was extracted with diethyl ether (30 mL×3). Water was removed by lyophilization to afford 380 mg of the title compound. Yield: 87%. 1H NMR (300 MHz, CDCl3) δ 1.43 (m, 2H), 1.69 (m, 2H), 2.05 (m, 2H), 2.46 (s, 3H), 2.48 (s, 3H), 2.62 (t, J=7.5 Hz, 2H), 4.82 (t, J=7.2 Hz, 2H), 7.18-7.58 (m, 9H), 7.76 (d, J=6.3 Hz, 1H), 9.07 (d, J=6.3 Hz, 1H), 9.29 (s, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 17.1, 20.4, 25.6, 30.7, 31.7, 35.2, 60.7, 126.8, 126.9, 127.0, 128.4, 128.7, 128.8, 138.2, 138.5, 140.7, 141.1, 141.7, 143.3, 157.4 ppm.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][CH:19]3[CH2:20][CH2:21][O:16][CH2:17][CH2:18]3)=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCOCC1
Reactant: Nc1ccc(C#Cc2ccccc2)cn1
Product: C(#Cc1ccc(NC2CCOCC2)nc1)c1ccccc1

Procedure:
The title compound, MS: m/e=279.3 (M+H+), can be prepared in accordance with the general method of example 13, step 2 from 5-phenylethynyl-pyridin-2-ylamine (example 13, step 1) and tetrahydro-4H-pyran-4-one.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])[C:5]([Cl:22])=[CH:4][N:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[CH2:26][CH2:25]1>C(Cl)Cl.CO>[Cl:22][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])=[N:7][C:2]([NH:35][C:34]2[CH:33]=[CH:32][C:31]([CH2:30][N:27]3[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]3)=[CH:37][CH:36]=2)=[N:3][CH:4]=1
Reactant: O=C(c1ccccc1Nc1nc(Cl)ncc1Cl)N1CCCC1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(Cc2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)N4CCCC4)n3)cc2)CC1
Yield: 73 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)(pyrrolidin-1-yl)methanone and 4-((4-methylpiperazin-1-yl)methyl)aniline in 73% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 9.68 (s, 1H), 8.40 (d, 1H, J=8.2 Hz), 8.04 (s, 1H), 7.46 (d, 2H, J=8.2 Hz), 7.39-7.34 (m, 2H), 7.21 (d, 2H, J=8.2 Hz), 7.06 (t, 1H, J=7.5 Hz), 3.65 (t, 2H, J=7.0 Hz), 3.48 (t, 2H, J=6.3 Hz), 3.44 (s, 2H), 2.44 (bs, 8H), 2.26 (s, 3H), 1.95 (m, 2H), 1.83 (m, 2H); MS (ESI): 506.1 [M+H]+.