Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:22])[CH2:7][O:6][C:5]([NH2:8])=[N:4][C@@:3]1([C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([O:19]C)=[CH:12][C:11]=1[F:21])[CH3:9].B(Br)(Br)Br>ClCCl>[NH2:8][C:5]1[O:6][CH2:7][C:2]([F:1])([F:22])[C@:3]([C:10]2[C:11]([F:21])=[CH:12][C:13]([OH:19])=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=2)([CH3:9])[N:4]=1
Reactant: COc1cc(F)c([C@@]2(C)N=C(N)OCC2(F)F)cc1[N+](=O)[O-]
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C[C@]1(c2cc([N+](=O)[O-])c(O)cc2F)N=C(N)OCC1(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
A solution of (R)-5,5-difluoro-4-(2-fluoro-4-methoxy-5-nitro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A6.11) (558 mg, 1.75 mmol) in dichloromethane (16 ml) was cooled to 0° C. and treated with a solution of boron tribromide in dichloromethane (1M, 2.62 ml). After stirring at room temperature for 2 hours, the reaction mixture was diluted with dichloromethane, then extracted with water (3 ml). The organic layer was separated, dried over sodium sulphate and evaporated. The crude product was purified by flash chromatography on silica gel using a gradient of hexane/ethyl acetate=100:0 to 0:100 as the eluent. The 4-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-2-nitro-phenol (intermediate F2.1) (300 mg, 56% yield) was obtained as a brown solid. MS (ISP): m/z=457.3 [M+H]+.
Reaction SMILES: Cl.Cl.[C:3]([N:6]1[CH2:11][CH2:10][N:9]([NH2:12])[CH2:8][CH2:7]1)(=[O:5])[CH3:4].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>C(O)C.C(N(CC)CC)C>[C:3]([N:6]1[CH2:11][CH2:10][N:9]([N:12]=[CH:18][C:17]2[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)N1CCN(N)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)N1CCN(N=Cc2ccc(F)cc2)CC1
Temperature: 80 °C

Procedure:
To a solution of 1-acetyl-4-aminopiperazine dihydrochloride (300 mg) in ethanol (10 ml) and triethylamine (0.78 ml) was added p-fluorobenzaldehyde (0.164 ml), and the mixture was heated at 80° C. for 2 hours. After removal of the solvent in vacuo, the residue was triturated with ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate, and concentrated. The residue was crystallized from diisopropyl ether to give 1-acetyl-4-(4-fluorobenzylidene)aminopiperazine (0.15 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][C:19]3[C:24]([N:25]=2)=[CH:23][C:22]([C:26]([O:28]C)=[O:27])=[CH:21][N:20]=3)=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CCO>[CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][C:19]3[C:24]([N:25]=2)=[CH:23][C:22]([C:26]([OH:28])=[O:27])=[CH:21][N:20]=3)=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cnc2sc(Nc3ncc(Br)cc3OCc3ccccc3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnc2sc(Nc3ncc(Br)cc3OCc3ccccc3)nc2c1
Reaction time: 8 h
Yield: 102.9 %

Procedure:
A 10 mL round-bottomed flask was charged with methyl 2-(3-(benzyloxy)-5-bromopyridin-2-ylamino)thiazolo[5,4-b]pyridine-6-carboxylate (80 mg, 0.17 mmol) and EtOH (3 mL). Sodium hydroxide (0.51 ml, 0.51 mmol) was added and stirred overnight. The methanol was removed and the residue was partitioned between methylene chloride and 0.5 N HCl. Solid K2CO3 was added to adjust to pH 5 and additional methanol was added. The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo to afford the title compound (80 mg, 103% yield) as an off-white solid. 1H NMR (DMSO-d6) δ 11.0 (bs, 1H), 8.85 (d, 1H), 8.26 (d, 1H), 8.10 (d, 1H), 7.75 (d, 1H), 7.61 (d, 2H), 7.42 (t, 2H), 7.36 (m, 1H), 5.33 (s, 2H). Mass spectrum (apci) m/z=457.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](I)[C:5]([Cl:9])=[CH:4][C:3]=1[OH:10].[CH:11]1([Mg]Br)[CH2:13][CH2:12]1>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[CH:7]=[C:6]([CH:11]2[CH2:13][CH2:12]2)[C:5]([Cl:9])=[CH:4][C:3]=1[OH:10]
Reactant: Nc1cc(I)c(Cl)cc1O
Reactant: Br[Mg]C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: Nc1cc(C2CC2)c(Cl)cc1O
Temperature: 25 °C
Yield: 63.1 %

Procedure:
To a mixture of 2-amino-5-chloro-4-iodophenol (500 mg, 1.9 mmol), PdCl2(dppf) (136 mg, 0.19 mmol) in THF (10 mL) under argon at RT, cyclopropylmagnesium bromide (16 mL, 11.4 mmol, 0.7 M in THF) was added and the mixture was stirred at reflux for 15 h. The mixture was allowed to cool to RT, and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (10-20% ethyl acetate/hexanes) to afford the desired product (220 mg, 63% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ: 9.27 (s, 1H), 6.62 (s, 1H), 6.22 (s, 1H), 4.53 (s, 2H), 1.89-1.93 (m, 1H), 0.83-0.87 (m, 2H), 0.46-0.49 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13](O)=[O:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CO>C1COCC1>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][CH2:12][CH2:13][OH:14])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(CCC(=O)O)cc(OC)c1
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(CCCO)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(3,5-dimethoxyphenyl)propanoic acid (2.00 g, 9.51 mmol) in THF (2.0 mL) was added dropwise to a stirred solution of borane-tetrahydrofuran complex (20.93 mL, 20.93 mmol) so as to maintain reaction temperature below 35° C. The mixture was allowed to stir overnight at room temperature. Methanol was added dropwise to the stirred mixture until visible reaction had ceased. An additional 20 mL of methanol was added and the reaction was stirred for 4 hours. The crude mixture was concentrated, filtered and purified by silica gel chromatography (1:1 heptane:EtOAc as eluant). Fractions containing product were combined and concentrated to give 3-(3,5-dimethoxy-phenyl)-propan-1-ol as an oil.
Reaction SMILES: [NH:1]([CH3:18])[C@H:2]([C:15]([NH2:17])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.[NH:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:20]([C:24]([OH:26])=O)[CH:21]([CH3:23])[CH3:22].C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>CN(C=O)C.C(OCC)(=O)C>[NH:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:20]([C:24]([N:1]([CH3:18])[C@H:2]([C:15]([NH2:17])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:12])([CH3:13])[CH3:14])[CH:5]=1)=[O:26])[CH:21]([CH3:22])[CH3:23]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 120 mg (0.480 mmol) of N-Me-Tyr(3-tBu)-NH2,156 mg (0.718 mmol) of Boc-Val-OH and 110 mg (0.718 mmol) of HOBT in 2 ml of DMF, 0.111 ml (0.718 mmol) of DIC was added under cooling with ice and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed first with saturated aqueous NaHCO3, then with water, and finally with saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n-hexane=2:1) to give Boc-Val-N-Me-Tyr(3-tBu)-NH2 in the amount of 147 mg (68%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[CH3:19][CH:20]([S:23](Cl)(=[O:25])=[O:24])[CH2:21][CH3:22]>>[CH3:19][CH:20]([S:23]([NH:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:25])=[O:24])[CH2:21][CH3:22]
Reactant: CCC(C)S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCOc1cccc(N)c1
Product: CCC(C)S(=O)(=O)Nc1cccc(OCCNC(=O)OC(C)(C)C)c1

Procedure:
Sulfonation of tert-butyl 2-(3-aminophenoxy)ethylcarbamate (3) using butane-2-sulfonyl chloride following the method described in Example 1 gave tert-butyl 2-(3-(1-methylpropylsulfonamido)phenoxy)ethylcarbamate (6) as a light yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 7.17 (t, J=8.0 Hz, 1H), 6.97 (t, J=6.0 Hz, 1H), 6.76-6.78 (m, 2H), 6.59-6.62 (m, 1H), 3.87 (t, J=5.6 Hz, 2H), 3.24 (q, J=6.4 Hz, 2H), 2.93-3.02 (m, 1H), 1.80-1.91 (m, 1H), 1.40-1.48 (m, 1H), 1.35 (s, 9H), 1.19 (d, J=6.8 Hz, 3H), 0.88 (t, J=7.2 Hz, 3H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:17]([N:20]2[CH2:25][CH2:24][CH:23]([O:26][CH3:27])[CH2:22][CH2:21]2)(=[O:19])=[O:18])=[CH:5][C:6]=1[C:7]1[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=1[CH3:16].C([Li])CCC>C1COCC1>[CH3:27][O:26][CH:23]1[CH2:22][CH2:21][N:20]([S:17]([C:4]2[S:3][CH:2]=[C:6]([C:7]3[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=3[CH3:16])[CH:5]=2)(=[O:18])=[O:19])[CH2:25][CH2:24]1
Reactant: COC1CCN(S(=O)(=O)c2cc(-c3sc(NC(C)=O)nc3C)c(Br)s2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC1CCN(S(=O)(=O)c2cc(-c3sc(NC(C)=O)nc3C)cs2)CC1
Temperature: -70 °C
Reaction time: 0.67 h

Procedure:
N-{5-[2-Bromo-5-(4-methoxy-piperidine-1-sulfonyl)-thiophen-3yl]-4-methyl-thiazol-2-yl}-acetamide obtained in Step I as described above (250 mg; 0.51 mmol; 1 eq), is dissolved in anhydrous THF (20 ml). The reaction mixture is cooled down to −70° C. and put under nitrogen. n-Butyllithium (2 ml; 1.6 M; 4.04 mmol; 8 eq) is added dropwise. The reaction is stirred 40 minutes and quenched with water. Solvents are evaporated and the resulting crude product is purified by preparative HPLC, affording Compound (34) as a white-off powder (127 mg; 47%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1>[Br:1][C:2]1[S:6][C:5]([CH2:7][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: O=Cc1ccc(Br)s1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: Brc1ccc(CN2CCCCC2)s1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
5-Bromo-2-thiophenecarboxaldehyde (10 mmol) and piperidine (10 mmol) were mixed in THF (10 mL) and dibutyltin dichloride (0.2 mmol) was added. After stirring at RT for 5 minutes, phenylsilane (11 mmol) was added and the reaction allowed to stir at room temperature for a further 17 h. The reaction was then concentrated in vacuo and the residue purified by flash chromatography (silica gel, DCM) to give 1-(5-bromo-thiophen-2-ylmethyl)-piperidine: m/z=260, 262 in MS ES+ as a golden oil which was used directly in the subsequent step. A reaction tube containing a magnetic stirrer bar was charged with 4-carboxyphenylboronic acid (0.05 mmol), the thiophene bromide (0.05 mmol), Pd(PPh3)4 (0.025 mmol), acetonitrile (2 mL) and 1M Na2CO3 (aq) (2 mL). The reaction tube was then sealed and heated by microwave irradiation (100 W, 4 mins) to 150° C. and held at that temperature for 10 mins. After being allowed to cool to room temperature the reaction were acidified to pH 1 with 1M HCl and the resulting precipitate filtered off. This crude product was then passed through a silica plug to remove any inorganic species and concentrated to give a the title compound as a brown powder m/z=304 in MS ES+, which was characterised by hplc and MS and used in the next step without any further purification.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=O)C(F)(F)F)[CH2:16][CH2:15]2)[CH:10]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH2:9]1)=[O:7].C=O>C(Cl)(Cl)Cl>[F:39][C:36]([F:37])([F:38])[C:34]1[CH:33]=[C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[CH:10]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)[CH2:9]2)=[O:7])[CH:4]=[C:3]([C:2]([F:40])([F:1])[F:41])[CH:35]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(N2CCN(C(=O)C(F)(F)F)CC2)C(c2ccc(Cl)cc2)C1
Agent: C=O
Solvent: ClC(Cl)Cl
Product: CN1CCN(C2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2c2ccc(Cl)cc2)CC1

Procedure:
The title compound, MS: m/e=534.3 (M+H+), [α]58920=−53.04, [α]54620=−65.78, [α]43620=−135.72, [α]36520=−277.94 (c=0.3846, chloroform), was prepared in accordance with the general methods of example 102 (part1) and example 125 from (−)-(1-{4-[1-(3,5-bis-trifluoromethyl-benzoyl)-3-(4-chloro-phenyl)-piperidin-4-yl]-piperazin-1-yl}-2,2,2-trifluoro-ethanone and formaldehyde.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[F:29][C:30]1[CH:35]=[CH:34][C:33]([O:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[CH:32][CH:31]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: Oc1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3ccc(F)cc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.6 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 4-fluorophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (4.20 mg, 64.7% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.40 (m, 2H), 7.30-7.20 (m, 5H), 7.20 (m, 3H), 6.97 (apparent d, 1H, J=7.7 Hz), 6.87 (m, 1H), 6.76 (m, 1H), 5.26 (apparent dd, 1H, J=4.0, 8.1 Hz), 3.09 (m, 2H), 2.66 (m, 2H), 2.51 (m, 2H), 2.3-2.1 (m, 6H), 1.82 (m, 2H), 1.25 (d, 6H, overlapped); ESMS m/e: 475.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1>[O-2].[O-2].[Mn+4].ClCCl>[NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Nc1ncccc1C=O
Reaction time: 8 h
Yield: 83 %

Procedure:
To a mixture of (2-aminopyridin-3-yl)-methanol described in Preparation Example J-3 (130 mg, 1.1 mmol) and dichloromethane (10 mL) was added manganese dioxide (1.3 g, 15 mmol) at room temperature, and the solution was stirred overnight. The reaction solution was filtered through Celite pad, then, the solvent was evaporated in vacuo, and the title compound (108 mg, 0.88 mmol, 83%) was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:20]=[CH:19][C:12]([CH:13]=[C:14]([C:17]#[N:18])[C:15]#[N:16])=[CH:11][CH:10]=2)[CH2:4][O:3]1.[C:22]([CH2:24][C:25]([NH2:27])=[S:26])#[N:23].CN1CCOCC1>C(O)C>[NH2:18][C:17]1[C:14]([C:15]#[N:16])=[C:13]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH:5]3[CH2:4][O:3][C:2]([CH3:21])([CH3:1])[O:6]3)=[CH:20][CH:19]=2)[C:24]([C:22]#[N:23])=[C:25]([SH:26])[N:27]=1
Reactant: CC1(C)OCC(COc2ccc(C=C(C#N)C#N)cc2)O1
Reactant: N#CCC(N)=S
Solvent: CCO
Solvent: CN1CCOCC1
Product: CC1(C)OCC(COc2ccc(-c3c(C#N)c(N)nc(S)c3C#N)cc2)O1

Procedure:
0.43 g (1.51 mmol) of the compound from Example 2A, 0.38 g (3.78 mmol) of cyanothioacetamide and 0.38 g (3.78 mmol) of 4-methylmorpholine are dissolved in 15 ml of ethanol, and the mixture is stirred under reflux for 6 h. After cooling, the reaction solution is concentrated using a rotary evaporator, and the residue is chromatographed on silica gel 60. After removal of by-products (mobile phase gradient cyclohexane→cyclohexane/ethyl acetate 1:1), the product fractions are eluted (mobile phase gradient ethyl acetate→ethyl acetate/methanol 20:1). This is followed by fine purification via preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [C:1]1([CH:7]([CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1([CH:27]([N:34]=[C:35]=[O:36])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH:27]([NH:34][C:35]([N:11]1[CH2:10][CH2:9][N:8]([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)=[O:36])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN1CCC(C(c2ccccc2)N2CCNCC2)CC1
Reactant: O=C=NC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CN1CCC(C(c2ccccc2)N2CCN(C(=O)NC(c3ccccc3)c3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a solution of 1-((phenyl)(1-methylpiperidin-4-yl)methyl)piperazine 0.1 g (0.36 mmol) dissolved in methylene chloride (20 ml) was added diphenylmethyl isocyanate 0.075 g (0.36 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated. The residue was applied to flash column chromatography using methylene chloride and methanol (100:10) as eluents to give 0.15 g of desired product.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][O:9][C:4]2=[CH:3][CH:2]=1.C([Li:14])CCC>>[O:9]1[C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=2[CH:7]=[C:8]1[Li:14]
Reactant: [Li]CCCC
Reactant: c1ccc2occc2c1
Product: [Li]c1cc2ccccc2o1

Procedure:
To a solution of 2,3-benzofuran (2.0 ml, 18.15 mmol, in 50 ml of anhydrous ether) was added 1.6M n-butyllithium in hexanes (12.5 ml, 20 mmol). To the 2-benzofuranyl lithium formed by stirring the solution at room temp. for 1 hour was added (ice bath) the compound 5(b) (1.62 g, 7.22 mmol) dissolved in anhydrous tetrahydrofuran (70 ml). The reaction was continued at ice-bath temperature for 3 hours then worked-up as described to afford 0.89 g (44%) of product as off-white solids. This material was converted to the dihydrochloride by addition of 1M hydrochloric acid in ether (8 ml) as described. The dihydrochloride obtained was recrystallized from methanol-ether and dried under vacuum at 60° C. overnight to afford the ketone dihydrochloride as off-white crystals (0.82 g). m.p.: 193°-195° C.
Reaction SMILES: [NH2:1][C:2]1[N:20]=[C:5]2[C:6]([O:10][CH2:11][C:12]3[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=3[C:14]#[N:15])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.Br[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:34][N:31]1[CH2:32][CH2:33][N:28]([C:24]2[CH:25]=[C:26]([NH:1][C:2]3[N:20]=[C:5]4[C:6]([O:10][CH2:11][C:12]5[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=5[C:14]#[N:15])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)[CH:27]=[CH:22][CH:23]=2)[CH2:29][CH2:30]1
Reactant: N#Cc1ccccc1COc1cccn2nc(N)nc12
Reactant: CN1CCN(c2cccc(Br)c2)CC1
Product: CN1CCN(c2cccc(Nc3nc4c(OCc5ccccc5C#N)cccn4n3)c2)CC1

Procedure:
2-{2-[3-(4-Methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yloxymethyl}benzonitrile was prepared from 2-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yloxymethyl)-benzonitrile (115.0 mg, 0.434 mmol) and 1-(3-bromo-phenyl)-4-methyl-piperazine (128 mg, 0.500 mmol in a manner analogous to Example 2d. Product was isolated as a pale orange solid (0.111 g, 58%). MP=68-70° C. (foam). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.46 (s, 1H), 8.43 (d, J=6.4 Hz, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.81-7.79 (m, 2H), 7.64-7.62 (m, 1H), 7.33 (s, 1H), 7.20 (d, J=7.2 Hz, 1H), 7.09 (d, J=4.8 Hz, 2H), 6.96-6.92 (m, 1H), 6.47-6.44 (m, 1H), 5.50 (s, 2H), 3.12-3.09 (m, 4H), 2.44-2.42 (m, 4H), 2.22 (s, 3H). MS=440 (MH)+.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH2:6][C:7]1[C:8]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[N:9][O:10][C:11]=1[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl.O>[C:13]([C:8]1[C:7]([NH:6][C:3](=[O:4])[CH2:2][Br:1])=[C:11]([CH3:12])[O:10][N:9]=1)(=[O:14])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Br)CBr
Reactant: Cc1onc(C(=O)c2ccccc2)c1N
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1onc(C(=O)c2ccccc2)c1NC(=O)CBr
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Bromoacetylbromide (40 g, 0.2 mole) was added slowly to a mixture of 20 g (0.1 mole)(4-amino-5-methylisoxazol-3-yl)-phenylmethanone of Example Ib in 500 ml dichloromethane with 200 ml of 2N sodium carbonate and 500 ml saturated sodium bicarbonate at 5° C. After stirring for 30 minutes the mixture was diluted with 400 ml dichloromethane and 400 ml water. The organics were washed with water and brine and dried (magnesium sulfate). Concentration gave 32 g of an oil which was chromatographed on high pressure liquid chromatograph (HPLC) using dichloromethane as an eluent to yield 23 g (71%) of a solid, melting point 89°-92° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([N:15]=[C:16]([NH:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1.Br[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([N:15]=[C:16]([NH:18][CH:19]3[CH2:24][CH2:23][N:22]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=4)[CH2:21][CH2:20]3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Fc1ccc(-c2cccn3nc(NC4CCNCC4)nc23)c(Cl)c1
Reactant: Cc1cc(Br)ccn1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N2CCC(Nc3nc4c(-c5ccc(F)cc5Cl)cccn4n3)CC2)ccn1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
A mixture of 8-(2-chloro-4-fluorophenyl)-N-(piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (69 mg, 2 mmol), 4-bromo-2-methylpyridine (34 mg, 0.2 mmol) and N,N-diisopropylethylamine (40 mg, 0.3 mmol) in 1,4-dioxane (0.8 mL) was stirred for 30 minutes at 150° C. in the microwave. Purification by chromatography of the reaction mixture (SiO2, heptane:ethyl acetate 1:1 to ethyl acetate:methanol:ammoniumhydroxide 80:18:2 afforded the title compound as yellow semisolid (21 mg, 24%).
Reaction SMILES: O=C1NC(C(NCC2C=CN=C(OCCCC3N=CNN=3)C=2)=O)=NC2SC=C(COCC3C=CC(C(OCC)=O)=CC=3)C1=2.[O:44]=[C:45]1[NH:50][C:49]([C:51](=[O:69])[NH:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([O:60][CH2:61][CH2:62][O:63][C:64]3[N:68]=[CH:67][NH:66][N:65]=3)[CH:55]=2)=[N:48][C:47]2[S:70][CH:71]=[C:72]([C:73]3[CH:74]=[C:75]([CH:81]=[CH:82][CH:83]=3)[C:76]([O:78]CC)=[O:77])[C:46]1=2>>[O:44]=[C:45]1[NH:50][C:49]([C:51](=[O:69])[NH:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([O:60][CH2:61][CH2:62][O:63][C:64]3[N:68]=[CH:67][NH:66][N:65]=3)[CH:55]=2)=[N:48][C:47]2[S:70][CH:71]=[C:72]([C:73]3[CH:74]=[C:75]([CH:81]=[CH:82][CH:83]=3)[C:76]([OH:78])=[O:77])[C:46]1=2
Reactant: CCOC(=O)c1cccc(-c2csc3nc(C(=O)NCc4cccc(OCCOc5nc[nH]n5)c4)[nH]c(=O)c23)c1
Agent: CCOC(=O)c1ccc(COCc2csc3nc(C(=O)NCc4ccnc(OCCCc5nc[nH]n5)c4)[nH]c(=O)c23)cc1
Product: O=C(O)c1cccc(-c2csc3nc(C(=O)NCc4cccc(OCCOc5nc[nH]n5)c4)[nH]c(=O)c23)c1

Procedure:
By a method similar to that in Example 42 and using, instead of ethyl 4-[({[4-oxo-2-({[(2-{[3-(1H-1,2,4-triazol-3-yl)propyl]oxy}pyridin-4-yl)methyl]amino}carbonyl)-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl]methyl}oxy)methyl]benzoate, ethyl 3-[4-oxo-2-({3-[2-(1H-1,2,4-triazol-3-yloxy)ethoxy]benzyl}carbamoyl)-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl]benzoate obtained in Example 69, the title compound was obtained as a white powder (80.0 mg, 73%).