Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:15].[H-].[Na+].[I-].[K+].Br[CH2:21][CH:22]([O:25][CH3:26])[O:23][CH3:24]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[N:7]([CH2:21][CH:22]([O:25][CH3:26])[O:23][CH3:24])[CH:6]=[C:5]2[CH3:15]
Reactant: COC(=O)c1cc(Cl)cc2c(C)c[nH]c12
Reactant: COC(CBr)OC
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)cc2c(C)cn(CC(OC)OC)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.7 %

Procedure:
To a stirred solution of methyl 5-chloro-3-methyl-1H-indole-7-carboxylate (1.4 g, 4.5 mmol) from Step B above in DMF (10 ml) was added sodium hydride (313 mg, 7.8 mmol) in portions. The mixture was stirred at room temperature for 1 h, then potassium iodide (60 mg, 0.4 mmol) and 2-bromo-1,1-dimethoxyethane (2.1 ml, 17.9 mmol) were added. The mixture was heated to 80° C. for 15 h. After cooling to room temperature, the reaction was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate (3×), washed with brine, filtered, and dried over sodium sulfate. The filtrate was concentrated under reduced pressure and the residue purified by column chromatography (silica gel, 70:30 hexanes/ethyl acetate) to afford methyl 5-chloro-1-(2,2-dimethoxyethyl)-3-methyl-1H-indole-7-carboxylate (908 mg, 68%) as a semitransparent liquid: 1H NMR (500 MHz, CDCl3) δ 7.64 (d, J=1.0 Hz, 1H), 7.61 (d, J=1.0 Hz, 1H), 6.94 (s, 1H), 4.62 (t, J=5.0 Hz, 1H), 4.39 (d, J=5.0 Hz, 1H), 3.96 (s, 3H), 3.30 (s, 6H), 2.27 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][CH2:5][CH2:6][CH2:7][OH:8].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[N:17]1[C:22]2[N:23]=[C:24](S(C)(=O)=O)[N:25]=[C:26]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=3[CH3:34])[C:21]=2[CH:20]=[CH:19][C:18]1=[O:39]>>[F:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[C:11]=1[N:17]1[C:22]2[N:23]=[C:24]([O:8][CH2:7][CH2:6][CH2:5][S:4][CH3:3])[N:25]=[C:26]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=3[CH3:34])[C:21]=2[CH:20]=[CH:19][C:18]1=[O:39]
Reactant: CSCCCO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Product: CSCCCOc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reaction time: 0.08 h

Procedure:
NaH (12 mg, 0.5 mmol) was added to 3-(methylthio)-1-propanol (0.5 mL) and the mixture was stirred under Ar at 23°. After 5 min, gas evolution ceased, and the product of Example 48 (223 mg, 0.5 mmol) was added in a single portion. The mixture was stirred for 30 minutes. Most of the excess 3-(methylthio)-1-propanol was removed in vacuo, and the residue partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography eluted with 10-30% EtOAc/hexane, followed by recrystallization from CH2Cl2/hexane gave the title compound as a white crystalline solid. mp 127-128°, LC MS m/z=472 (MH+) Retention time=2.47 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[Cl:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S([O-])(=O)=O.[F:26][C:27]([F:49])([F:48])[CH2:28][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:17][C:10]1[CH:11]=[C:12]([CH:13]=[CH:28][C:27]([F:49])([F:48])[F:26])[CH:15]=[CH:16][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(Cl)c1
Reactant: FC(F)(F)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)C=Cc1ccc(OCc2ccccc2)c(Cl)c1

Procedure:
A solution of 4-benzyloxy-3-chlorobenzaldehyde (0.25 g, 2.0 mmol), 2,2,2-trifluoroethyltriphenylphosphonium trifluoromethanesulfonate (0.49 g, 1.0 mmol) and CsF (0.76 g, 5.0 mmol) in DMF (10 mL) was stirred at 25° C. for 16 h. The reaction was then diluted with ethyl acetate, washed with water and dried. Removal of the solvent gave a residue which was purified by preparative TLC to give 1-(3-chloro-4-benzyloxyphenyl)-3,3,3-trifluoropropene. This product (65 mg, 0.2 mmol) was dissolved in ethyl acetate (2 mL) and hydrogenated (1 atm) in the presence of 10% palladium on carbon for 1 hr. Removal of the catalyst and solvent give 2-chloro-4 (3,3,3-trifluoropropyl)phenol as an oil.
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([CH2:11][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[N:8][C:7]=2[CH:31]=1.C([Li])CCC.[CH:37]([C:39]1[CH:40]=[C:41]([CH:46]=[CH:47][CH:48]=1)[C:42]([O:44][CH3:45])=[O:43])=O>CCCCCC.O1CCCC1>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9](/[CH:11]=[CH:37]/[C:39]3[CH:40]=[C:41]([CH:46]=[CH:47][CH:48]=3)[C:42]([O:44][CH3:45])=[O:43])=[N:8][C:7]=2[CH:31]=1
Reactant: Fc1ccc2sc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc2c1
Reactant: COC(=O)c1cccc(C=O)c1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)c1cccc(/C=C/c2nc3cc(F)ccc3s2)c1
Yield: 76.5 %

Procedure:
Using the procedure of Preparation El and starting with 5.65 g of 5-fluorobenzothiazol-2-ylmethyl triphenyl phosphonium chloride (prepared by reacting 4.0 g of 2-chloromethyl-5-fluorobenzothiazole and 5.22 g of triphenylphosphine in 50 ml of toluene at reflux temperature for 17 hours), 7.61 ml of 1.6M n-butyl lithium solution in hexane and 2.0 g of methyl 3-formylbenzoate in 80 ml of dry tetrahydrofuran there was obtained 2.92 g of the titled product, m.p. 172°-173° C.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]([C:35]([N:37]2[C:45]3[C:40](=[CH:41][C:42]([F:46])=[CH:43][CH:44]=3)[CH:39]=[CH:38]2)=[O:36])[CH:30]=1>CN(C=O)C>[F:46][C:42]1[CH:41]=[C:40]2[C:45](=[CH:44][CH:43]=1)[N:37]([C:35]([C:31]1[N:32]=[CH:33][N:34]=[C:29]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:30]=1)=[O:36])[CH:38]=[CH:39]2
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: O=C(c1cc(Cl)ncn1)n1ccc2cc(F)ccc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)n1ccc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
75.0 mg (0.26 mmol) 1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one dihydrochloride and 150 μL (0.87 mmol) DIPEA were added to 70 mg (0.25 mmol) (6-chloropyrimidin-4-yl)-(5-fluoroindol-1-yl)-methanone in 5 mL DMF. The reaction mixture was stirred overnight at RT and then evaporated down i. vac. The residue was taken up in 20 mL water and stirred for 10 min. The precipitate was suction filtered, dissolved in 2.5 mL DMF and purified by preparative HPLC. The product fractions were combined and concentrated by rotary evaporation using the rotary evaporator.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[NH:10][CH2:11][C@H:12]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][C:28]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:29]=1[CH:30]=O.C([BH3-])#N.[Na+].C(N(CC)CC)C.C(OC(OC(OCC1C=CC=CC=1)=O)=O)C1C=CC=CC=1>CO.[Pd]>[C:22]([O:21][C:19](=[O:20])[NH:18][C@@H:12]([CH2:11][N:10]([C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:26])[CH2:30][C:29]1[CH:32]=[CH:33][C:34]([CH3:36])=[CH:35][C:28]=1[CH3:27])[C@@H:13]([OH:17])[CH2:14][CH2:15][CH3:16])([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1ccc(C=O)c(C)c1
Reactant: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C(OCc1ccccc1)OC(=O)OCc1ccccc1
Agent: [BH3-]C#N
Solvent: CO
Solvent: CCN(CC)CC
Product: CCC[C@H](O)[C@H](CN(Cc1ccc(C)cc1C)C(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of {(2S,3S)-(2-tert-butoxycarbonylamino-3-hydroxy-hex-4-ynyl)-carbamic acid benzyl ester (1.7 g, 4.8 mmol, prepared as described in WO PCT 0250019) in MeOH (72 mL) was charged with 5% Pd/C, Degussa style (350 mg), stirred under H2 (1 atm) for 12 h at RT, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (47 mL). The resultant solution was charged sequentially with 2,4-dimethylbenzaldehyde (0.66 mL, 4.7 mmol) and sodium cyanoborohydride (360 mg, 5.7 mmol), stirred for 12 h at RT, quenched with sat. NaHCO3, and extracted twice with EtOAc. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was dissolved in THF (66 mL). The resultant solution was charged sequentially with triethylamine (1.2 mL, 9.0 mmol) and dibenzyldicarbonate (1.5 g, 5.4 mmol), stirred for 36 h at RT, quenched with sat. NH4Cl, and extracted twice with EtOAc. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford (1S,2S)-(1-([benzyloxycarbonyl-(2,4-dimethyl-benzyl)-amino]-methyl}-2-hydroxy-pentyl)-carbamic acid tert-butyl ester as a clear and colorless oil (2.0 g, 86% yield). MS found: (M+Na)+=507.4.
Reaction SMILES: [Br:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([OH:23])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[H-].[Na+]>CN(C=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([O:23][C:4]2[CH:3]=[C:2]([Br:1])[C:9]([CH3:10])=[CH:8][C:5]=2[C:6]#[N:7])[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: Cc1cc(C#N)c(F)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C#N)c(OC2CN(C(=O)OC(C)(C)C)C2)cc1Br
Yield: 75.3 %

Procedure:
Prepared according to Example 28 using 4-bromo-2-fluoro-5-methyl-benzonitrile (1.0 g, 4.7 mmol), 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (1.1 g, 6.5 mmol), DMF (20 mL) and NaH (60% in mineral oil, 156 mg, 6.5 mmol) to provide the title compound (1.3 g, 74%). MS (ESI): mass calcd. for C16H19BrN2O3, 366.1. m/z found, 389.1 [M+Na]+. 1H NMR (CDCl3): 7.45 (s, 1H), 6.83 (s, 1H), 4.97-4.88 (m, 1H), 4.35 (ddd, J=9.8, 6.4, 0.9 Hz, 1H), 4.09 (dd, J=10.0, 3.9 Hz, 1H), 2.36 (s, 3H), 1.47 (s, 9H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[CH:11]=[C:12]([CH:26]=[CH:27][CH:28]=3)[CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:17][CH:16]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O1CCC[CH2:30]1>C(OCC)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[CH:11]=[C:12]([CH:26]=[CH:27][CH:28]=3)[CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH3:30])=[O:24])=[CH:17][CH:16]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C1CCOC1
Reactant: O=C(O)CCc1ccc(OCc2cccc(-c3ccc4[nH]ccc4c3)c2)cc1
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc(OCc2cccc(-c3ccc4[nH]ccc4c3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
To a solution of 3-(4-{[3-(1H-indol-5-yl)benzyl]oxy}phenyl)propanoic acid (1.0 g, 2.69 mmol) in tetrahydrofuran (30 mL) was added a 2 mol/L trimethylsilyldiazomethane diethyl ether solution (1.5 mL, 3.0 mmol), and the mixture was stirred at room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, and the mixture washed successively with aqueous citric acid solution, water and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:5-1:3-1:2) to give the title compound (0.90 g, yield 86%) as a pale-yellow oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:13]=1[F:19])O.S(Cl)([Cl:22])=O>C(#N)C>[Br:18][C:16]1[CH:15]=[CH:14][C:13]([F:19])=[C:12]([CH:10]([Cl:22])[C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[CH:17]=1
Reactant: OC(c1cc2ccccc2s1)c1cc(Br)ccc1F
Reactant: O=S(Cl)Cl
Solvent: CC#N
Product: Fc1ccc(Br)cc1C(Cl)c1cc2ccccc2s1
Temperature: 15 °C
Reaction time: 3.5 h
Yield: 99.6 %

Procedure:
Into an acetonitrile (10 ml) solution of 1-benzothien-2-yl(5-bromo-2-fluorophenyl)methanol (1.0 g) was dropwise added thionyl chloride (706 mg) at a temperature of 5° C. or lower, followed by stirring at 5.0 to 25.0° C. for 3.5 hours. The reaction mixture was subjected to distillation under reduced pressure to distill off the solvent and the residue was subjected to vacuum drying to obtain 2-[(5-bromo-2-fluorophenyl)(chloro)methyl]-1-benzothiophene [1.05 g, yield: 100%, purity: 99% (HPLC)].
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.CC(C)([O-])C.[Na+].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16]1.C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.[C].[Pd]>[N:6]1[CH:7]=[CH:8][C:3]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)=[CH:4][CH:5]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Clc1ccncc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)ccn2-c1ccncc1
Temperature: 25 °C

Procedure:
In 600 mL of toluene were dissolved 30.0 g (0.20 mol) of 4-chloropyridine hydrochloride, 53.8 g (0.56 mol) of sodium t-butoxide, 19.6 g (0.01 mol) of 10 w/w % palladium-carbon (Pd—C) (containing 54 w/w % water), 23.4 g (0.20 mol) of indole, and 5.39 g (0.01 mol) of DPEphos. The resultant mixture was stirred for 10 hours with refluxing. After completion of the reaction, the reaction mixture was cooled to room temperature and the palladium-carbon was filtered off. This liquid reaction mixture was concentrated. 300 mL of ethyl acetate and 300 mL of 1-M hydrochloric acid were added to the residue to extract the target compound with the aqueous layer. Subsequently, 300 mL of ethyl acetate and 200 mL of 2-M aqueous sodium hydroxide solution were added to the aqueous layer to extract the target compound with the organic layer this time. This organic layer was washed with 200 mL of water and then dried with magnesium sulfate. The organic layer was filtered and concentrated to obtain 33.3 g (yield, 86%) of the target compound as an oily substance. The purity thereof was 99.8%.
Reaction SMILES: CS([C:5]1[N:6]=[C:7]([O:21][CH2:22][CH2:23][CH3:24])[C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)[O:11][C:9]=2[N:10]=1)(=O)=O.Cl.[NH2:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(N(CC)CC)C>CN(C=O)C>[CH2:22]([O:21][C:7]1[C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)[O:11][C:9]=2[N:10]=[C:5]([NH:26][CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:6]=1)[CH2:23][CH3:24]
Reactant: CCCOc1nc(S(C)(=O)=O)nc2oc(-c3cccc(C)c3)nc12
Reactant: NC1CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCOc1nc(NC2CCOCC2)nc2oc(-c3cccc(C)c3)nc12
Yield: 20.7 %

Procedure:
A mixture of 100 mg of 5-methanesulfonyl-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine, 40 mg of 4-aminotetrahydropyran hydrochloride and 39 μl of triethylamine in 3 ml of DMF was heated for 8 h to 50° C. After filtration, the solvent was distilled off in vacuo, and the product was isolated via preparative HPLC to yield 22 mg of the title compound.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[O:13]=[C:14]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29]3[CH:37]=[CH:36][C:32]([C:33]([NH2:35])=[O:34])=[CH:31][N:30]=3)[CH:27]=2)[O:22][C:16]2([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:15]1.[CH2:38]([O:40][C:41]1[CH:46]=[C:45]([C:47](O)=[O:48])[CH:44]=[C:43]([O:50][CH2:51][CH3:52])[C:42]=1[C:53]1[CH:58]=[CH:57][C:56]([C:59]([O:61][CH3:62])=[O:60])=[CH:55][CH:54]=1)[CH3:39].O>CN(C=O)C>[C:33]([C:32]1[CH:36]=[CH:37][C:29]([C:26]2[CH:27]=[C:28]3[C:23](=[CH:24][CH:25]=2)[O:22][C:16]2([CH2:21][CH2:20][N:19]([C:47]([C:45]4[CH:44]=[C:43]([O:50][CH2:51][CH3:52])[C:42]([C:53]5[CH:58]=[CH:57][C:56]([C:59]([O:61][CH3:62])=[O:60])=[CH:55][CH:54]=5)=[C:41]([O:40][CH2:38][CH3:39])[CH:46]=4)=[O:48])[CH2:18][CH2:17]2)[CH2:15][C:14]3=[O:13])=[N:30][CH:31]=1)(=[O:34])[NH2:35]
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1-c1ccc(C(=O)OC)cc1
Reactant: NC(=O)c1ccc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)nc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4ccc(C(N)=O)cn4)ccc2O3)cc(OCC)c1-c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
TEA (0.657 ml, 4.71 mmol) was added to a stirred mixture of HOBT (313 mg, 2.04 mmol), WSCDI (361 mg, 1.89 mmol), 6-(4-oxospiro[chroman-2,4′-piperidin]-6-yl)nicotinamide dihydrochloride (2.61 g, 6.97 mmol) and 2,6-diethoxy-4′-(methoxycarbonyl)biphenyl-4-carboxylic acid (2.00 g, 5.81 mmol) in DMF (30 ml) and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into water (600 ml) and stirred for 30 min. The resulted precipitate was filtered, washed with water and the solid was dried in vacuo at 70° C. The crude product was purified by silicagel column chromatography (CHCl3/Acetone) to give intended compound (3.85 g, quantitative) as a colorless solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH3:4].[N:6]1([CH2:13][C:14]2[S:18][C:17]([C:19](=[S:21])[NH2:20])=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[ClH:22]>C(O)C>[ClH:1].[ClH:22].[CH3:4][C:3]1[N:20]=[C:19]([C:17]2[S:18][C:14]([CH2:13][N:6]3[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)=[CH:15][CH:16]=2)[S:21][CH:2]=1
Reactant: CC(=O)CCl
Reactant: NC(=S)c1ccc(CN2CCCCCC2)s1
Agent: Cl
Solvent: CCO
Product: Cc1csc(-c2ccc(CN3CCCCCC3)s2)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
730 mg of chloroacetone was added to 30 ml of ethanol solution containing 2.0 g of 5-[(hexahydro-1H-azepin-1-yl)methyl]-2-thiophenecarbothioamide, and the mixture was stirred overnight at 80° C. The reaction solution was ice-cooled, adjusted to pH 1 by adding hydrochloric acid and then concentrated under a reduced pressure. The resulting residue was then recrystallized from acetonitrile to give 1.6 g of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.CC(C)([O-])C.[K+].O>O1CCOCC1>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:4]1[CH:3]=[C:2]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[C:11]2[C:6]([N:5]=1)=[N:7][CH:8]=[CH:9][N:10]=2
Reactant: Nc1ccncc1
Reactant: Fc1ccccc1-c1cc(Cl)c2nccnc2n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Fc1ccccc1-c1cc(Nc2ccncc2)c2nccnc2n1
Reaction time: 0.08 h

Procedure:
A solution of 52.2 mg (0.20 mmol) 8-chloro-6-(2-fluoro-phenyl)-pyrido[2,3-b]pyrazine in 1 ml dioxane was heated to 80° C. under nitrogen. Then 20.7 mg (0.22 mmol) 4-aminopyridine and 47.3 mg (0.42 mmol) potassium-tert-butoxide were added and the mixture was stirred at the same temperature for 5 minutes. Water was added to the reaction mixture. The resulting precipitate was filtered off and washed with water. The filtrate was extracted several times with dichloromethane; the organic phase was dried over sodium sulphate and evaporated. The residue was combined with the filtrate and purified by preparative HPLC. The fractions containing product were evaporated and partitioned between sodium hydrogen carbonate solution and dichloromethane. The organic phase was dried over sodium sulphate and evaporated yielding [6-(2-fluoro-phenyl)-pyrido[2,3-b]pyrazin-8-yl]-pyridin-4-yl-amine as yellow crystals HPLC/MS (A): 1.37 min, [M+H] 318.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27]>CC(C)=O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[O:17][CH2:27][CH:26]=[CH2:25]
Reactant: COC(=O)c1cc(-c2ccc(F)cc2)ccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(-c2ccc(F)cc2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6.6 g. of methyl-5-(4'-fluorophenyl)-2-hydroxy-benzoate, 5.5 g. of potassium carbonate, 25 ml. of acetone, and 4.5 g. of allyl bromide is heated at reflux for 2 hours, and then stirred at 25° C. overnight. The reaction mixture is partitioned between 100 ml. of water and 100 ml. of ether, the ether solution is dried over magnesium sulfate and concentrated to a thick oil, 6.0 g. This material shows a strong absorption band in the infra-red at 5.75 μ (non-bonded ester) and is homogeneous by thin layer chromatography.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]([C:12]1[CH:13]=[C:14]([CH2:31][NH2:32])[CH:15]=[CH:16][C:17]=1[Sn:18]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].[C:35]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36]1>C1COCC1>[F:34][C:2]([F:1])([F:33])[C:3]([C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][C:17]=1[Sn:18]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:31][NH:32][C:35](=[O:41])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]
Reactant: O=C1CCC(=O)O1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(CN)cc1C(OCOC)(C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(CNC(=O)CCC(=O)O)cc1C(OCOC)(C(F)(F)F)C(F)(F)F
Temperature: 20 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
Compound 8 (401 mg, 661 μmol) was dissolved in freshly distilled THF (5 mL) under nitrogen atmosphere and succinic anhydride (165 mg, 1.65 mmol) was added. After stirring 20 h at 20° C., the solvent was removed under reduced pressure and dissolved in n-hexane. The white precipitate was removed by filtration and the filtrate evaporated to dryness. The residue was purified over silica gel by dichloromethane/methanol (9/1) to give 461 mg (661 μmol, 99% yield) of a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:8])[C:4]([F:7])([F:6])[F:5].[H-].[Na+].Br[CH2:12][C:13]1[N:18]=[C:17]([CH2:19][N:20]2[C:24]3[N:25]=[C:26]([NH2:34])[N:27]=[C:28]([C:29]4[O:30][CH:31]=[CH:32][CH:33]=4)[C:23]=3[N:22]=[N:21]2)[CH:16]=[CH:15][CH:14]=1.O>CN(C=O)C>[NH2:34][C:26]1[N:27]=[C:28]([C:29]2[O:30][CH:31]=[CH:32][CH:33]=2)[C:23]2[N:22]=[N:21][N:20]([CH2:19][C:17]3[N:18]=[C:13]([CH2:12][N:2]([CH3:1])[C:3](=[O:8])[C:4]([F:7])([F:6])[F:5])[CH:14]=[CH:15][CH:16]=3)[C:24]=2[N:25]=1
Reactant: CNC(=O)C(F)(F)F
Reactant: Nc1nc(-c2ccco2)c2nnn(Cc3cccc(CBr)n3)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cccc(Cn2nnc3c(-c4ccco4)nc(N)nc32)n1)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of N-methyl-2,2,2-trifluoroacetamide (197 mg, 1.55 mmol) in DMF (5 mL) at 0° C. was treated with sodium hydride (60% dispersion in mineral oil; 62 mg, 1.55 mmol), stirred for 15 min, treated with 3-(6-bromomethyl-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (120 mg, 0.310 mmol), stirred at 50° C. for 1 h, cooled to room temperature, poured into water (20 mL), extracted with EtOAc (3×10 mL) and the combined organic phase dried (MgSO4) and concentrated in vacuo to give N-(6-(5-amino-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)-2-pyridylmethyl)-N-methyltrifluoroacetamide. A solution of this product in MeOH (20 mL) was treated with a solution of sodium (71 mg, 3.10 mmol) in MeOH (10 mL), stirred for 16 h, concentrated in vacuo, treated with EtOAc (20 mL), filtered through Celite and concentrated in vacuo. The resulting solid was suspended in MeOH (2 mL), treated with HCl (4-M in dioxane, 1.0 mL), stirred for 10 min, concentrated in vacuo and triturated with Et2O to give the title compound (80 mg, 58%) as a yellow solid.