Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2=[C:16]([NH2:20])[N:17]([CH3:19])[N:18]=[C:11]12.[CH3:21][CH2:22][CH2:23][C:24](=O)[CH2:25][CH2:26][CH3:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2=[C:16]([NH:20][CH:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][CH3:21])[N:17]([CH3:19])[N:18]=[C:11]12
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3N)c(Cl)c1
Reactant: CCCC(=O)CCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCC(CCC)Nc1c2c(nn1C)N(c1c(C)cc(C)cc1Cl)CCC2
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine (45.7 mg) and 4-heptanone (24 μL) were dissolved and stirred in 3 mL of dichloroethane. After 15 min, 44.5 mg of sodium triacetoxyborohydride was added. The reaction mixture was stirred at 60° C. during the day and at room temperature over night during 3 d. During this period, an additional 109 μL of 4-heptanone and an additional 104 mg of sodium triacetoxyborohydride were added to drive the reaction to completion. The reaction mixture was then partitioned between ethyl acetate and water. The ethyl acetate was dried with magnesium sulfate and concentrated. The crude product was chromatographed on silica gel eluting with an acetone/hexane gradient to provide 11 mg of [7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl](1-propyl butyl)amine as a crystalline film, ms m/z 389 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[OH-].[Ca+2].[OH-].[C:13](=O)([O-])[O-:14].[Na+].[Na+].Cl>O.C(Cl)(Cl)Cl>[Cl:8][C:5]1[CH:4]=[C:3]([OH:9])[C:2]([Cl:1])=[CH:7][C:6]=1[CH:13]=[O:14]
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(Cl)ccc1Cl
Agent: Cl
Agent: [Ca+2]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=Cc1cc(Cl)c(O)cc1Cl
Reaction time: 2 h
Yield: 7.7 %

Procedure:
2,5-Dichlorophenol (CAS 583-78-8) (10 g, 0.060 mol), calcium hydroxide (19.5 g, 0.260 mol), and sodium carbonate (22.76 g, 0.220 mol) were suspended in water (140 mL). Chloroform (14.6 g, 0.120 mol) was added for 30 min, and the mixture was refluxed under vigorous stirring for 2 h. The reaction mixture was cooled on ice bath. Concentrated HCl (80 mL) and chloroform (200 mL) were added. The aqueous layer was discarded. The organic one was dried with anhydrous Na2SO4 (10 g) and evaporated in vacuo. The residue was purified by chromatography (silica gel 63-100 μm, 150 g, CCl4→CCl4:EtOAc (60:40)). Fractions containing the product were combined, evaporated to give the title compound (0.88 g, 4.60 mmol, 8%) as yellow crystals. 1H NMR data (DMSO-d6): 11.95 (s, 1H, COH); 10.09 (s, 1H, OH); 7.83 (s, 1H, Ar—H); 7.09 (s, 1H, Ar—H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH2:11])=[O:10].[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13].C(N(CC)CC)C>CN(C=O)C.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.[Cu]I>[CH3:15][Si:14]([C:12]#[C:13][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH2:11])=[O:10])([CH3:17])[CH3:16]
Reactant: C#C[Si](C)(C)C
Reactant: NC(=O)Nc1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccccc1NC(N)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a degassed solution of 1-(2-iodophenyl)urea (2.62 g, 10 mmol, 1 eq), ethynyltrimethyl silane (4.16 mL, 3 eq), and triethylamine (5.58 mL, 4 eq) in anhydrous DMF (15 mL) was added bis(triphenylphosphine)palladium(II) dichloride (702 mg, 0.1 eq) and copper(I) iodide (190.4 mg, 0.1 eq). After the reaction mixture was stirred at room temperature for 30 minutes, it was partitioned between aqueous ammonium chloride and ethyl acetate. The organic layer was isolated, washed further with saturated sodium bicarbonate, brine, and lastly dried with sodium sulfate. The upper solution was decanted, concentrated, and the brown solid residue was treated with a small amount of DCM. The mixture was stirred at room temperature for 30 minute and filtered to obtain 1-{2-[(trimethylsilyl)ethynyl]phenyl}urea as a white solid in 1.645 g. The filtrate was concentrated and the residue was subject to a gradient column chromatography (EtOAc-hex from 1:100 to 1:1) to render 1-{2-[(trimethylsilyl)ethynyl]phenyl}urea with a second crop of 0.432 g in a total yield of 90%.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1.C(O[K])=O>C1COCC1.O.[Pd]>[NH2:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])=[CH:12][CH:13]=3)[N:8]=[CH:7][CH:6]=2)=[C:2]([F:1])[CH:24]=1
Reactant: CC(C)(O)COc1ccc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2c1
Agent: [Pd]
Agent: O=CO[K]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)COc1ccc2c(Oc3ccc(N)cc3F)ccnc2c1
Temperature: 45 °C
Reaction time: 5 h
Yield: 87.6 %

Procedure:
To a mixture of 1-((4-(2-fluoro-4-nitrophenoxy)quinolin-7-yl)oxy)-2-methylpropan-2-ol (10.04 g, 27 mmol) and HCOOK (15.87 g, 189 mmol) in THF/H2O (54 mL, THF/H2O=4:1) was added catalytic amount of Pd/C (5%, 53%˜55% water content, w/w). The reaction was stirred at 45° C. for 5 hours, and then diluted with THF/H2O (40 mL, v/v=1:1). The resulted mixture was filtered and the filtrate was concentrated in vacuo. The residue was washed with EtOH/H2O (30 mL×3, v/v=5:1), and dried in vacuo at 45° C. for 24 hours to give the title compound as a light gray solid (8.1 g, 87%).
Reaction SMILES: [OH-].[K+].Cl[CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]1=[O:19].[CH2:20]([OH:22])[CH3:21]>>[CH2:20]([O:22][C:8]([N:7]1[C:11]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=2[O:9][CH2:4][CH2:5][CH2:6]1)=[O:19])[CH3:21]
Reactant: O=c1oc2ccc([N+](=O)[O-])cc2n1CCCCl
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)N1CCCOc2ccc([N+](=O)[O-])cc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
Potassium hydroxide (2.19 g, 33.2 mmol) was dissolved in Ethanol (150 mL) and 3-(3-Chloro-propyl)-5-nitro-3H-benzoxazol-2-one (8.11 g, 31.6 mmol) was added. After 2 h, the mixture was concentrated in vacuo, and the solids redissolved in N,N-Dimethylformamide (150 mL). The mixture was heated to 80° C. for 2 h. The mixture was cooled and diluted with 500 mL EtOAc and washed with water (4×50 mL). The aq. washes were back extracted with 100 mL EtOAc. The combined organics were washed with water (50 mL) and brine (100 mL), dried over sodium sulfate and conc. in vacuo to give orange solids, which were triturated in 10% Ether:Hexane (100 mL) overnight. The orange solids were collected and washed with hexane to furnish 2-Nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid ethyl ester (6.45 g, 77%). 1H-NMR (DMSO): 8.19 (s, 1H), 8.02 (d, 1H, J=8.9 Hz), 7.19 (d, 1H, J=8.9 Hz), 4.25 (m, 2H), 4.15 (m, 2H), 3.76 (m, 2H), 2.05 (m, 2H), 1.19 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([NH2:19])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[O:26]1[CH2:31][CH2:30][CH:29]([CH2:32][C:33](Cl)=[O:34])[CH2:28][CH2:27]1.C(OCC)(=O)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[C:12]([NH:19][C:33](=[O:34])[CH2:32][CH:29]3[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Reactant: O=C(Cl)CC1CCOCC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CC1CCOCC1)Nc1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of N2-(3-chlorophenyl)-4-(trifluoromethyl)pyrimidine-2,5-diamine (147 mg), pyridine (62 μL), and dichloromethane (1 mL) was added a solution of the above crude tetrahydro-2H-pyran-4-ylacetyl chloride in dichloromethane (2 mL) under ice-cooling, followed by stirring at room temperature for 6 hours. To the reaction mixture was added ethyl acetate (50 mL), the organic layer was washed with a 10% aqueous citric acid solution, and then the solvent was evaporated under reduced pressure. The obtained residue was washed with warmed ethyl acetate to obtain N-{2-[(3-chlorophenyl)amino]-4-(trifluoromethyl)pyrimidin-5-yl}-2-(tetrahydro-2H-pyran-4-yl)acetamide (176 mg) as a colorless powder.
Reaction SMILES: [NH2:1][CH:2]1[C:39](=[O:40])[N:4]2[C:5]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[C:6]([C:9]3[C:12](=[O:13])[C:11](=[O:14])[C:10]=3[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7][S:8][C@H:3]12.[NH2:41][C:42]1[S:43][CH:44]=[C:45](/[C:47](=[N:57]/[O:58][CH3:59])/[C:48](N2C(=S)N(C)N=N2)=[O:49])[N:46]=1>O1CCCC1>[NH2:41][C:42]1[S:43][CH:44]=[C:45](/[C:47](=[N:57]/[O:58][CH3:59])/[C:48]([NH:1][CH:2]2[C:39](=[O:40])[N:4]3[C:5]([C:23]([O:25][CH:26]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[O:24])=[C:6]([C:9]4[C:12](=[O:13])[C:11](=[O:14])[C:10]=4[O:15][CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:7][S:8][C@H:3]23)=[O:49])[N:46]=1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3c(OCc4ccccc4)c(=O)c3=O)CS[C@H]12
Reactant: CO/N=C(\C(=O)n1nnn(C)c1=S)c1csc(N)n1
Solvent: C1CCOC1
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3c(OCc4ccccc4)c(=O)c3=O)CS[C@H]12)c1csc(N)n1
Yield: 40.1 %

Procedure:
Diphenylmethyl 7-amino-3-(2-benzyloxy-3,4-dioxo-1-cyclobutenyl)-3-cephem-4-carboxylate (544 mg, 0.984 mmol) was acylated with 1-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetyl]-4-methyltetrazole-5-thione (295 mg, 0.984 mmol) in tetrahydrofuran (3 mL), as described in Example 13, to afford the title compound (290 mg, 40% yield) as a yellow solid.
Reaction SMILES: [Br:1]Br.[C:3]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][C:11]=1[C:12]#[N:13])[NH2:8])#[N:4].C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][NH:8][C:7]1[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[C:5]([C:3]#[N:4])[CH:6]=1
Reactant: BrBr
Reactant: N#Cc1ccc(N)cc1C#N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1ccc(NBr)cc1C#N
Temperature: 25 °C

Procedure:
A solution of 6.7 g of bromine in 5 ml of acetic acid is slowly added dropwise at room temperature to a mixture of 5.7 g of 3,4-dicyanoaniline, 3.6 g of sodium acetate and 25 ml of acetic acid. When the addition of bromine is complete, the mixture is further stirred at room temperature until no more educt can be detected in a thin-layer chromatogram. The acetic acid is then removed in vacuo in a rotary evaporator. The residue is taken up in warm water and the product is isolated by filtration. The filter cake is washed well with water and dried in vacuo at 70° C., affording bromo-3,4-dicyanoaniline as a grey product which dissolves in dimethyl formamide to give an almost colourless solution. A thin-layer chromatogram shows the product to be a mixture of isomers. Rf values of the two main products: 0.43 and 0.55 respectively [determined on ready prepared silica gel plates 6 OF-254, MERCK Darmstadt; eluant:toluene/ethanol (4:1)].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:20][CH2:21][CH:22]=[C:23]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH2:27][CH2:26][C:25]2[CH:34]=[CH:35][CH:36]=[CH:37][C:24]1=2.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC.CCOCC.O>[CH2:17]([O:16][C:14]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10][N:11]([CH2:20][CH2:21][CH:22]=[C:23]2[C:24]3[CH:37]=[CH:36][CH:35]=[CH:34][C:25]=3[CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]2=3)[CH2:12][CH2:13]1)=[O:15])[CH3:18]
Reactant: BrCCC=C1c2ccccc2CCc2ccccc21
Reactant: CCOC(=O)C1(c2ccc(C)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CCC(C)=O
Product: CCOC(=O)C1(c2ccc(C)cc2)CCN(CCC=C2c3ccccc3CCc3ccccc32)CC1
Yield: 50 %

Procedure:
A mixture of ethyl 4-(4-methylphenyl)-4-piperidine carboxylate (3.0 g, 0.012 mol, prepared similarly as described in the method in Pol. Pat. 105 435 or Ber. 74, 1433 (1941)), 5-(3-bromo-1-propylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (4.50 g, 0.0145 mol), anhydrous potassium carbonate (5.00 g, 0.036 mol) and potassium iodide (4.0 g, 0.024 mol) in 2-butanone (100 ml) was stirred at 80° C. for 7.5 h. The mixture was diluted with ether (150 ml) and water (150 ml) and the layers were separated. The aqueous phase was extracted with additional ether (80 ml) and the combined organic extracts were washed with water (100 ml) and dried (MgSO4). The solvent was removed in vacuo and the oily residue (6.60 g) was purified by gradient column chromatography on silica gel using mixtures of benzene and ethyl acetate as eluents. The benzene/ethyl acetate (9:1) fraction afforded 2.90 g (50%) of 4-(4-methylphenyl)-1-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-4-piperidinecarboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[C:14](I)=[CH:15][N:16]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:11]2=[CH:10][CH:9]=1.[CH3:28][S:29]([C:32]1[N:37]=[C:36]([N:38]2[CH2:43][CH2:42][CH:41]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:40][CH2:39]2)[CH:35]=[C:34]([Sn](C)(C)C)[N:33]=1)(=[O:31])=[O:30]>CN(C=O)C.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[C:14]([C:34]3[N:33]=[C:32]([S:29]([CH3:28])(=[O:30])=[O:31])[N:37]=[C:36]([N:38]4[CH2:43][CH2:42][CH:41]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:49])([CH3:48])[CH3:50])[CH2:40][CH2:39]4)[CH:35]=3)=[CH:15][N:16]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:11]2=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc([Sn](C)(C)C)nc(S(C)(=O)=O)n2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(-c4ccccc4F)ccc32)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cc(N4CCC(NC(=O)OC(C)(C)C)CC4)nc(S(C)(=O)=O)n3)c3nc(-c4ccccc4F)ccc32)cc1
Temperature: 100 °C
Yield: 58.6 %

Procedure:
A glass microwave reaction vessel was charged with 5-(2-fluorophenyl)-3-iodo-1-tosyl-1H-pyrrolo[3,2-b]pyridine (100 mg, 0.203 mmol) and tert-butyl 1-(2-(methylsulfonyl)-6-(trimethylstannyl)pyrimidin-4-yl)piperidin-4-ylcarbamate (105 mg, 0.203 mmol) in DMF (1.5 mL) followed by Pd(PPh3)4 (11.74 mg, 10.16 μmol) and CuI (7.8 mg, 0.041 mmol). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 1 h. The mixture was diluted with DCM and washed with water, and brine. The organic layer was dried with MgSO4, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 20-80% EtOAc in hexanes) to give tert-butyl 1-(6-(5-(2-fluorophenyl)-1-tosyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-2-(methylsulfonyl)pyrimidin-4-yl)piperidin-4-ylcarbamate (86 mg, 0.119 mmol, 58.7% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 721.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:31][CH2:30][C@@H:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)[N:9]=[C:10]([C:11]3[CH:25]=[CH:24][C:14]([O:15][C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=4)=[CH:13][CH:12]=3)[C:3]=12>CO.[OH-].[NH4+].O.[Ni]>[NH2:21][CH2:20][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:14]2[CH:24]=[CH:25][C:11]([C:10]3[C:3]4[C:4](=[N:5][CH:6]=[N:7][C:2]=4[NH2:1])[N:8]([C@H:26]4[CH2:31][CH2:30][C@@H:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)[CH2:28][CH2:27]4)[N:9]=3)=[CH:12][CH:13]=2)=[CH:23][CH:22]=1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccc(C#N)cc5)cc4)c4c(N)ncnc43)CC2)CC1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccc(CN)cc5)cc4)c4c(N)ncnc43)CC2)CC1
Reaction time: 18 h
Yield: 745.8 %

Procedure:
Cis-4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzonitrile (0.600 g, 0.00118 mol) was dissolved in a mixture of methanol (50 mL) and concentrated solution of ammonium hydroxide in water (3 mL), 50% slurry of Raney nickel in water (2 mL) was added and the resulting mixture was hydrogenated at atmospheric pressure for 18 hours. The reaction mixture was filtered through a Celite pad, concentrated under reduced pressure and the residue digested with dichloromethane (50 mL). The organic phase was dried with magnesium sulfate, concentrated under reduced pressure and the residue suspended in diethyl ether (25 mL). The precipitate was collected by filtration and dried to yield cis-3-{4-[4-(aminomethyl)phenoxy]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.45 g, 0.0088 mol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)O)=[CH:9][N:10]=2)[N:7]=1.[I-].O[PH2]=O.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)=[CH:9][N:10]=2)[N:7]=1
Reactant: Cn1ncc2cc(C(O)c3cnc4ccc(Cl)nn34)c(F)cc21
Agent: O=[PH2]O
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cn1ncc2cc(Cc3cnc4ccc(Cl)nn34)c(F)cc21

Procedure:
(rac)-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-(6-fluoro-1-methyl-1H-indazol-5-yl)-methanol (Stage 278.4, 1 g, 3.01 mmol) was dissolved in acetic acid (80 mL) and introduced in 4 microwave reactors. Iodide (956 mg×4, 15.07 mmol), followed by H3PO2 50% (1.2 m×4, 45.2 mmol) were then added into each reactor. Then they were submitted to microwave irradiations 5 min at 150° C. After combination, it was basified by a 2.5 M NaOH solution and extracted twice with EtOAc. The organics were joined and washed with brine, dried over Na2SO4 and the solvent was removed. The residue was triturated with Et2O to afford the title compound (tR 1.26 min (conditions 2), MH+=316)
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[C:9]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:10]=3[O:11][C:12]=2[CH3:13])[N:7]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C.CO>ClCCCl>[C:21]([NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[C:9]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:10]=3[O:11][C:12]=2[CH3:13])[N:7]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1oc2c([N+](=O)[O-])cccc2c1-c1csc(N)n1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(=O)Nc1nc(-c2c(C)oc3c([N+](=O)[O-])cccc23)cs1
Yield: 64 %

Procedure:
A mixture of 3-(2-aminothiazol-4-yl)-2-methyl-7-nitrobenzo[b]furan hydrochloride (468 mg), acetic anhydride (306 mg) and triethylamine (455 mg) in 1,2-dichloroethane (20 ml) was refluxed for 1 day. To the reaction mixture was added methanol and the mixture was evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from diethyl ether to give 3-(2-acetylaminothiazol-4-yl)-2-methyl-7-nitrobenzo[b]furan (305 mg).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C@H:19]1[C@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@:22]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([CH2:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH3:59])=[C:53]([F:60])[CH:52]=3)[CH:44]=2)([O:41][CH3:42])[O:21][C@@H:20]1[CH2:61][OH:62])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C@H:19]1[C@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@:22]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([CH2:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH3:59])=[C:53]([F:60])[CH:52]=3)[CH:44]=2)([O:41][CH3:42])[O:21][C@@H:20]1[CH:61]=[O:62])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](C=O)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Oxalyl chloride (1.17 mL, 13.6 mmol) was dissolved in 20 mL dichloromethane and cooled to −78° C., followed by dropwise addition of a solution (20 mL) of dimethyl sulfoxide (1.56 mL, 21.9 mmol) in dichloromethane and a solution (50 mL) of [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 4i (7.6 g, 10.45 mmol) in dichloromethane. The reaction mixture was stirred for 30 minutes at −78° C. Triethylamine (7.25 mL, 52.3 mmol) was added before the reaction mixture was warmed and stirred for 2 hours at room temperature. Thereafter, the reaction mixture was partitioned after 50 mL 1 M hydrochloric acid were added. The organic extract was washed with saturated sodium chloride solution (50 mL×2). The aqueous phase was extracted with dichloromethane (50 mL). The organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 4j (7.58 g, colourless grease), which was used directly without purification in the next step.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]2[N:9]=[C:10]([CH3:23])[C:11]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)=[C:4]2[N:3]=1.[OH-].[Na+].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.Cl.O=P(Cl)(Cl)Cl.C(N(CC)C1C=CC=CC=1)C>O1CCCC1.O.C(O)C>[Cl:8][C:6]1[N:5]2[N:9]=[C:10]([CH3:23])[C:11]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)=[C:4]2[N:3]=[C:2]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:7]=1
Reactant: C1COCCN1
Reactant: Cc1nn2c(Cl)cc(Cl)nc2c1Cc1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)c1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1nn2c(Cl)cc(N3CCOCC3)nc2c1Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.3 %

Procedure:
To the solution of 5,7-dichloro-2-methyl-3-(1-naphthalenylmethyl)pyrazolo[1,5-a]pyrimidine (1.5 g, 4.38 mmol) in Tetrahydrofuran (THF) (40 mL) was added sodium hydroxide (21.92 mL, 43.8 mmol). The reaction was stirred at rt for 18 h and heated at 50° C. for 7 h. The reaction was concentrated and acidified. The reaction mixture was extracted with EtOAc (80 mL×2). The organic phases were combined, dried and concentrated. The mixture was transferred to a 20 mL MW vial. Morpholine (1.909 mL, 21.92 mmol) and Ethanol (2 mL) was added in. The mixture was subjected to MW irradiation at 150° C. for 3 h. Water (10 mL) was added to the reaction mixture which was acidified with 6 N HCl. The reaction was extracted with EtOAc (100 mL×3). The organic phases were combined, dried and concentrated. To the resulted solid was added POCl3 (6.13 mL, 65.7 mmol) and N,N-diethylaniline (1.308 g, 8.77 mmol). The reaction was heated at 90° C. for 5 h. The reaction was cooled down. Crushed ice was added in. The aqueous mixture was extracted with EtOAc (100 mL×3). The organic phases were combined, dried and concentrated. The crude was purified on silica column (EtOAc/Hexane: 20˜40%) to give the product (1.02 g, 59%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.20 (s, 3H) 3.54-3.74 (m, 8H) 4.33 (s, 2H) 7.00 (s, 1H) 7.32 (d, J=6.57 Hz, 1H) 7.37-7.44 (m, 1H) 7.45-7.55 (m, 2H) 7.76 (d, J=8.08 Hz, 1H) 7.90 (m, 1H) 8.44 (m, 1H); LC/MS: MS (ES+) m/e 393.1 [M+H]+.