Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[N:16][C:8]=3[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)C.C(=O)(O)[O-].[Na+].[C:34]([O:38][C:39]([NH:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>C1(C)C=CC=CC=1>[C:20]1([C:3]2[N:4]=[C:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[NH:9][C:8]4[N:16]=[CH:17][CH:18]=[CH:19][C:7]=4[N:6]3[C:2]=2[C:46]2[CH:47]=[CH:48][C:43]([CH2:42][NH:41][C:39](=[O:40])[O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:44][CH:45]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Reactant: Brc1c(-c2ccccc2)nc2n1-c1cccnc1Nc1ccccc1-2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1ccc(-c2c(-c3ccccc3)nc3n2-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To a suspension of 3-bromo-2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.250 g, 1 eq.) in a mixture of toluene (5 mL), ethanol (5 mL), and saturated sodium bicarbonate (1 mL) was added (4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (0.1 g, 1.5 eq.). The reaction was degassed (nitrogen) for 5 minutes and tetrakis(triphenylphosphine)palladium(0) added (0.025 g). The reaction was again degassed for 5 minutes and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and poured onto water (50 mL). The aqueous phase was extracted with dichloromethane (2×50 mL) and the organic extracts were combined and washed with water (1×50 mL), brine (1×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (25-75% ethyl acetate in hexanes) gave the product which was triturated with ether to give tert-butyl 4-(2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)benzylcarbamate (0.133 g, 40%). LCMS: 516 [M+H].
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][CH:27]=1)[CH:16]=[C:17]([C:22]([CH3:24])=O)[C:18]([O:20][CH3:21])=[O:19]>C(O)(=O)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:16]2[C:3]3[C:4](=[O:11])[N:5]([CH3:10])[C:6](=[O:9])[N:7]([CH3:8])[C:2]=3[NH:1][C:22]([CH3:24])=[C:17]2[C:18]([O:20][CH3:21])=[O:19])[CH:25]=[CH:26][CH:27]=1
Reactant: Cn1c(N)cc(=O)n(C)c1=O
Reactant: COC(=O)C(=Cc1cccc(Cl)c1)C(C)=O
Solvent: CC(=O)O
Product: COC(=O)C1=C(C)Nc2c(c(=O)n(C)c(=O)n2C)C1c1cccc(Cl)c1
Yield: 55 %

Procedure:
A mixture of 6-amino-N,N'-dimethyluracil (1.5 g, 10 mM) and methyl 2-(3-chlorobenzylidene)acetoacetate (2.38 g, 10 mM) in glacial acetic acid (20 ml) was stirred at reflux under N2 for 3 hrs., cooled to ambient, evaporated in vacuo and diluted with acetone to precipitate out the product. Recrystallization from MeOH/Acetone gave the title compound (2.0 g,53%), mp. 230° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:9]=[C:8]2[C:3]=1[C:4]1[CH2:21][CH2:20][CH2:19][CH2:18][C:5]=1[C:6](=[O:17])[O:7]2.N1C=CN=C1.[C:27]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28].CCOCC>CN(C=O)C>[Si:31]([O:1][C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:9]=[C:8]2[C:3]=1[C:4]1[CH2:21][CH2:20][CH2:19][CH2:18][C:5]=1[C:6](=[O:17])[O:7]2)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:33])[CH3:32]
Reactant: CCCCCc1cc(O)c2c3c(c(=O)oc2c1)CCCC3
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCc1cc(O[Si](C)(C)C(C)(C)C)c2c3c(c(=O)oc2c1)CCCC3
Reaction time: 20 h
Yield: 99.2 %

Procedure:
32 g (112 mmol) of 1-hydroxy-3-pentyl-7,8,9,10-tetrahydrobenzo[c]chromen-6-one were initially introduced in 200 ml of DMF, 10 g of imidazole (145 mmol) were added, a solution of 21 g (135 mmol) of tert-butyldimethyl-silyl chloride in 100 ml of DMF was added dropwise at 0° C., and the mixture was stirred at room temp. for 20 h. MTB ether was subsequently added to the batch, which was then washed with water and dried over sodium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography with heptane/ethyl acetate (6:1), giving 44.5 g (94%) of 1-tert-butyl-dimethylsilyloxy-3-pentyl-7,8,9,10-tetrahydrobenzo[c]chromen-6-one as a yellow solid.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)([O-:3])=[O:2].[CH2:19]([NH2:22])[C:20]#[CH:21]>C(#N)C>[N+:1]([CH:4]=[C:5]([NH:22][C:19]#[C:20][CH3:21])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)([O-:3])=[O:2]
Reactant: C#CCN
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1ccccn1
Solvent: CC#N
Product: CC#CNC(=C[N+](=O)[O-])NCCSCc1ccccn1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
A mixture of the product of Step A (2.0 g; 7.03 mmoles and propargylamine (3.44 g; 62.5 mmoles) in acetonitrile (30 ml) was stirred and heated to reflux temperature under a positive pressure of nitrogen for 1.5 hours then stirred at ambient temperature for 42 hours. The reaction mixture was filtered and the product collected. Recrystallization from acetonitrile gave the title compound; mp 147°-148°.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][NH2:14])=[N:5][N:4]=1.C(N(CC)CC)C.[C:22](Cl)(=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCOCC1>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2=[N:13][N:14]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:5]2[N:4]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NNc1nnc(Cl)c2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Clc1nn2c(-c3ccccc3)nnc2c2ccccc12

Procedure:
To a solution of 1-chloro-4-hydrazinophthalazine hydrochloride (10 g) in dioxan (220 ml) was added triethylamine (7.24 ml) and benzoyl chloride (6.04 ml). This mixture was heated at reflux for 8 hours under nitrogen. After cooling the reaction mixture was concentrated under vacuum and the solid obtained was collected by filtration, washed with water and diethyl ether and dried under vacuum, to yield the title compound (12.0 g). 1H NMR (250 MHz, DMSO)•7.60 (3H, m), 8.00 (1H, t, J=8.4 Hz), 8.19 (1H, t, J=8.4 Hz), 8.31 (3H, m), 8.61 (1H, d, J=6.3 Hz).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:18])=[C:13]([CH:17]=1)[C:14]([OH:16])=O)=[O:7].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[N:42]1([CH2:47][CH2:48][CH2:49][S:50]([C:53]2[CH:58]=[CH:57][C:56]([NH:59][C:60]3[N:65]=[CH:64][C:63]([NH2:66])=[CH:62][N:61]=3)=[CH:55][CH:54]=2)(=[O:52])=[O:51])[CH2:46][CH2:45][CH2:44][CH2:43]1>C(Cl)Cl.CN(C=O)C>[CH3:18][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:19]=[CH:20][CH:21]=[C:3]([C:2]([F:1])([F:23])[F:22])[CH:4]=2)=[CH:17][C:13]=1[C:14]([NH:66][C:63]1[CH:64]=[N:65][C:60]([NH:59][C:56]2[CH:57]=[CH:58][C:53]([S:50]([CH2:49][CH2:48][CH2:47][N:42]3[CH2:46][CH2:45][CH2:44][CH2:43]3)(=[O:51])=[O:52])=[CH:54][CH:55]=2)=[N:61][CH:62]=1)=[O:16]
Reactant: Nc1cnc(Nc2ccc(S(=O)(=O)CCCN3CCCC3)cc2)nc1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1C(=O)O
Agent: COc1nc(Cl)nc(OC)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1C(=O)Nc1cnc(Nc2ccc(S(=O)(=O)CCCN3CCCC3)cc2)nc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 13.5 %

Procedure:
To a solution of intermediate 3 (Example 5) (170 mg, 0.5 mmol) in anhydrous CH2Cl2 (8 mL), 2-chloro-4,6-dimethoxy-1,3,5-triazine (100 mg, 0.6 mmol) and 4-methylmorpholine (210 mg, 2 mmol) were added. After the reaction mixture was stirred at room temperature for 75 minutes, intermediate 2 (Example 3) (100 mg, 0.3 mmol) in anhydrous DMF (2.5 mL) was added into the solution. The solution was stirred under argon for overnight. The residue was dissolved in CH2Cl2 (20 mL) and washed with aqueous saturated NaHCO3 solution (20 mL). The aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic phase was dried (Na2SO4) and the solvent was removed. The crude product was purified by silica gel column with CHCl3 to 10% CH3OH/CHCl3 as eluents to give the final product as a white solid (27 mg, 15%).
Reaction SMILES: CC(NC[CH:7]([OH:15])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1Cl)(C)C.[C:16]([O:31]C(C)C)(=[O:30])[CH2:17][CH2:18]CCCCCCCCCCC.[C:35](OCC)(=O)C>>[C:16]([O:15][CH2:7][CH:8]([CH2:13][CH3:12])[CH2:9][CH2:10][CH2:11][CH3:35])(=[O:30])[CH:17]=[CH2:18].[C:16]([OH:31])(=[O:30])[CH:17]=[CH2:18]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)NCC(O)c1ccccc1Cl
Reactant: CCCCCCCCCCCCCC(=O)OC(C)C
Product: C=CC(=O)O
Product: C=CC(=O)OCC(CC)CCCC

Procedure:
2-Ethylhexyl acrylate (95 parts) and acrylic acid (5 parts) were polymerized in ethyl acetate under an inert gas atmosphere to give an acrylic adhesive solution. To this solution was added tulobuterol and isopropyl myristate as an additive so that their contents in the plaster layer were 20% and 30%, respectively, and the mixture was stirred well. As a crosslinking agent, a polyisocyanate compound (trademark CORONATE HL, manufactured by NIPPON POLYURETHANE INDUSTRY CO., LTD.) was added in a proportion of 0.15% of the acrylic adhesive, and the mixture was stirred thoroughly. This solution was cast onto a release liner so that the thickness after drying became 60 μm, and dried to give a plaster layer. Then, the plaster layer was adhered to a support [laminate film of a polyester nonwoven fabric (basic weight 12 g/m2) and 6 μm thick polyester film] on the nonwoven fabric side to give a percutaneous absorption type preparation of the present invention.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH:6]([C:11](=O)[CH2:12][CH3:13])[C:7](=O)[CH2:8][CH3:9])[CH3:2].O.[NH2:17][NH2:18]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[C:11]([CH2:12][CH3:13])=[N:17][NH:18][C:7]=1[CH2:8][CH3:9])[CH3:2]
Reactant: CCOC(=O)CC(C(=O)CC)C(=O)CC
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Cc1c(CC)n[nH]c1CC
Yield: 98.4 %

Procedure:
Combine 4-oxo-3-propionylhexanoic acid ethyl ester (2.49 g, 11.6 mmol) and hydrazine hydrate (0.70 g, 13.9 mmol) in glacial acetic acid (20 mL) and stir at room temperature for 88 hr. Concentrate to an oil. Partition this residue between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution (50 mL). Separate the organic layer; dry (sodium sulfate), filter and concentrate to provide (3,5-diethyl-1H-pyrazol-4-yl)-acetic acid ethyl ester (2.4 g, 98%). 1H-NMR (400 MHz, CDCl3) δ 8.64 (bs, 1H), 4.08 (q, 2H), 3.35 (s, 2H), 2.61 (q, 4H), 1.21 (m, 9H).
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:39])(=[O:38])[NH:11][C:12](=[O:37])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:23][CH3:24])=[CH:17][CH:16]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>O1CCOCC1.CO>[C:31]1([C:21]([C:18]2[CH:19]=[CH:20][C:15]([CH:14]=[CH:13][C:12]([NH:11][S:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:40])=[O:2])=[CH:9][CH:8]=3)(=[O:39])=[O:38])=[O:37])=[CH:16][CH:17]=2)=[C:22]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:23][CH3:24])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccc(C(=O)OC)cc2)cc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccc(C(=O)O)cc2)cc1)c1ccccc1

Procedure:
Prepared by hydrolyzing 1s using 4N aq sodium hydroxide (2 eq) in 4:1 dioxane/methanol at room temperature. Yield (82%); 1H NMR (d6-DMSO) δ 13.48 (br s, 1H), 12.36 (br s, 1H), 8.10 (d, J=8.0 Hz, 2H), 8.02 (d, J=8.0 Hz, 2H), 7.39-7.07 (m, 13H), 6.84 (d, J=8.1 Hz, 2H), 6.41 (d, J=15.7 Hz, 1H), 2.35 (q, J=7.7 Hz, 2H), 0.82 (t, J=7.7 Hz, 3H); APcI m/z: 538 (M+H+).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[O:3][C:4]1[CH:31]=[CH:30][C:7]([CH2:8][N:9]([C:16]2[N:17]=[C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]3[C:28]=2[CH3:29])[S:10]([CH2:13][CH2:14]O)(=[O:12])=[O:11])=[CH:6][CH:5]=1.C(Br)(Br)(Br)[Br:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:33])([F:32])[O:3][C:4]1[CH:31]=[CH:30][C:7]([CH2:8][N:9]([C:16]2[N:17]=[C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]3[C:28]=2[CH3:29])[S:10]([CH2:13][CH2:14][Br:35])(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1c(N(Cc2ccc(OC(F)(F)F)cc2)S(=O)(=O)CCO)nc2cc(C(F)(F)F)ccn12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1c(N(Cc2ccc(OC(F)(F)F)cc2)S(=O)(=O)CCBr)nc2cc(C(F)(F)F)ccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.8 %

Procedure:
To a solution of compound 17-G (0.031 g, 0.062 mmol) and carbon tetrabromide (0.025 g, 0.075 mmol) in methylene chloride (1.5 mL) at 0° C. was added triphenylphosphine (0.020 g, 0.075 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the resulting residue was purified by flash column chromatography, eluting with a hexanes-EtOAc gradient to give compound 17-H as a white solid (0.010 g, 29%); MS m/z (M+H+) 560.
Reaction SMILES: CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[C:20]([O:24][C:25]([NH:27][CH2:28][C@H:29]1[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:31]([C:41]([OH:43])=O)[CH2:30]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].Cl.[Cl:45][C:46]1[C:47]([CH3:58])=[C:48]([N:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)[CH:49]=[CH:50][CH:51]=1.ON1C2C=CC=CC=2N=N1>O1CCCC1.CN(C)C=O>[C:37]([O:36][C:34]([NH:32][CH2:33][C@H:29]1[CH2:28][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[C@H:31]([C:41]([N:55]2[CH2:54][CH2:53][N:52]([C:48]3[CH:49]=[CH:50][CH:51]=[C:46]([Cl:45])[C:47]=3[CH3:58])[CH2:57][CH2:56]2)=[O:43])[CH2:30]1)=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)NC[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Cc1c(Cl)cccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1N1CCN(C(=O)[C@@H]2C[C@@H](CNC(=O)OC(C)(C)C)CN2C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-Methylmorpholine (60 μL) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (94 mg) were added to a solution of trans-4-(N-tert-butoxycarbonylaminomethyl)-N-tert-butoxycarbonyl-L-proline (Compound 109 (D), 120 mg), 1-(3-chloro-2-methylphenyl)piperazine hydrochloride (A, 128 mg) and 1-hydroxybenzotriazole (70 mg) in tetrahydrofuran (6 mL) and N,N-dimethylformamide (2 mL) at room temperature. After stirring at room temperature for 16 hr, the reaction mixture was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic layer was washed with saturated sodium hydrogen carbonate and brine. After drying over anhydrous sodium sulfate, the organic layer was concentrated in vacuo. The residue was washed with hexane to give the titled compound (98 mg) as a white powder: 1H NMR (400 MHz, ) δ 1.42-1.59 (18H), 1.80-2.00 (br s, 2H), 2.36 (s, 3H), 2.86 (br s, 4H), 2.98 (br s, 0.5H), 3.23 (br s, 2.5H), 3.60-3.80 (6 H), 4.68 (m, 1H), 6.89 (br m, 1H), and 7.11 (m, 2H); mass spectrum (EI+) m/e 511 (M).
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:17]=[C:18]2[C:33]([CH3:34])=[N:32][N:31]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:19]2=[N:20][C:21]=1[N:22]([CH2:27][CH:28]1[CH2:30][CH2:29]1)[CH2:23][CH:24]1[CH2:26][CH2:25]1)[C:8]1[N:13]=[CH:12][C:11](Br)=[CH:10][N:9]=1.[NH2:48][C@@H:49]1[CH2:54][CH2:53][CH2:52]C[C@H]1N.C([O-])([O-])=[O:57].[K+].[K+]>O1CCOCC1.[Cu]I>[CH:24]1([CH2:23][N:22]([CH2:27][CH:28]2[CH2:30][CH2:29]2)[C:21]2[N:20]=[C:19]3[N:31]([C:35]([CH3:38])([CH3:37])[CH3:36])[N:32]=[C:33]([CH3:34])[C:18]3=[CH:17][C:16]=2[CH2:15][N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:47])([F:46])[F:1])[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=2)[C:8]2[N:13]=[CH:12][C:11]([N:48]3[CH2:52][CH2:53][CH2:54][C:49]3=[O:57])=[CH:10][N:9]=2)[CH2:26][CH2:25]1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: O=C([O-])[O-]
Reactant: Cc1nn(C(C)(C)C)c2nc(N(CC3CC3)CC3CC3)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3ncc(Br)cn3)cc12
Agent: [Cu]I
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1nn(C(C)(C)C)c2nc(N(CC3CC3)CC3CC3)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3ncc(N4CCCC4=O)cn3)cc12
Temperature: 100 °C
Reaction time: 28 h

Procedure:
5-(((3,5-Bis(trifluoromethyl)benzyl)(5-bromopyrimidin-2-yl)amino)methyl)-1-(tert-butyl)-N,N-bis(cyclopropylmethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-6-amine (0.2 g, 0.293 mmol), obtained in step (vi) of Example 1,2-pyrrolidinone (0.024 g, 0.293 mmol), CuI (0.005 mg, 0.029 mmol), trans-1,2-diaminocyclohexane (0.007 g, 0.064 mmol) were taken in a sealed tube in 1,4-dioxane (5 mL), which was degassed with argon for 15 min. K2CO3 (0.08 g, 0.586 mmol) was added to it. The reaction mixture was stirred at 100° C. for 28 h. Thereafter the reaction mixture was filtered through celite, extracted with EtOAc. The combined organic layer was washed with water, dried over Na2SO4, concentrated under reduced pressure, and purified by column chromatography using EtOAc-petroleum ether as eluent to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:25]=[C:26]([NH:30]C(=O)C(F)(F)F)[CH:27]=[CH:28][CH:29]=4)=[N:17][N:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=34)[CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[O:37][CH2:38][CH2:39]Cl.[NH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1>>[NH2:30][C:26]1[CH:25]=[C:24]([C:16]2[C:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:37][CH2:38][CH2:39][N:41]5[CH2:45][CH2:44][CH2:43][CH2:42]5)[CH:4]=4)[N:14]=3)=[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]3[N:17]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc(Cl)c(OCCCl)c3)n2)c1)C(F)(F)F
Reactant: C1CCNC1
Product: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc(Cl)c(OCCN4CCCC4)c3)n2)c1
Yield: 50 %

Procedure:
The compound was synthesized from N-(3-{3-[2-({4-chloro-3-[(2-chloroethyl)oxy]phenyl}amino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)-2,2,2-trifluoroacetamide and pyrrolidine using procedure outlined in Example 10, Step D, to afford a solid in 50% yield. ES-LC/MS m/z 526-[M+H]+.
Reaction SMILES: [CH:1]([CH:3]([CH:9]=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=O.[NH2:11][NH:12][C:13]([NH2:15])=[S:14].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)=O>C(O)C>[Cl:27][C:22]1[CH:21]=[C:20]([C:18]2[N:15]=[C:13]([N:12]3[CH:9]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:1]=[N:11]3)[S:14][CH:17]=2)[CH:25]=[CH:24][C:23]=1[Cl:26]
Reactant: CCOC(=O)C(C=O)C=O
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Reactant: NNC(N)=S
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of ethyl 2-formyl-3-oxopropanoate (0.57 g, 3.0 mmol) in ethanol (5 mL) was added thiosemicarbazide (1.37 g, 15 mmol), and the reaction mixture was stirred at room temperature for 1 hr. 2-Bromo-1-(3,4-dichlorophenyl)ethanone (0.54 g, 2.0 mmol) was added, and the mixture was stirred at 80° C. for 30 min, and cooled to room temperature. The precipitated crystals were collected by filtration to give the title compound (545 mg, 74%) as orange crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][C:6](=[O:8])[O:5][C:3]1=[O:4].[F:10][C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][C:17]([CH2:21][O:22][C:23]3[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=3)[NH2:26])=[N:18]2)=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][C:17]([CH2:21][O:22][C:23]3[CH:24]=[C:25]([NH:26][C:6](=[O:8])[CH2:7][C:2]([CH3:9])([CH3:1])[C:3]([OH:5])=[O:4])[CH:27]=[CH:28][CH:29]=3)=[N:18]2)=[CH:13][CH:12]=1
Reactant: CC1(C)CC(=O)OC1=O
Reactant: Nc1cccc(OCc2ccc3ccc(F)cc3n2)c1
Product: CC(C)(CC(=O)Nc1cccc(OCc2ccc3ccc(F)cc3n2)c1)C(=O)O

Procedure:
The title compound is prepared analogously to the compound described in Example 20 from 2,2-dimethylsuccinic acid anhydride and 3-(7-fluoro-2-quinolinylmethoxy)aniline; colourless crystals of m.p. 209°-210°.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[CH3:48][C:49]([CH3:54])([CH3:53])[C:50](Cl)=[O:51]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:50](=[O:51])[C:49]([CH3:54])([CH3:53])[CH3:48])[CH2:42][CH2:41]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 31 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 2,2-dimethylpropanoyl chloride as starting materials in 31% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.50 (s, 1H), 9.33 (s, 1H), 9.30 (s, 1H), 8.13 (s, 1H), 7.98 (s, 1H), 7.77 (s, 1H), 7.21 (d, 1H), 7.04 (m, 2H), 6.87 (d, 1H), 6.79 (d, 1H), 4.27 (m, 2H), 2.81 (m, 6H), 2.25 (m, 2H), 2.01 (m, 1H), 1.76 (m, 2H), 1.19 (s, 9H), 1.04 (m, 2H). LCMS for C30H36ClN6O2 (M+H)+: m/z=547.2.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N([O-])=O.[Na+].[BrH:17]>CO.CC(C)=O.O>[Br:17][CH:6]([CH2:5][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(N)ccc1F
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(CC(Br)C(=O)OC)ccc1F
Yield: 45 %

Procedure:
To a solution of methyl 5-amino-2-fluorobenzoate (4.12 g) in 47% hydrobromic acid (11.4 ml), methanol (20 ml) and acetone (50 ml), a solution of sodium nitrite (1.88 g) in water (3 ml) was slowly added dropwise under cooling with salt-ice and stirring so as to keep an internal temperature of not higher than -5° C. After stirred for 30 minutes as it was, ice bath was removed, methyl acrylate (13.3 ml) was added, and cuprous oxide (225 mg) was added little by little while stirring vigorously. After no nitrogen became to generate, the reaction liquor was concentrated under reduced pressure. The residue was dissolved into ethyl acetate, washed with water, saturated aqueous solution of sodium hydrogencarbonate and water in order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by means of silica gel column chromatography (developing solvent; n-hexane:ethyl acetate=10:1) to obtain 3.48 g (45%) of aimed compound as an oily material.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]=1[C:7]#[N:8].S(=O)(=O)(O)[OH:14].N>>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]=1[C:7]([NH2:8])=[O:14]
Reactant: O=S(=O)(O)O
Reactant: CC(C)(C)c1csc(N)c1C#N
Agent: N
Product: CC(C)(C)c1csc(N)c1C(N)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 180 g (1 mole) of 2-amino-3-cyano-4-tert.-butyl-thiophene and 750 ml of 95-97% strength sulphuric acid was stirred at 100°-110° C. for one hour, whereupon a slightly exothermic reaction started, so that when a temperature of 100° C. was reached no further heating was required. The reaction mixture was left to cool and was stirred into 5 liters of ice-water and neutralized with about 3 liters of 25% strength aqueous ammonia solution. The solid product which precipitated was filtered off, washed with water and dried at 50° C. 194 g of 2-amino-3-aminocarbonyl-4-tert.-butyl-thiophene of melting point 145° C. were obtained in this manner.