Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:10][C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:16][CH:15]=2)=[O:12])[NH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:10][C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:16][CH:15]=2)=[O:12])[N:8]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)[nH]n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 77.9 %

Procedure:
A mixture of the above urea (0.022 g, 0.050 mmol), phenylboronic acid (0.012 g, 0.1 mmol), copper (II) acetate (0.014 g, 0.075 mmol), pyridine (0.01 mL, 0.1 mmol) and molecular sieves (4 Å activated, 0.030 g) in methylene chloride (2 mL) was stirred at room temperature for 14 h under air. After filtration through diatomaceous earth, the filtrate was concentrated in vacuo and purified by flash chromatography (EtOAc 100% to EtOH 100%) to give the title compound as a yellow-white solid (0.02 g, 73%), mp 142-143° C.; 1H NMR (DMSO) δ 1.26(s, 9H), 2.53(t, 4H) 2.83(t, 2H), 3.57(t, 4H), 4.24(t, 2H), 6.34(s, 1H), 6.94(d, 1H), 7.40(d, 1H), 7.55(m, 7H), 7.90(d, 1H), 8.15(d, 1H), 8.82(s, 1H), 8.92(s, 1H); MS (CI) 514(M++H).
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:9])[CH2:3][C:2]2=[O:10].C(N(CC)CC)C.[CH3:18][S:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[C:24]([CH3:31])[C:23]=1[CH2:32][O:33][CH3:34])(=[O:21])=[O:20]>C(Cl)Cl>[O:9]=[C:4]1[CH:5]2[CH2:8][CH:1]([CH2:7][CH2:6]2)[C:2]([O:10][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[C:23]([CH2:32][O:33][CH3:34])[C:24]=2[CH3:31])=[CH:3]1
Reactant: COCc1c(S(C)(=O)=O)ccc(C(=O)Cl)c1C
Reactant: O=C1CC(=O)C2CCC1C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCc1c(S(C)(=O)=O)ccc(C(=O)OC2=CC(=O)C3CCC2C3)c1C
Temperature: 0 °C
Yield: 101.6 %

Procedure:
0.8 g (5.8 mmols) of bicyclo[3.2.1]octan-2,4-dione (the preparation thereof is described for example in U.S. Pat. No. 5,608,101 and in the references cited therein) are dissolved in 15 ml of methylene chloride at 20° C. The solution is mixed with 0.97 ml of triethylamine and cooled to a temperature of 0° C. Then, a solution of 1.6 g (5.8 mmols) of 4-methylsulphonyl-3-methoxymethyl-2-methylbenzoic acid chloride in 10 ml of methylene chloride is added dropwise. The reaction mixture is stirred for half an hour at a temperature of 0° C. and is subsequently diluted with methylene chloride. After washing and drying, the organic phase is concentrated by evaporation. 2.23 g of 4-methylsulphonyl-3-methoxymethyl-2-methylbenzoic acid-4-oxo-bicyclo[3.2.1]oct-2-en-2-yl-ester is obtained in amorphous form. This can be used for the next step without purification.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Cl:13][C:14]1[C:15]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:16]([NH:20][NH2:21])[N:17]=[N:18][CH:19]=1.O>C1COCC1>[Cl:13][C:14]1[CH:19]=[N:18][N:17]2[C:1](=[O:2])[NH:21][N:20]=[C:16]2[C:15]=1[C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNc1nncc(Cl)c1-c1ccc(Cl)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(Cl)cnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
To a solution of 1,1′-carbonyldiimidazole (1.78 g, 11 mmol) in THF (10 mL) at RT was added a suspension of 1-(5-chloro-4-(4-chlorophenyl)pyridazin-3-yl)hydrazine (560 mg, 2.19 mmol) in THF (10 mL). After addition, the reaction became a clear solution and was stirred at RT for 1 h. The reaction mixture was then poured into water and extracted with EtOAc (3×50 mL). The combined organic layers were washed with saturated NaCl. The organic layer was dried (Na2SO4), filtered and concentrated. To the obtained residue was added EtOAc (20 mL), and the resulting yellow precipitate was collected by filtration and washed with hexane to give the title compound, 7-chloro-8-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one as a yellow solid (300 mg, 61%). LC/MS (method A): RT=2.86 min, (M+H)+=281.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1)([CH3:3])[CH3:2].[CH3:12][N:13]1[C@H:27]2[C@@H:17]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:28]=3[C:25]([CH2:26]2)=[CH:24][NH:23]4)[CH2:16][C:15](=O)[CH2:14]1>[Pd]>[CH3:12][N:13]1[C@H:27]2[C@@H:17]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:28]=3[C:25]([CH2:26]2)=[CH:24][NH:23]4)[CH2:16][CH:15]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[N:6][CH:7]=2)[CH2:14]1
Reactant: CC(C)Oc1ccc(N)cn1
Reactant: CN1CC(=O)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Agent: [Pd]
Product: CC(C)Oc1ccc(NC2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cn1

Procedure:
The following compounds (isomers Ia and Ib) are obtained in a manner analogous to that described in Example 3, from 2-isopropoxy-5-aminopyridine and 6-methyl-8-oxo-ergoline in the presence of palladium:
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].I[C:16]1[N:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([CH3:21])=[CH:19][N:20]=1>>[CH3:8][C:7]1[O:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:1]#[C:2][C:16]1[N:17]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:18]([CH3:21])=[CH:19][N:20]=1
Reactant: Cc1cnc(I)n1-c1ccccc1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: Cc1onc(-c2ccccc2)c1C#Cc1ncc(C)n1-c1ccccc1
Yield: 21 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted [using 2-iodo-5-methyl-1-phenyl-1H-imidazole (prepared from 5-methyl-1-phenyl-1H-imidazole by reaction of 4(5)-methyl-1-phenyl-1H-imidazole with N-iodosuccinimide in N,N-dimethylformamide at ambient temperature) instead of 2-chloro-4-iodopyridine] to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 35 mg, 21%) which was obtained as a brown solid. MS: m/e=340.2 [M+H]+.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[C:14]([NH:15][C:16](=[O:22])[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[C:13]([NH:23][CH:24]([CH3:26])[CH3:25])[N:12]=[C:11](Cl)[N:10]=1)[CH2:2]2.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35]([NH:37][C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)=[O:36])[CH:29]=1>>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[C:14]([NH:15][C:16](=[O:22])[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[C:13]([NH:23][CH:24]([CH3:26])[CH3:25])[N:12]=[C:11]([C:41]3[CH:40]=[CH:39][C:38]([NH:37][C:35]([NH:34][C:30]4[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=4)=[O:36])=[CH:43][CH:42]=3)[N:10]=1)[CH2:2]2
Reactant: CC(C)Nc1nc(Cl)nc(N2CC3CCC(C2)O3)c1NC(=O)CCN(C)C
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3cccnc3)cc2)OC1(C)C
Product: CC(C)Nc1nc(-c2ccc(NC(=O)Nc3cccnc3)cc2)nc(N2CC3CCC(C2)O3)c1NC(=O)CCN(C)C

Procedure:
N-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(isopropylamino)-2-(4-(3-pyridin-3-ylureido)phenyl)pyrimidin-5-yl)-3-(dimethylamino)propanamide was prepared by Suzuki coupling using the general method from scheme 2 for the preparation of 6 using N-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-2-chloro-6-(isopropylamino)pyrimidin-5-yl)-3-(dimethylamino)propanamide (49, 0.050 g, 0.126 mmoles) and 1-(pyridin-3-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (52, 0.047 g, 0.139 mmoles). The crude product was purified by HPLC to provide the title compound as a yellow solid. Yield: 0.049 g (68%). HRMS; [M+H]+ Calc'd=574.3249, [M+H]+ Obs'd=574.3241.
Reaction SMILES: [CH2:1]1[N:5]2[C:6]3[C:11]([NH:12][CH2:13][C@H:4]2[CH2:3][CH2:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[C:14]1([CH3:38])[CH:19]=[CH:18][C:17]([C:20]2[CH:37]=[CH:36][CH:35]=[CH:34][C:21]=2[C:22]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)=[O:23])=[CH:16][CH:15]=1>>[C:14]1([CH3:38])[CH:15]=[CH:16][C:17]([C:20]2[CH:37]=[CH:36][CH:35]=[CH:34][C:21]=2[C:22]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([N:12]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]4[CH2:1][CH2:2][CH2:3][C@@H:4]4[CH2:13]3)=[O:30])=[CH:27][CH:26]=2)=[O:23])=[CH:18][CH:19]=1
Reactant: c1ccc2c(c1)NC[C@H]1CCCN21
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)O)cc2)cc1
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3C[C@H]4CCCN4c4ccccc43)cc2)cc1
Yield: 31.7 %

Procedure:
The same procedures used in Example 1 were repeated using (3aR)-1,2,3,3a,4,5-hexahydro-pyrrolo[1,2-a]quinoxaline prepared in Reference Example 15 and 4-[[2-(4-tolyl)benzoyl)amino]benzoic acid to give the title compound after recrystallization from ethyl acetate-hexane. Yield 31.7%.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].Cl[C:20]1C=CC(S(CC)(=O)=O)=CC=1C(O)=O.N1CCCC1>>[CH2:1]([S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3])[CH3:20]
Reactant: CCS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Solvent: C1CCNC1
Product: CCS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Yield: 73 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid from 2-Chloro-5-(ethane-2-sulfonyl)-benzoic acid and pyrrolidine and obtained in 73% yield. MS (m/e): 282.2 (MH−, 100%).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2=[CH:16][S:17][C:18]([CH3:19])=[C:5]12)=[O:3].[CH2:20]([N:22]([CH2:35][CH3:36])[CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][NH2:34])[CH2:28][CH2:27]1)[CH3:21]>C(#N)C>[CH2:35]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][NH:34][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7](=[O:15])[C:6]3=[CH:16][S:17][C:18]([CH3:19])=[C:5]23)=[O:3])[CH2:28][CH2:27]1)[CH3:36]
Reactant: Cc1scc2c1N(C(=O)Cl)c1ccccc1NC2=O
Reactant: CCN(CC)CCCC1CCN(CCN)CC1
Solvent: CC#N
Product: CCN(CC)CCCC1CCN(CCNC(=O)N2c3ccccc3NC(=O)c3csc(C)c32)CC1
Yield: 52 %

Procedure:
Prepared analogously to Example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2-[4-[3-(diethylamino)propyl]-piperidin-l-yl]ethanamine in a yield of 52% of theory. Colourless crystals, m.p. 131°-133° C. (acetonitrile).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:28][CH2:29][CH3:30])=[C:16](/[CH:22]=[CH:23]/[C:24]([O:26][CH3:27])=[O:25])[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.N12CCCN=C1CCCCC2.[N+:42]([CH3:45])([O-:44])=[O:43]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:28][CH2:29][CH3:30])=[C:16]([CH:22]([CH2:45][N+:42]([O-:44])=[O:43])[CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: C[N+](=O)[O-]
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1/C=C/C(=O)OC
Solvent: C1CCC2=NCCCN2CC1
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C(CC(=O)OC)C[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 22 h
Yield: 48 %

Procedure:
A solution of methyl (2E)-3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}acrylate (0.40 g, 0.93 mmol) in nitromethane (6.3 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL, 0.93 mmol) and stirred at 90° C. for 22 h. The reaction mixture was concentrated, diluted with methanol, and purified by preparative LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.1% trifluoroacetic acid, at flow rate of 60 mL/min). The LCMS fractions were concentrated to remove acetonitrile, treated with solid sodium bicarbonate, and extracted into ethyl acetate. The ethyl acetate was concentrated to give the desired product (0.22 g, 48%) as a mixture of diastereoisomers. LCMS for C22H28ClN6O5 (M+H)+: m/z=491.2; Found: 491.2.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12](=[O:17])[N:13]2[CH3:16])=[CH:8][CH:7]=1.[I-:18].[Na+].C(#N)C>O>[I:18][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12](=[O:17])[N:13]2[CH3:16])=[CH:8][CH:7]=1
Reactant: Cn1c(=O)ccc2ccc(OCCCCl)cc21
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cn1c(=O)ccc2ccc(OCCCI)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.4 %

Procedure:
7-(3-Chloropropoxy)-1-methyl-1H-quinolin-2-one (2.5 g) and sodium iodide (3.0 g) were added to 30 ml of acetonitrile. The mixture was stirred for 18 hours while heated under reflux. After cooled to room temperature, water was added to the reaction mixture, followed by extraction using dichloromethane. The organic layer was dried with sodium sulfate and was condensed under reduced pressure to give the title compound (2.4 g) as a pale brown powder.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[C:5](=[O:11])[N:4]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([O:23][C:24]2[CH:25]=[CH:26][C:27]3[N:28]([CH:30]=[C:31]([NH:33][C:34]([CH:36]4[CH2:38][CH2:37]4)=[O:35])[N:32]=3)[CH:29]=2)=[C:21]([F:41])[CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH:36]1([C:34]([NH:33][C:31]2[N:32]=[C:27]3[CH:26]=[CH:25][C:24]([O:23][C:22]4[CH:39]=[CH:40][C:19]([NH:18][C:8]([C:6]5[C:5](=[O:11])[N:4]([C:12]6[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=6)[N:3]([CH2:1][CH3:2])[CH:7]=5)=[O:10])=[CH:20][C:21]=4[F:41])=[CH:29][N:28]3[CH:30]=2)=[O:35])[CH2:37][CH2:38]1
Reactant: CCn1cc(C(=O)O)c(=O)n1-c1ccccc1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccccc1
Yield: 32.8 %

Procedure:
Using 1-ethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (270 mg, 1.2 mmol), N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (260 mg, 0.79 mmol), HATU (450 mg, 1.2 mmol), diisopropylethylamine (300 mg, 2.4 mmol) and N,N-dimethylformamide (6 mL) as starting materials and in the same manner as in Example 35, the title compound (140 mg, 34%) was obtained as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[O:17]1[C:21]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=O)[O:30]C3C=CC([N+]([O-])=O)=CC=3)[CH:25]=[CH:26][CH:27]=2)=[N:20][CH:19]=[N:18]1>C(#N)C.CN(C)C=O>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]([OH:16])[C@H:2]([NH:1][C:29]([NH:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([C:21]4[O:17][N:18]=[CH:19][N:20]=4)[CH:23]=3)=[O:30])[C:7]=2[CH:8]=1)#[N:13]
Reactant: O=C(Nc1cccc(-c2ncno2)c1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=O)Nc2cccc(-c3ncno3)c2)[C@@H]1O
Temperature: 80 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
A mixture of (3S-trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.65 g, 0.0030 mol, from example 1, part B) and [3-(1,2,4-oxadiazol-5-yl)]phenylcarbamic acid, 4-nitrophenyl ester (1.08 g, 0.0033 mol) in acetonitrile (25 mL) and dimethylformamide (20 mL) was stirred at 80° C. for one hour. The reaction mixture was concentrated in vacuo and the residue, diluted with ethyl acetate, was washed with 10% citric acid and water. The organic layer was dried over MgSO4 and concentrated in vacuo. The product was purified by flash chromatography (Sorbisol C 60 flash silica gel, 400 mL) and eluted with Hexane/EtOAc (2:1) and Hexane/EtOAc (1:1). The solvent was removed in vacuo, to give a solid that was triturated with anhydrous ether and dried in vacuo to yield 1.08 g of the title compound, m.p. 168°-170° C. TLC, silica gel, EtOAc/Hexane(2:l), Rf =0.42. 1H-NMR (DMSO-d6) δ9.1 (s, 1H), 9.0 (s, 1H), 8.5 (s, 1H), 7.5 (m, 4H), 7.0 (d, J=8.8 Hz 1H), 6.8 (d, J=8.8 Hz, 1H), 5.7 (d, J=5.9 Hz, 1H), 4.7 (t, J=8.8 Hz, 1H), 3.7 (dd, J=5.9 & 3.5 Hz, 1H), 3.4 (s, 1H), 1.5 (s, 3H), 1.2 (s, 3H); 13C-NMR (DMSO-d6) δ174.8, 158.6, 156.3, 155.7, 141.4, 132.6, 132.5, 130.0, 125.9, 123.7, 122.3, 120.6, 119.1, 117.9, 116.7, 102.7,l 80.4, 71.3, 49.5, 26.6, 18.9; IR (KBr) 2228, 1667, 1574, 1551, 1489 cm-1.M.S. (M+H)+ at 406, M.W. 405; [α]D =-55.20° (c=0.86 DMSO).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=O.C(O)=O.C([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=O.Cl>O>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=CN1CCCCC1
Reactant: Cc1ccsc1C=O
Agent: Cl
Solvent: O=CO
Solvent: O
Product: Cc1ccsc1CN1CCCCC1

Procedure:
A mixture of 3-methyl-2-thiophenecarboxaldehyde (20 g), formic acid (6 ml) and N-formyl piperidine (44.4 ml) was heated under reflux for 12 h. Water (50 ml) and 2 M hydrochloric acid (30 ml) were added; and the aqueous solution was washed with ether. The solution was basified to pH 10 with 2 M sodium hydroxide (30 ml) and extracted with ether. The organic extract was evaporated to give a brown oil which was distilled to afford the title compound as a colourless oil (11.8 g) b.p. 70°/0.4 mm. NMR (CDCl3) 2.9,d, (1H); 3.27,d, (1H); 6.48,s, (2H); 7.6,m, (4H); 7.83,s, (3H); ca. 8.5,m, (>6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:13][C:14]3[N:15]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH3:32])[C:16](=[O:25])[C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][C:18]=4[CH3:24])[N:9]=[C:10]([CH2:11]O)[C:3]=12.C(N(S(F)(F)[F:39])CC)C>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:13][C:14]3[N:15]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH3:32])[C:16](=[O:25])[C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][C:18]=4[CH3:24])[N:9]=[C:10]([CH2:11][F:39])[C:3]=12
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1ccccc1-n1c(Cn2nc(CO)c3c(N)ncnc32)cc2cccc(C)c2c1=O
Solvent: ClCCl
Product: Cc1ccccc1-n1c(Cn2nc(CF)c3c(N)ncnc32)cc2cccc(C)c2c1=O
Reaction time: 5 h
Yield: 20 %

Procedure:
To a stirred suspension of 3-((4-amino-3-(hydroxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one (compound 4503) (50 mg, 0.12 mmol) in anhydrous DCM (2 mL) at 0° C. under an argon atmosphere, diethylaminosulfur trifluoride (DAST, 77 μL, 0.59 mmol) was slowly added and the resulting mixture was stirred from 0° C. to room temperature for 5 h. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by prep-TLC plate (7% MeOH/DCM) to afford the desired product, 3-((4-amino-3-(fluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one (4504, compound 310 in Table 4) (10.3 mg, 20% yield) as a white solid.
Reaction SMILES: CN1CCCC1=O.[CH2:8]([NH:15][C:16]1[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[CH:28][CH:27]=2)[N:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:43]([O:42][C:40](=[O:41])[CH2:39][N:35]1[CH2:36][CH2:37][N:32]([C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:18]3[N:17]=[C:16]([NH:15][CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=3)=[CH:27][CH:28]=2)[CH2:33][CH2:34]1)[CH3:44]
Reactant: CCOC(=O)CBr
Reactant: NC(=O)c1cnc(Nc2ccc(N3CCNCC3)cc2)nc1NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)CN1CCN(c2ccc(Nc3ncc(C(N)=O)c(NCc4ccccc4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 5 ml portion of 1-methyl-2-pyrrolidone solution of 400 mg of 4-benzylamino-2-[(4-piperazin-1-ylphenyl)amino]pyrimidine-5-carboxamide was mixed with 0.12 ml of ethyl bromoacetate and 200 mg of potassium carbonate, followed by stirring at room temperature for 30 minutes. The reaction mixture was mixed with water, and the organic layer was extracted with ethyl acetate-THF mixed solvent. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and then the residue obtained by evaporating the solvent was washed with methanol to obtain ethyl[4-(4-{[5-(aminocarbonyl)-4-(benzylamino)pyrimidin-2-yl]amino}phenyl)piperazin-1-yl]acetate as a pale brown solid.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:13])[CH2:8]2
Reactant: C1CCNCC1
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Product: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1N1CCCCC1

Procedure:
Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 88 mg; 0.30 mmol) and piperidine (0.31 mL; 3.1 mmol) under microwave irradiation according to the procedure described for Example 14 provided after purification by reverse phase HPLC, 1-methyl-5-piperidin-1-yl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (52 mg, 51%) as an off-white powder. ES-HRMS m/e calcd for C20H31N4O (M+H+) 343.2493, found 343.2489.
Reaction SMILES: [Na].Cl.[C:3]([NH2:6])(=[NH:5])[CH3:4].Cl.O=[C:9]1[CH:14]([C:15](OCC)=[O:16])[CH2:13][CH2:12][N:11]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10]1>C(O)C>[CH3:4][C:3]1[N:6]=[C:13]2[CH2:12][N:11]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:10][CH2:9][CH:14]2[C:15](=[O:16])[N:5]=1
Reactant: CC(=N)N
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CC1=NC(=O)C2CCN(Cc3ccccc3)CC2=N1
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
Sodium metal (4.4 g, 0.19 mol) was dissolved in ethanol (300 ml) and acetamidine hydrochloride (9.3 g, 0.1 mol) was added. After 30 min, commercially available ethyl 3-oxo-1-(phenylmethyl)-piperidine-4-carboxylate hydrochloride (25 g, 0.084 mol) was added and the reaction mixture was refluxed for 18 h. The reaction mixture was filtered and the concentrated in vacuo to give the title compound (20 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:11])(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1.[CH2:26](S)C.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:11][CH3:26])[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1
Reactant: COc1cc(-c2nc(N)nc(S(C)(=O)=O)c2C#N)cc(OC)c1OC
Reactant: CCS
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CCSc1nc(N)nc(-c2cc(OC)c(OC)c(OC)c2)c1C#N

Procedure:
From 2-amino-4-methanesulfonyl-6-(3,4,5-trimethoxy-phenyl)-pyrimidine-5-carbonitrile, ethyl mercaptan and DBU in DME. EI-MS m/e (%):46 (M+, 100), 315 (52).