Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][C@@H:14]3[CH2:19][CH2:18][O:17][CH2:16][C@H:15]3[NH2:20])[CH2:8]2)=[CH:4][CH:3]=1.C1([O:29][C:30](=O)[NH:31][C:32]2[S:33][C:34]([C:38](=[O:40])[CH3:39])=[C:35]([CH3:37])[N:36]=2)C=CC=CC=1>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][C@@H:14]3[CH2:19][CH2:18][O:17][CH2:16][C@H:15]3[NH:20][C:30]([NH:31][C:32]3[S:33][C:34]([C:38](=[O:40])[CH3:39])=[C:35]([CH3:37])[N:36]=3)=[O:29])[CH2:8]2)=[CH:21][CH:22]=1
Reactant: CC(=O)c1sc(NC(=O)Oc2ccccc2)nc1C
Reactant: N[C@@H]1COCC[C@H]1CN1CCC[C@@H](Cc2ccc(F)cc2)C1
Solvent: CC#N
Product: CC(=O)c1sc(NC(=O)N[C@@H]2COCC[C@H]2CN2CCC[C@@H](Cc3ccc(F)cc3)C2)nc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 23 %

Procedure:
(3S,4S)-4-[(S)-3-(4-Fluoro-benzyl)-piperidin-1-ylmethyl]-tetrahydro-pyran-3-ylamine (49 mg, 160 μmol) and (5-acetyl-4-methylthiazol-2-yl)-carbamic acid phenyl ester (49 mg, 176 μmol) were dissolved in acetonitrile (1 mL) and the mixture was stirred at room temperature. After 24 h , the mixture was concentrated, dissolved in ethyl acetate, washed with water, dried (Na2SO4) and concentrated. The residue was purified by reverse phase high pressure liquid chromatography (C18, 10-100% acetonitrile in water, containing 0.05% trifluoroacetic acid), then by flash column chromatography (5% methanol in dichloromethane, containing 0.5% ammonium hydroxide) to provide the product as a glass (18 mg, 23%). 1H NMR (300 mHz, CD3OD) δ7.05 (m, 2H), 6.87 (m, 2H), 3.90 (dd, J=11.0, 4.4 Hz, 1H), 3.84 (m, 1H), 3.53 (td, J=9.5, 4.3 Hz, 1H), 3.40 (bt, 1H), 3.10 (m, 1H), 2.90 (bd, 1H), 2.75 (bd, 1H), 2.58 (s, 3H), 2.48 (s, 3H), 2.45 (m, 3H), 2.21 (dd, J=13.6, 6.3 Hz, 1H), 1.91 (bt, 1H), 1.8-1.5 (7H), 1.37 (m, 1H), 0.92 (m, 1H), ESI MS: (M+H)+=489.4 (100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[C:29](Cl)[N:28]=[CH:27][N:26]=4)[CH2:21][CH2:20]3)=[O:18])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:32][NH2:33]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[C:29]([NH:33][CH3:32])[N:28]=[CH:27][N:26]=4)[CH2:21][CH2:20]3)=[O:18])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=C(N1CCN(c2cc(Cl)ncn2)CC1)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Solvent: CCO
Product: CNc1cc(N2CCN(C(=O)N3CCN(S(=O)(=O)c4ccc(Br)cc4)CC3)CC2)ncn1

Procedure:
A solution of 1-(4-bromophenylsulphonyl)-4-[1-(6-chloropyrimidin-4-yl)-piperazin-4-ylcarbonyl]piperazine (1.20 g) in 33% methylamine in ethanol (35 ml) was heated at 110° C. in a Carius tube for 16 hours. The mixture was evaporated to dryness and then dissolved in dichloromethane and washed with saturated aqueous ammonium chloride solution, dried (Na2SO4) and evaporated. The residue was recrystallised from methanol/ethyl acetate to give, as a solid 1-(4-bromophenylsulphonyl)4-[1-(6-methylaminopyrimidin-4-yl)-piperazin-4-ylcarbonyl]piperazine (0.65 g), mp 219-221° C. Found C, 45.80; H, 5.10 and N, 18.50%. C20H26BrN7O3S requires C, 45.80; H, 5.00 and N, 18.70% NMR (CDCl3): 2.85 (d, 3H), 3.00 (m, 4H), 3.30 (m, 4H), 3.40 (m, 4H), 3.60 (m, 4H). 4.75 (m, 1H), 5.40 (s, 1H), 7.60 (d, 2H), 7.70 (d, 2H) and 8.15 (s, 1H); m/z 524 (M+1).
Reaction SMILES: B1([O-])OO1.[OH2:5].[OH2:6].O.O.[Na+].C(O)(=O)C.[NH2:14][C:15]1[NH:19][N:18]=[CH:17][C:16]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]>O>[N+:14]([C:15]1[NH:19][N:18]=[CH:17][C:16]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])([O-:6])=[O:5]
Reactant: O
Reactant: CCOC(=O)c1cn[nH]c1N
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Product: CCOC(=O)c1cn[nH]c1[N+](=O)[O-]
Temperature: 85 °C

Procedure:
A mixture of sodium perborate tetrahydrate (95%, 15.7 g, 96.9 mmol) and acetic acid (60 mL) was heated to 85° C. Ethyl 5-amino-1H-pyrazole-4-carboxylate (3.0 g, 19 mmol) was added, and the mixture was allowed to react at 85° C. for 18 hours. The reaction was then poured into water and extracted with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo; purification via silica gel chromatography (Gradient: 0% to 100% EtOAc in heptane) provided C1. Yield: 1.41 g, 7.62 mmol, 40%. LCMS m/z 184.0 (M−1). 1H NMR (400 MHz, CDCl3) δ 1.39 (t, J=7.2 Hz, 3H), 4.40 (q, J=7.1 Hz, 2H), 8.32 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C:12]=3[CH:25]=2)=[CH:4][C:3]=1[N+:26]([O-:28])=[O:27].[ClH:29]>CO.O1CCOCC1>[ClH:29].[ClH:29].[N+:26]([C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[CH:25]=2)[CH:4]=1)([O-:28])=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3cnc(N)c([N+](=O)[O-])c3)cc2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1ncc(-c2ccc3c(c2)CNCCO3)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
A mixture of 1,1-dimethylethy 7-(6-amino-5-nitropyridin-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (3.5 g, 9.1 mmol, example 26, step 1) in methanol (75 mL) and 4N hydrogen chloride in dioxane (11 mL) was stirred at 50° C. for 1.5 h and then concentrated. The resulting residue was triturated with a 10% methanol in diethyl ether solution (50 mL) to provide 3-nitro-5-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)pyridin-2-amine dihydrochloride (3.1 g, 95%) as a red solid. 1H NMR (400 MHz, d6-DMSO) δ 9.76 (bs, 2H), 8.80 (d, 1H), 8.60 (s, 1H), 7.90 (s, 1H), 7.73 (dd, 1H), 7.16 (d, 1H), 4.39 (bs, 2H), 4.25 (bs, 2H), 3.48 (bs, 2H); MS (EI) for C14H14N4O3: 287 (MH+).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[CH2:18]([O:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[CH:33]=O)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CCO.N1CCCCC1>[C:15]([C:3]1[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[N:5][NH:6][C:2]=1[N:1]=[CH:33][CH:29]1[CH2:30][CH2:31][CH2:32][N:28]1[C:26]([O:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:27])(=[O:16])[NH2:17]
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: O=CC1CCCN1C(=O)OCc1ccccc1
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N=CC1CCCN1C(=O)OCc1ccccc1

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in EtOH and benzyl-2-formylpyrrolidine-1-carboxylate (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3[CH2:12][O:11]3)[CH:7]=[CH:6][C:5]=12.[CH3:13][C:14]1([NH2:18])[CH2:17][CH2:16][CH2:15]1>C(O)C>[CH3:13][C:14]1([NH:18][CH2:12][C@@H:10]([C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[N:2][N:1]=3)[CH:9]=2)[OH:11])[CH2:17][CH2:16][CH2:15]1
Reactant: CC1(N)CCC1
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Solvent: CCO
Product: CC1(NC[C@H](O)c2ccc3nnnn3c2)CCC1
Yield: 70.4 %

Procedure:
A solution of 375 mg (2.31 mmol) of (R)-2-(tetrazolo [1,5-a]pyrid-6-yl)oxirane and 972 mg (11.42 mmol) of (1-methylcyclobutyl)amine [J. Am. Chem. Soc., 83, 2723 (1961)] in 0.9 ml of absolute ethanol was heated at 70° C. for 3 hours with stirring under nitrogen. The reaction mixture was then concentrated to dryness (wt. 547 mg) and the residue purified by preparative Tlc on silica gel (95:5:1 methylene chloride:methanol:conc. ammonium hydroxide) to give 402 mg of product.
Reaction SMILES: ON1C2N=CC=CC=2N=N1.CCN=C=NCCCN(C)C.[C:22]([O:26][C:27]([NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][CH:31]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23].[C:39]1([S:45]([NH:48][NH2:49])(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.Cl>CN(C)C=O>[C:39]1([S:45]([NH:48][NH:49][C:34]([C:33]2[CH:32]=[CH:31][C:30]([NH:29][C:27](=[O:28])[O:26][C:22]([CH3:23])([CH3:24])[CH3:25])=[CH:38][CH:37]=2)=[O:36])(=[O:46])=[O:47])[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: NNS(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(C(=O)NNS(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
12.1 mmol (1.65 g) of 1-hydroxy-7-azabenzotriazole and 18 mmol (3.45 g) of EDCI are added in succession to a solution of 12 mmol (2.85 g) of 4-[(tert-butoxycarbonyl)amino]benzoic acid in 20 ml of dimethylformamide. The reaction mixture is stirred at room temperature for one hour, and 18 mmol (3.1 g) of benzenesulphonohydrazide are added. After stirring for eight hours at room temperature, the reaction mixture is poured into 100 ml of a 10% hydrochloric acid solution and extracted four times with 50 ml of ethyl acetate. The organic phase is washed twice with 50 ml of water and then three times with an aqueous saturated sodium hydrogen carbonate solution and once with 50 ml of an aqueous saturated sodium chloride solution. After drying over magnesium sulphate, filtration and concentration, the expected product is obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:10][C:11]1[CH:36]=[CH:35][C:14]([CH2:15][C:16]23[CH2:23][CH2:22][CH2:21][N:20]2[C:19](=[O:24])[N:18]([C:25]2[CH:30]=[C:29]([Cl:31])[C:28]([OH:32])=[C:27]([Cl:33])[CH:26]=2)[C:17]3=[O:34])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][C:16]23[CH2:23][CH2:22][CH2:21][N:20]2[C:19](=[O:24])[N:18]([C:25]2[CH:30]=[C:29]([Cl:31])[C:28]([O:32][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:27]([Cl:33])[CH:26]=2)[C:17]3=[O:34])=[CH:35][CH:36]=1
Reactant: O=C1N(c2cc(Cl)c(O)c(Cl)c2)C(=O)C2(Cc3ccc(Br)cc3)CCCN12
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1c(Cl)cc(N2C(=O)N3CCCC3(Cc3ccc(Br)cc3)C2=O)cc1Cl
Temperature: 80 °C
Yield: 89.2 %

Procedure:
Ethyl 4-bromobutyrate (28 mg) was added to a mixture of the compound from Example 135 (55 mg) and K2CO3 (18 mg) in 2 mL anhydrous DMF and the resulting mixture was heated at 80° C. for 5 hours. The solution was partitioned between EtOAc/H2O. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC to yield the titled compound (61 mg).
Reaction SMILES: [CH2:1]([C:5]1([CH2:36][CH2:37][CH2:38][CH3:39])[C:17]2[CH:16]=[C:15]([C:18]#[C:19][C:20]3[S:24][C:23]([CH:25]=[O:26])=[CH:22][CH:21]=3)[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][C:8]([C:27]#[C:28][C:29]1[S:33][C:32]([CH:34]=O)=[CH:31][CH:30]=1)=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4].[I-].[CH2:41]([N:47]([CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH3:79])[C:48]1[CH:53]=[CH:52][C:51]([CH2:54][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:50][CH:49]=1)[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46].C(O[K])(C)(C)C>C(Cl)Cl>[CH2:74]([N:47]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:48]1[CH:49]=[CH:50][C:51](/[CH:54]=[CH:34]/[C:32]2[S:33][C:29]([C:28]#[C:27][C:8]3[CH:7]=[C:6]4[C:11]([C:12]5[CH:13]=[CH:14][C:15]([C:18]#[C:19][C:20]6[S:24][C:23]([CH:25]=[O:26])=[CH:22][CH:21]=6)=[CH:16][C:17]=5[C:5]4([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:9]=3)=[CH:30][CH:31]=2)=[CH:52][CH:53]=1)[CH2:75][CH2:76][CH2:77][CH2:78][CH3:79]
Reactant: CCCCC1(CCCC)c2cc(C#Cc3ccc(C=O)s3)ccc2-c2ccc(C#Cc3ccc(C=O)s3)cc21
Reactant: CCCCCCN(CCCCCC)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)O[K]
Agent: [I-]
Solvent: ClCCl
Product: CCCCCCN(CCCCCC)c1ccc(/C=C/c2ccc(C#Cc3ccc4c(c3)C(CCCC)(CCCC)c3cc(C#Cc5ccc(C=O)s5)ccc3-4)s2)cc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 41.8 %

Procedure:
To a solution of 5,5′-(9,9-dibutyl-9H-fluorene-2,7-diyldi-2,1-ethynediyl)bis-2-thiophenecarboxaldehyde (1.14 g, 2.085 mmol) and [[4-(dihexylamino)phenyl]methyl]triphenylphosphonium iodide (1.66 g, 2.501 mmol) in anhydrous CH2Cl2 (40 mL), was added tBuOK (0.352 g, 3.137 mmol). The mixture was stirred at 20° C. for 16 h, then filtered through a short pad of silica gel. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (heptane/CH2Cl2 gradient from 70:30 to 30:70) to yield 701 mg (42%) of 5-[[7-[[5-[(1E)-2-[4-(dihexylamino)phenyl]ethenyl]thien-2-yl]ethynyl]-9,9-dibutyl-9H-fluorene-2-yl]ethynyl]thiophene-2-carboxaldehyde; 1H NMR (300.13 MHz, CDCl3) δ 9.88 (s, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.69 and 7.35 (AX, JAX=3.9 Hz, 2H), 7.68 (d, J=7.8 Hz, 1H), 7.56-7.49 (m, 4H), 7.33 and 6.61 (AA′XX′, JAX=8.9 Hz, 4H), 7.17 and 6.87 (AX, JAX=3.8 Hz, 2H), 6.95 (d, J=16.0 Hz, 1H), 6.86 (d, J=16.0 Hz, 1H), 3.28 (m, 4H), 2.00 (m, 4H), 1.60 (m, 4H), 1.33 (m, 12H), 1.11 (m, 4H), 0.91 (t, J=6.8 Hz, 6H), 0.69 (t, J=7.3 Hz, 6H), 0.59 (m, 4H).
Reaction SMILES: [CH:1]1([NH:7][C:8]([C@H:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[C:19]([NH2:24])[N:18]=1.C(N(CC)CC)C>CC#N>[NH2:24][C:19]1[N:20]=[C:21]([N:12]2[CH2:13][CH2:14][CH2:15][C@H:10]([C:8]([NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[O:9])[CH2:11]2)[CH:22]=[C:17]([Cl:16])[N:18]=1
Reactant: O=C(NC1CCCCC1)[C@H]1CCCNC1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1nc(Cl)cc(N2CCC[C@H](C(=O)NC3CCCCC3)C2)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To (3S)—N-cyclohexyl-3-piperidinecarboxamide (446 mg, 2.12 mmol) in CH3CN (10 mL) was added 4,6-dichloro-2-pyrimidinamine (382 mg, 2.332 mmol) and triethylamine (0.591 mL, 4.24 mmol), and the reaction mixture was stirred overnight at 50° C. LCMS show no starting material after 3 hours. The reaction was concentrated, and 3 mL of EtOAc was added until solid dissolved. Then 15 mL of hexane was added and solid crashed out of the solution. The solid was isolated by filtration to afford the title compound (430 mg) as a white solid. LC-MS (ES) m/z=338 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:39])[NH:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:41][O:42][C:43](=[O:68])[NH:44][CH:45]([C:49]([N:51]1[CH2:55][CH2:54][CH2:53][CH:52]1[C:56]1[NH:57][C:58]([C:61]2[CH:66]=[CH:65][C:64](Br)=[CH:63][CH:62]=2)=[CH:59][N:60]=1)=[O:50])[CH:46]([CH3:48])[CH3:47].C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[CH3:1][O:2][C:3](=[O:40])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:39])[NH:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:25]=[CH:26][C:27]([C:64]3[CH:65]=[CH:66][C:61]([C:58]4[NH:57][C:56]([CH:52]5[CH2:53][CH2:54][CH2:55][N:51]5[C:49](=[O:50])[CH:45]([NH:44][C:43]([O:42][CH3:41])=[O:68])[CH:46]([CH3:48])[CH3:47])=[N:60][CH:59]=4)=[CH:62][CH:63]=3)=[CH:28][CH:29]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1C(=O)Nc1cccc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1CCCC1C(=O)Nc1cccc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)c1)C(C)C
Temperature: 85 °C
Yield: 5.1 %

Procedure:
(2-Methyl-1-{2-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-3-ylcarbamoyl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester (135 mg, 0.246 mmol), (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (110 mg, 0.246 mmol), Pd(PPh3)4 (14 mg, 0.0123 mmol) and a 2 M aqueous solution of potassium carbonate (0.246 mL, 0.492 mmol) were degassed in 1,2-dimethoxyethane (2.5 mL) for 13 min. The stirred suspension was heated to 85° C. for 3 hours then concentrated, brought up in DMF/water and purified by reverse phase preparative HPLC to provide {1-[2-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-[1,1′;4′,1″]terphenyl-3″-ylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (10 mg, 5%). (MeOH-d4, 400 MHz) 7.90 (s, 1H), 7.82-7.66 (m, 8H), 7.54-7.51 (m, 1H), 7.40-7.37 (m, 2H), 4.59 (m, 1H), 4.24 (m, 1H), 4.02-3.73 (m, 4H), 3.66 (s, 3H), 3.65 (s, 3H), 2.36-2.02 (m, 10H), 1.15-0.88 (m, 12H); MS (ESI) m/z 792 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([NH:17][C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[N:19]=2)[CH:10]=1.[OH-:26].[Na+].OO>CS(C)=O>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]([NH2:14])=[O:26])=[C:11]([NH:17][C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[N:19]=2)[CH:10]=1
Reactant: [OH-]
Reactant: Cc1cc(C)nc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)ccc2C#N)c1
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)nc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)ccc2C(N)=O)c1
Temperature: 35 °C
Reaction time: 0.67 h

Procedure:
To a mixture of rel-4-{[(1R,2S)-2-aminocyclohexyl]amino}-2-[(4,6-dimethylpyridin-2-yl)amino]benzonitrile (70 mg, 0.21 mmol) and sodium hydroxide (4.0 M in water, 0.25 mL, 1.0 mmol) in DMSO (2.5 mL) was added hydrogen peroxide (30% aqueous solution, 0.10 mL, 0.98 mmol). The reaction mixture was heated to 35° C. After 40 minutes, the reaction mixture was filtered and purified via reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient) to give rel-4-{[(1R,2S)-2-aminocyclohexyl]amino}-2-[(4,6-dimethylpyridin-2-yl)amino]benzamide. MS ESI calc'd. for C20H28N5O [M+H]+ 354. Found 354. 1H NMR (300 MHz, CD3OD) δ 7.67 (s, 1H), 7.47 (d, J=8.7 Hz, 1H), 6.55 (m, 2H), 6.21-6.25 (m, 1H), 3.55-3.52 (m, 1H), 3.17 (br s, 1H), 2.37 (s, 3H), 2.22 (s, 3H), 1.77-1.42 (m, 8H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH:10][CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:12][C:13]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[F:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][NH:10][CH3:11])=[CH:3][C:2]=1[C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([CH2:25][N:22]2[CH2:23][CH2:24][N:19]([C:17]([O:16][C:13]([CH3:15])([CH3:14])[CH3:12])=[O:18])[CH2:20][CH2:21]2)[CH:27]=1
Reactant: CNCc1ccc(F)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(B(O)O)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CNCc1ccc(F)c(-c2cccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c2)c1
Temperature: 150 °C
Yield: 65.8 %

Procedure:
To the solution of [(3-bromo-4-fluorophenyl)methyl]methylamine (0.52 g, 2.39 mmol) in p-dioxane/H2O (15/5 mL) was added {3-[(4-{[(1,1-dimethylethyl)oxy]carbonyl}-1-piperazinyl)methyl]phenyl}boronic acid (1.15 g, 3.60 mmol), Pd(PPh3)4 (139 mg, 0.12 mmol), and K2CO3 (1.33 g, 9.6 mmol). The result mixture was heated in a microwave machine at 150° C. for 15 mins. The organic layer was separated and concentrated. The residue was redissolved in EtOAc (˜70 mL), washed with H2O (20 mL), brine (20 mL), dried over Na2SO4, filtered, concentrated and purified by CombiFlash chomatograph to afford 0.65 g (66%) of the title compound. LC-MS m/z 414 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]2)=[N:4][CH:5]=[C:6](I)[CH:7]=1.[C:17]1([C:23]#[CH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:1][C:2]1[C:3]([NH:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]2)=[N:4][CH:5]=[C:6]([C:24]#[C:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1
Reactant: C#Cc1ccccc1
Reactant: O[C@H]1CC[C@H](Nc2ncc(I)cc2F)CC1
Product: O[C@H]1CC[C@H](Nc2ncc(C#Cc3ccccc3)cc2F)CC1

Procedure:
The title compound, yellow solid, MS: m/e=311.2 (M+H+), can be prepared in accordance with the general method of example 1, step 1 from trans-4-(3-fluoro-5-iodopyridin-2-ylamino)cyclohexanol (example 18, step 1) and phenylacetylene.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15]([C@H:17]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][N:18]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=O.[CH3:34][O:35][C:36]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:37]=1[CH2:38][NH2:39]>CO.C(Cl)Cl>[CH3:34][O:35][C:36]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:37]=1[CH2:38][NH:39][CH2:15][C@H:17]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][N:18]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@@H]1C=O
Reactant: COc1ccc(CN)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CNC[C@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)c(OC)c1
Temperature: 25 °C
Yield: 63 %

Procedure:
Sodium triacetoxyborohydride (3.1 g, 15 mm) was added to a mixture of (3R)-tert-butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.3 g, 5.0 mmol theory), 2,4-dimethoxybenzylamine (0.77 ml, 5.5 mmol), and dry 4 A sieves in 1,2-dichloroethane (25 ml) stirring at ambient temperature. After stirring at ambient temperature overnight the reaction solution was transferred to a separatory funnel with EtOAc and saturated NaHCO3. Extraction with EtOAc (2×), washing the combined organic layers with brine and drying over MgSO4 afforded 1.6 g of crude product. Flash chromatography (SiO2, 1 to 10% 2N N3 in MeOH/CH2Cl2) gave pure product (1.3 g, 63% yield over the previous 3 steps). MS (ESI) 413 (M+H).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH3:9][C:10]1([CH3:17])[CH2:15][CH2:14][CH2:13][C:12](=O)[CH2:11]1>O.CO>[CH3:9][C:10]1([CH3:17])[CH2:15][CH2:14][CH2:13][C:12](=[N:2][OH:3])[CH2:11]1
Reactant: CC1(C)CCCC(=O)C1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(C)CCCC(=NO)C1

Procedure:
Hydroxylamine hydrochloride (8.76 g) was dissolved in water (100 mL). To the solution, a solution of sodium acetate (17.8 g) and 3,3-dimethylcyclohexanone (4.55 g) in methanol (20 mL) was added at room temperature, and the mixture was heated to reflux for 1.5 hours. Organic matter was extracted with ethyl acetate and dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure to obtain a crude product of 3,3-dimethylcyclohexanone oxime.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[NH:8]2)=[C:4]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:34])[CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:20][CH2:19]2)[N:3]=1.[C:35](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:8]2[CH3:35])=[C:4]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:34])[CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:20][CH2:19]2)[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(-c3ccc(F)cc3)[nH]c2n1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(-c2ccc(F)cc2)nc2c(N3CCN(C(=O)COc4ccc(Cl)cc4)CC3)nc(N)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
To a solution of 2-amino-6-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-8-(4-fluorophenyl)-9H-purine (48 mg, 0.1 mmol) in DMF (2 ml) was added potassium carbonate (28 mg, 0.2 mmol) and methyl iodide (6 μl, 0.1 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was evaporated in vacuo and the crude residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1:50), yielding the pure title compound (40 mg, 80%).