Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH2:12][CH3:13])[CH:6]=[C:7]([Br:10])[C:8]=1[OH:9].Cl.[CH3:16][O:17][NH2:18].C(O)C.C>N1C=CC=CC=1>[CH3:16][O:17][N:18]=[C:11]([C:5]1[CH:6]=[C:7]([Br:10])[C:8]([OH:9])=[C:3]([CH2:2][NH2:1])[CH:4]=1)[CH2:12][CH3:13]
Reactant: CCC(=O)c1cc(Br)c(O)c(CN)c1
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCC(=NOC)c1cc(Br)c(O)c(CN)c1
Yield: 78.9 %

Procedure:
A solution of 9.0 g of 3'-aminomethyl-5'-bromo-4'-hydroxypropiophenone and 9.0 g of O-methylhydroxylamine hydrochloride in 80 ml of pyridine and 40 m of ethanol is refluxed with heating for 25 minutes. Activated charcoal is added to the reaction mixture and then filtered off. The filtrate is concentrated under reduced pressure and to the residue are added 200 ml of ice-cold water and 6.0 g of sodium hydrogencarbonate and stirred. The insoluble substance is collected by filtration and washed with water and then dried to give 7.9 g of 3'-aminomethyl-5'-bromo-4'-hydroxypropiophenone O-methyloxime as fine powdery solid, melting at 178°-178.5° C. with decomposition.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[NH:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=[C:37]1[NH:45][CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>>[CH3:34][O:33][C:29]1[CH:28]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:49]2[CH2:48][CH2:47][CH:46]([NH:45][C:37]3[NH:36][C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=4[N:38]=3)[CH2:51][CH2:50]2)([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:9]1)=[O:7]
Reactant: c1ccc2[nH]c(NC3CCNCC3)nc2c1
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: I
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 6.6 using 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine and (1H-benzimidazol-2-yl)(piperidin-4-yl)amine hydriodic acid to give, after purifying by chromatography on silica gel eluting with 25% methanol/ethyl acetate, the title compound: Rf=0.20 (silica gel, 40% methanol/ethyl acetate).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][OH:12].[CH3:13]N(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.O>C(Cl)Cl>[CH3:13][O:12][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][OH:1]
Reactant: OCCCc1ccccc1CO
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: O
Solvent: ClCCl
Product: COCCCc1ccccc1CO
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of the title A compound, 3-(2-hydroxymethyl-phenyl)-propan-1-ol (14.9 g, 90 mmol) and proton-sponge (25 g, 1.3 eq.) in methylene chloride (500 mL) is added at 0° C. under nitrogen trimethyloxonium-tetrafluoroborate (17.3 g, 117 mmol). The reaction mixture is further stirred for 5 h at room temperature before filtration. The filtrate is poured into water and the aqueous layer extracted twice with methylene chloride. The combined organic extracts are dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (hexane/EtOAc 7/3 to 1/1 and to AcOEt/MeOH 9/1) to afford the title compound: TLC, Rf (hexane/AcOEt 4/1)=0.57. MS 198.0 [M+18].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].C(N(CC)CC)C.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C1COCC1>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][CH2:2][CH2:3][OH:4])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: NCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCO)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
To a solution of 2-aminoethanol (2.3 mL, 39 mmol), and triethylamine (16 mL, 120 mmol) in anhydrous THF (100 mL) was added 4-bromobenzene-1-sulfonyl chloride (10 g, 39 mmol) portion wise and the reaction mixture stirred at room temperature for 16 h. The reaction was filtered, the filtrate was concentrated and the residue was purified by column chromatography (silica, ethyl acetate/hexanes gradient) to afford the desired product (5.5 g, 50%): 1H NMR (500 MHz, CDCl3) δ 7.74 (td, J=9.0, 2.1 Hz, 2H), 7.67 (td, J=9.0, 2.1 Hz, 2H), 5.08 (s, 1H), 3.72 (t, J=5.1 Hz, 2H), 3.12 (t, J=4.8 Hz, 2H), 1.83 (s, 1H).
Reaction SMILES: I[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)[CH:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([N:26]1[CH2:27][CH:28]=[C:29]([C:2]2[CH:3]=[C:4]([NH:8][C:9]3[CH:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[N:16]4)=[CH:11][CH:10]=3)[N:5]=[CH:6][N:7]=2)[CH2:30][CH2:31]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Ic1cc(Nc2ccc3cccnc3c2)ncn1
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(Nc3ccc4cccnc4c3)ncn2)CC1

Procedure:
This compound could be prepared from (6-iodo-pyrimidin-4-yl)-quinolin-7-yl-amine and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester via Suzuki coupling reaction.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH2:4][S:5][CH2:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].C(N(CC)CC)C.[CH:19]1([N:25]=[C:26]=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(#N)C>[CH:19]1([NH:25][C:26]([NH:2][C:3]2[CH2:4][S:5][CH2:6][C:7]=2[C:8]([O:10][CH3:11])=[O:9])=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)C1=C(N)CSC1
Reactant: O=C=NC1CCCCC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C1=C(NC(=O)NC2CCCCC2)CSC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
9.3 parts by weight of 3-amino-4-methoxycarbonyl-1,5-dihydrothiophene hydrochloride, 6.0 parts by weight of triethylamine, 7.4 parts by weight of cyclohexyl isocyanate and 30 parts by weight of acetonitrile were combined, and the mixture was stirred for 3 hours at 25° C. and then evaporated down. The residue was washed with water and recrystallized from toluene. 4.5 parts by weight of N-cyclohexyl-N'-(3-methoxycarbonyl-2,5-dihydrothien-4-yl)-urea of melting point 153°-154° C. were obtained.
Reaction SMILES: CCCP(=O)=O.[CH:7]1([C:10]2[C:11]([NH2:25])=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:18]=3)[CH:15]=2)[CH2:9][CH2:8]1.[N:26]1([C:30]([C:32]2[CH:36]=[N:35][N:34]([CH3:37])[C:33]=2[C:38](O)=[O:39])=[O:31])[CH2:29][CH2:28][CH2:27]1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH:7]1([C:10]2[C:11]([NH:25][C:38]([C:33]3[N:34]([CH3:37])[N:35]=[CH:36][C:32]=3[C:30]([N:26]3[CH2:29][CH2:28][CH2:27]3)=[O:31])=[O:39])=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:18]=3)[CH:15]=2)[CH2:9][CH2:8]1
Reactant: Nc1cc2nc(-c3ccccc3)cn2cc1C1CC1
Reactant: Cn1ncc(C(=O)N2CCC2)c1C(=O)O
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1cc2nc(-c3ccccc3)cn2cc1C1CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 17.6 %

Procedure:
Propylphosphonic anhydride solution (50% in ethyl acetate, 0.59 ml) was added to a cooled (0° C.) solution of 6-cyclopropyl-2-phenyl-imidazo[1,2-a]pyridin-7-ylamine (100 mg, 0.40 mmol), 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (Step 3, 167 mg, 0.51 mmol), and N,N-diisopropylethylamine (311 mg) in ethyl acetate (3 ml). The mixture was stirred for 30 min at 0° C. and overnight at r.t. The reaction mixture was taken up in ethyl acetate, washed with water, dried (Na2SO4) and evaporated. The title compound (31 mg, 18%) was isolated from the residue by preparative, inverse-phase HPLC (Agilent Zorbax XdB-C18 column, time per run ˜7 min, flow rate 30 ml/min, solvent gradient H2O/CH3CN=95:5-5:95). MS (m/e)=441.3 [M+H+].
Reaction SMILES: C[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].ClC1C=CC(S(=O)(=O)[NH:30][CH:31]([CH3:33])[CH3:32])=CC=1C(O)=O.N1CCCC1>>[CH:31]([NH:30][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])([CH3:33])[CH3:32]
Reactant: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Reactant: CC(C)NS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Solvent: C1CCNC1
Product: CC(C)NS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Yield: 40 %

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-isopropylsulfamoyl-benzoic acid and pyrrolidine and obtained in 40% yield. MS (m/e): 311.2 (MH−, 100%).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[H][H]>O1CCCC1.[Pd]>[CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([C:10]3[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(C2CCN(C3CC3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(C2CCN(C3CC3)CC2)cc1

Procedure:
0.57 g 1-cyclopropyl-4-(4-nitro-phenyl)-piperidine are dissolved in 30 mL tetrahydrofuran and combined with Pd/C. The mixture is hydrogenated for 72 h at 7 bar hydrogen pressure. Then the catalyst is filtered off and the solvent is eliminated in vacuo. The residue is used in the next stage of the synthesis without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](SC)=[N:7][C:6]=2[CH:18]=1.C(OC([NH:26][CH:27]1[CH2:32][CH2:31][N:30](N)[CH2:29][CH2:28]1)=O)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N:30]3[CH2:31][CH2:32][CH:27]([NH2:26])[CH2:28][CH2:29]3)=[N:7][C:6]=2[CH:18]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(N)CC1
Reactant: CSC1=Nc2cc(Cl)ccc2Nc2ccccc21
Product: NC1CCN(C2=Nc3cc(Cl)ccc3Nc3ccccc32)CC1
Yield: 18.1 %

Procedure:
8-Chloro-11-methylsulfanyl-5H-dibenzo[b,e][1,4]diazepine (166JO50) (50 mg, 0.11 mmol) and 4-(tert-butoxycarbonylamino)-aminopiperidine (39 mg, 0.2 mmol) were reacted according to GP8 to give 6.5 mg of the title compound (166JO55). MS (ESI) 327 (MH+). Purity for MH+ (UV/MS) 100/99.
Reaction SMILES: [Br-].[O:2]1[CH2:7][CH2:6][CH2:5][O:4][CH:3]1[CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[C:35]([C:37]1[CH:42]=[CH:41][C:40]([C@H:43]2[CH2:48][CH2:47][C@H:46]([C@H:49]3[CH2:54][CH2:53][C@H:52]([CH:55]=O)[CH2:51][CH2:50]3)[CH2:45][CH2:44]2)=[CH:39][CH:38]=1)#[N:36]>C1COCC1>[O:4]1[CH2:5][CH2:6][CH2:7][O:2][CH:3]1[CH2:8][CH:9]=[CH:55][C@H:52]1[CH2:53][CH2:54][C@H:49]([C@H:46]2[CH2:45][CH2:44][C@H:43]([C:40]3[CH:39]=[CH:38][C:37]([C:35]#[N:36])=[CH:42][CH:41]=3)[CH2:48][CH2:47]2)[CH2:50][CH2:51]1
Reactant: N#Cc1ccc([C@H]2CC[C@H]([C@H]3CC[C@H](C=O)CC3)CC2)cc1
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc([C@H]2CC[C@H]([C@H]3CC[C@H](C=CCC4OCCCO4)CC3)CC2)cc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A mixture of (2-(1,3-dioxan-2-yl)ethyl)triphenylphosphonium bromide (25.0 g, 54.7 millimols) with THF (150 ml) was cooled down to -20° C., followed by adding t-BuOK (6.1 g, 54.7 millimols) to the mixture, stirring for 30 minutes, dropwise adding to the mixture, a THF (80 ml) solution of trans-4-(trans-4-(4-cyanophenyl)cyclohexyl)cyclohexanecarbaldehyde (14.4 g, 49.8 millimols) so as to keep the temperature at -20° C. or lower, stirring the mixture at the same temperature for 2 hours, and treating the reaction product in the same manner as in Example 2, except that the quantity of ethyl acetate used for extraction was made 400 ml, to obtain raw 4-(trans-4-(trans-4-(3-(1,3-dioxan-2-yl)propenyl)cyclohexyl)cyclohexyl)benzonitrile (17.5 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[C:6]([NH:8][C:9]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:29][C:10]=1[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[N:15]=1)=[O:12])=[O:7].[SH:42][C:43]1[CH:51]=[CH:50][C:46]([C:47]([OH:49])=[O:48])=[CH:45][CH:44]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:33]1([C:30]2[CH:31]=[CH:32][C:9]([NH:8][C:6]([C:5]3[CH:4]=[C:3]([CH:41]=[CH:40][CH:39]=3)[CH2:2][S:42][C:43]3[CH:51]=[CH:50][C:46]([C:47]([OH:49])=[O:48])=[CH:45][CH:44]=3)=[O:7])=[C:10]([C:11](=[O:12])[NH:13][C:14]3[CH:18]=[CH:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=4)[N:15]=3)[CH:29]=2)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: O=C(Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1)c1cccc(CCl)c1
Reactant: O=C(O)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(SCc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3C(=O)Nc3ccn(-c4cccc(C(F)(F)F)c4)n3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
Into a round bottom flask was placed a solution of intermediate 21a (0.0580 mmol, 1 equiv), 4-mercaptobenzoic acid (11 mg, 0.0696 mmol, 1.2 equiv), potassium carbonate (24 mg, 3 equiv), and DMF (1 mL). The solution was stirred at room temperature overnight. The solvent was evaporated at reduced pressure and the residue was partitioned between dichloromethane and water. The organic phase was dried (Na2SO4). The solvent was evaporated and the residue was purified by reverse phase HPLC eluting with 0.05% TFA in a water/acetonitrile gradient to give 34 mg of product. 1H-NMR (400 MHz, DMSO, ppm): δ 11.55 (s, 1H), 11.48 (s, 1H), 8.67 (d, J=2.6 Hz, 1H), 8.32 (d, J=8.3 Hz, 1H), 8.19 (S, 1H), 8.16 (d, J=7.8 Hz, 1H), 8.01 (s, 1H), 7.85-7.71 (m, 5H), 7.65 (d, J=7.5 Hz, 3H), 7.52 (t, J=7.7 Hz, 1H), 7.44 (d, J=8.7 Hz, 2H), 7.04 (d, J=2.7 Hz, 1H), 4.46 (s, 2H), 3.30 (s, 4H), 1.70 (s, 4H), 1.59 (s, 2H). MS (ES, m/z) 700 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)=[N:15]3)=[C:10]([CH3:30])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:31][C:32]1[CH:33]=[C:34]([CH2:38][S:39]([N:42]([CH3:44])[CH3:43])(=[O:41])=[O:40])[CH:35]=[CH:36][CH:37]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>O1CCOCC1>[CH3:43][N:42]([CH3:44])[S:39]([CH2:38][C:34]1[CH:35]=[CH:36][CH:37]=[C:32]([NH:31][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:16]4[C:11]([CH:12]=[N:13][C:14]([NH:17][C:18]5[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=5)=[N:15]4)=[C:10]([CH3:30])[N:9]=3)[CH:3]=2)[CH:33]=1)(=[O:40])=[O:41]
Reactant: CN(C)S(=O)(=O)Cc1cccc(N)c1
Reactant: COc1cc(Nc2ncc3c(C)nc(-c4cccc(Br)c4)n3n2)cc(OC)c1OC
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccc(Nc5cccc(CS(=O)(=O)N(C)C)c5)c4)n3n2)cc(OC)c1OC
Temperature: 140 °C
Yield: 24.4 %

Procedure:
In a similar manner as described in Example 66, 7-(3-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (Example 9) (40 mg, 0.085 mmol), 1-(3-aminophenyl)-N,N-dimethylmethanesulfonamide (21.9 mg, 0.102 mmol), (S)-(−)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl ((S)-BINAP) (15.9 mg, 0.026 mmol), Tris(dibenzylidineacetone)dipalladium (0) (7.8 mg, 0.008 mmol) and sodium t-butoxide (11.4 mg, 0.12 mmol) in 1,4-dioxane (1.5 mL) were heated with microwave radiation at 140° C. for 60 minutes in a sealed reaction vessel to give N,N-dimethyl-1-{3-[(3-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]imidazo[5,1-f][1,2,4]triazin-7-yl}phenyl)amino]phenyl}methanesulfonamide (0.0125 g) as a yellow solid. 1H NMR (CDCl3) δ8.80 (s, 1H), 8.15 (dd, J=1.8, 1.8 Hz, 1H), 8.06-8.04 (m, 1H), 7.36 (dd, J=8.0, 7.9 Hz, 1H), 7.25-7.22 (m, 2H), 7.16 (dd, J=1.9, 1.8, 1H), 7.10 (ddd, J=8.1, 2.4, 0.9 Hz, 1H), 6.93-6.91 (m, 4H), 6.10 (s, 1H), 4.17 (s, 2H), 3.84-3.83 (m, 9H) 2.76 (s, 6H), 2.60 (s, 3H). MS m/z 605 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][N:14]=1>C(#N)C>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([I:19])=[CH:15][N:14]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(I)cn1
Reactant: O=C(CBr)c1ccc(O)cc1
Solvent: CC#N
Product: Oc1ccc(-c2cn3cc(I)ccc3n2)cc1
Temperature: 110 °C
Yield: 60.7 %

Procedure:
987 mg (corresponding to 4.55 mmol) of 2-bromo-4′-hydroxyacetophenone and 1.00 g (corresponding to 4.55 mmol) of 2-amino-5-iodopyridine were dissolved in 50 mL of acetonitrile. The resulting solution was refluxed in an oil bath at 110° C. for 2 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered and recovered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 10 mL of water and 1 mL of methanol. Then, about 10 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 5 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 927 mg (corresponding to 2.76 mmol) of 2-(4′-hydroxyphenyl)-6-iodoimidazo[1,2-a]pyridine (FIG. 2-10, Step 2).
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].Br[C:31]1[CH:32]=[C:33]([C:37]2[CH:42]=[C:41]([NH:43][CH:44]3[CH2:46][CH2:45]3)[N:40]=[C:39]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=3)[CH:38]=2)[CH:34]=[N:35][CH:36]=1>COCCOC.C(Cl)Cl>[CH:44]1([NH:43][C:41]2[N:40]=[C:39]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=3)[CH:38]=[C:37]([C:33]3[CH:34]=[N:35][CH:36]=[C:31]([C:12]4[CH:11]=[CH:10][C:9]([C:7]([N:1]5[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]5)=[O:8])=[CH:14][CH:13]=4)[CH:32]=3)[CH:42]=2)[CH2:46][CH2:45]1
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCNCC3)cc2)OC1(C)C
Reactant: Brc1cncc(-c2cc(NC3CC3)nc(-c3ccccn3)c2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: O=C(c1ccc(-c2cncc(-c3cc(NC4CC4)nc(-c4ccccn4)c3)c2)cc1)N1CCNCC1

Procedure:
To a solution of piperazin-1-yl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (1.2 eq, 0.163 mmol, 0.052 g) in dry DME (1 ml) under an inert atmosphere of argon is added 2M Na2CO3 (3 eq, 0.408 mmol, 0.2 ml) followed by (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-cyclopropyl-amine (Example 1.26) (1 eq, 0.136 mmol, 0.050 g) and PdCl2dppf (0.1 eq, 0.0136 mmol, 0.001 g). The reaction mixture is heated using microwave radiation at 90° C. for 2 hours 30. The reaction mixture is dissolved in DCM and washed with water. The organic layer is dried over drying agent MgSO4, filtered and the organic solvent is reduced in vacuo. The crude residue is purified by reverse phase column chromatography (Isolute™ C18, 0-40% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH and followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 477.
Reaction SMILES: Br[C:2]1[C:3]2[CH2:19][N:18]([CH3:20])[CH2:17][CH2:16][C:4]=2[C:5]2[N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9][C:10]=2[CH:11]=1.[Li][CH:22](CC)C.CI>O1CCCC1>[CH3:15][O:14][C:7]1[C:8]([O:12][CH3:13])=[N:9][C:10]2[CH:11]=[C:2]([CH3:22])[C:3]3[CH2:19][N:18]([CH3:20])[CH2:17][CH2:16][C:4]=3[C:5]=2[N:6]=1
Reactant: [Li]C(C)CC
Reactant: COc1nc2cc(Br)c3c(c2nc1OC)CCN(C)C3
Solvent: CI
Solvent: C1CCOC1
Product: COc1nc2cc(C)c3c(c2nc1OC)CCN(C)C3
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A solution of the product from Example 100 (0.50 g, 1.48 mol) in 20 mL of tetrahydrofuran was cooled to −78° C. and treated dropwise with sec-BuLi (1.7 mL, 1.17 M in cyclohexane). The resulting green-black solution was stirred at −78° C. for 30 minutes. The reaction mixture was treated with MeI (123 μL, 2.00 mmol) and the resulting solution stirred at −78° C. for 30 minutes. The reaction mixture was warmed to room temperature and quenched with saturated aqueous NH4Cl solution (2.0 mL). The reaction mixture was extracted with CHCl3 (4×20 mL) and the combined organic extracts were dried and concentrated. The residue was broken up in heptane and collected by suction filtration to give the title compound as a orange solid (0.196 g, 48% yield).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[CH2:31]1[CH2:35][O:34][CH2:33][CH2:32]1>>[CH2:16]([N:20]([CH2:21][CH3:23])[CH2:31][CH2:35][O:34][C:33]1[CH:32]=[CH:11][C:6]([NH:5][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:30])=[CH:7][CH:8]=1)[CH3:15]
Reactant: C1CCOC1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Product: CCN(CC)CCOc1ccc(NC=C2C(=O)Nc3cc(C(=O)c4cccc(NC(=O)c5cc(C)nn5C)c4)ccc32)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 8.8 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 100 mg, 0.249 mmol) and THF (2 mL). To the resulting solution was added 4-(2-Diethylamino-ethoxy)-phenylamine1 (51.7 mg, 0.249 mmol), and the mixture was stirred for 24 h at 65° C. The reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The filtrate was then concentrated in vacuo and then redissolved into EtOAc and then Hexanes were added causing a precipitate to form. The precipitate was then filtered and washed with ˜1 mL of i-prOH yielding 8.8% (0.013 g, 0.022 mmol) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][C:30]=1[C:31]([NH:33][CH3:34])=[O:32]>>[C:39]([C:36]1[CH:37]=[CH:38][C:29]([NH:28][C:2]2[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([CH2:17][P:18](=[O:25])([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24])=[CH:26][CH:27]=3)[N:3]=2)=[C:30]([C:31](=[O:32])[NH:33][CH3:34])[CH:35]=1)#[N:40]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: CNC(=O)c1cc(C#N)ccc1N
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C#N)cc3C(=O)NC)n2)cc1)OCC
Yield: 21.8 %

Procedure:
The title compound was prepared using the procedure from Example 102 (Diethyl (4-{[4-{[4-fluoro-2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-benzyl)phosphonate) with diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (10.0 mg, 0.0236 mmol) and 2-amino-5-cyano-N-methylbenzamide (Compound 150A, 8.3 mg, 0.0472 mmol). The crude mixture was purified by MDP to obtain the title compound as white solid (2.9 mg, 22% yield). 1H NMR (400 MHz, CD3OD) δ=1.28 (t, J=7.1 Hz, 6 H), 2.92 (s, 3 H), 3.26 (d, J=21.5 Hz, 2 H), 4.07 (qd, J=7.3, 7.1 Hz, 4 H), 7.28 (dd, J=8.8, 2.5 Hz, 2 H), 7.56 (d, J=6.3 Hz, 2 H), 7.76 (d, J=8.6 Hz, 1 H), 8.04 (d, J=1.8 Hz, 1 H), 8.42 (s, 1 H), 8.88 (br. s., 1 H). MS (ES+): m/z 563.17 (100) [MH+]; HPLC: tR=1.04 min (UPLC, purity).