Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C@H:12]([C:14]([NH:16][C@H:17]([C:25]([NH:27][C@H:28]([C:32]([NH:34][CH2:35][C:36]([NH:38][CH2:39][C:40]1[C:53]([O:54][CH3:55])=[CH:52][CH:51]=[C:50]2[C:41]=1[O:42][C:43]1[C:44]([CH2:60][C:61]([O:63][CH3:64])=[O:62])=[C:45]([O:58][CH3:59])[CH:46]=[CH:47][C:48]=1[C:49]2([CH3:57])[CH3:56])=[O:37])=[O:33])[CH:29]([CH3:31])[CH3:30])=[O:26])[C@@H:18]([CH3:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:15])[CH3:13])=O)C1C=CC=CC=1>O1CCOCC1.[Pd]>[NH2:11][C@H:12]([C:14]([NH:16][C@H:17]([C:25]([NH:27][C@H:28]([C:32]([NH:34][CH2:35][C:36]([NH:38][CH2:39][C:40]1[C:53]([O:54][CH3:55])=[CH:52][CH:51]=[C:50]2[C:41]=1[O:42][C:43]1[C:44]([CH2:60][C:61]([O:63][CH3:64])=[O:62])=[C:45]([O:58][CH3:59])[CH:46]=[CH:47][C:48]=1[C:49]2([CH3:57])[CH3:56])=[O:37])=[O:33])[CH:29]([CH3:31])[CH3:30])=[O:26])[C@@H:18]([CH3:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:15])[CH3:13]
Reactant: COC(=O)Cc1c(OC)ccc2c1Oc1c(ccc(OC)c1CNC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C)C(C)C)C2(C)C
Agent: [Pd]
Solvent: C1COCCO1
Product: COC(=O)Cc1c(OC)ccc2c1Oc1c(ccc(OC)c1CNC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](C)N)[C@@H](C)OC(C)(C)C)C(C)C)C2(C)C
Reaction time: 19 h
Yield: 99.2 %

Procedure:
A solution of 70 mg of methyl 5-[(N-benzyloxycarbonyl-L-alanyl-O-tert-butyl-L-threonyl-L-valyl-glycyl)aminomethyl]-3,6-dimethoxy-9,9-dimethylxanthene-4-acetate in 20 ml of dioxan was treated with 47 mg of palladium/charcoal (10%) and stirred under hydrogen for 19 hours. After filtering off the catalyst the filtrate was concentrated, whereby 59 mg of colourless methyl 5-[(L-alanyl-O-tert-butyl-L-threonyl-L-valyl -glycyl)aminomethyl]-3,6-dimethoxy-9,9-dimethylxanthene-4-acetate was obtained; IR 3300, 2970, 1741,. 1680, 1658, 1631, 1523, 1494 cm-1.
Reaction SMILES: CC(C)([O-])C.[K+].C(S[N:12]=[N:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:17]([OH:19])=[O:18])(C)(C)C.Cl>CS(C)=O>[NH:13]1[C:14]2[C:22](=[CH:21][CH:20]=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH:23]=[N:12]1
Reactant: Cc1ccc(C(=O)O)cc1N=NSC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)c1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
To a stirred solution of potassium tert-butoxide (8.14 g, 72.7 mmol) in DMSO (30 mL) is added a solution of 3-(tert-butylthio)diazenyl-4-methylbenzoic acid (1.85 g, 7.34 mmol) in DMSO (20 mL). The mixture is stirred overnight at rt. The mixture is diluted with ice-water, acidified with 1N aqueous HCl to a pH of about 5 to about 6 and extracted with EtOAc (3×). The combined organic layers are washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo to afford 1.17 g (98%) of 1H-indazole-6-carboxylic acid as a tan solid: IR (diffuse reflectance) 3171, 3135, 3067, 3014, 2950, 2889, 2865, 1685, 1326, 1308, 1240, 960, 945, 762, 740 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 13.4, 13.0, 8.2, 8.2, 7.9, 7.7.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH:10]=[C:4]2[CH:3]=1.[C:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)(=[O:20])[CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCCC1>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:10]=[C:4]3[CH:3]=[C:2]([C:25]4[CH:26]=[C:21]([C:18](=[O:20])[CH3:19])[CH:22]=[CH:23][CH:24]=4)[CH:7]=[CH:6][N:5]3[N:8]=2)=[CH:12][CH:13]=1
Reactant: Fc1ccc(-c2cc3cc(Br)ccn3n2)cc1
Reactant: CC(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cccc(-c2ccn3nc(-c4ccc(F)cc4)cc3c2)c1
Yield: 78.8 %

Procedure:
The procedure described in stage 2.4 is followed, starting with 0.300 g (1.03 mmol) of 5-bromo-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine obtained in stage 2.3, 0.185 g (1.13 mmol) of 3-acetylphenylboronic acid, 1.00 g (3.09 mmol) of caesium carbonate and 0.084 g (0.10 mmol) of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in 5 ml of a 9/1 mixture of tetrahydrofuran and water. After chromatography on silica gel, elution being carried out with a mixture of cyclohexane and ethyl acetate (8/2), 0.268 g (78%) of the expected product is obtained in the form of a beige powder.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH3:19])=[CH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.Cl[C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37]>C(Cl)Cl.C1COCC1>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][C:14]([O:17][CH:18]([CH:20]3[CH2:25][CH2:24][N:23]([C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])[CH2:22][CH2:21]3)[CH3:19])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC(Oc1ccc(-c2ccc(S(C)(=O)=O)cc2)nc1)C1CCNCC1
Reactant: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)OC(=O)N1CCC(C(C)Oc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
A mixture of (±)-2-[4-(methylsulfonyl)phenyl]-5-{[1-(4-piperidinyl)ethyl]oxy}pyridine (0.27 g, 0.75 mmol) in CH2Cl2 (10 mL) and THF (5 mL) was treated with diisopropylethylamine (0.27 mL, 1.50 mmol). The mixture was cooled to 0° C., and then isopropyl chloroformate (1.0M in toluene, 0.82 mL, 0.82 mmol) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred overnight, diluted with CH2Cl2 (100 mL) and washed with water, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to a light brown oil. The crude material was purified by flash chromatography on a silica gel column eluted with 1:5 acetone/CH2Cl2 to give 0.31 g (93%) of the title compound as a white foam. 1H NMR (400 MHz, CDCl3): δ 8.38 (d, 1H, J=2.9 Hz), 8.13 (d, 2H, J=8.5 Hz), 8.01 (d, 2H, J=8.5 Hz), 7.73 (d, 1H, J=8.8 Hz), 7.35-7.25 (m, 1H), 4.91 (septet, 1H, J=6.2 Hz), 4.35-4.15 (m, 3H), 3.08 (s, 3H), 2.80-2.65 (m, 2H), 1.95-1.65 (m, 3H), 1.45-1.25 (m, 5H), 1.23 (d, 6H, J=6.3 Hz); LRMS (ESI), m/z 447 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[O:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:31](OC(N1C[C@@H]2C[C@H]1CN2)=O)(C)(C)C.N1(CC2C=CC([C@@H]3OC4=NC=CC=C4OC3)=CC=2)CCNCC1>>[C@H:10]12[CH2:31][C@H:13]([NH:8][CH2:9]1)[CH2:12][N:11]2[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]2[O:30][C:25]3=[N:26][CH:27]=[CH:28][CH:29]=[C:24]3[O:23][CH2:22]2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Agent: c1cnc2c(c1)OC[C@H](c1ccc(CN3CCNCC3)cc1)O2
Product: c1cnc2c(c1)OC[C@H](c1ccc(CN3C[C@@H]4C[C@H]3CN4)cc1)O2

Procedure:
The title product NN is prepared from NN-1 (prepared from Intermediate C and (1S,4S)-2,5-Diaza-bicyclo[2.2.1]-heptane-2-carboxylic acid tert-butyl ester according to General Method N) according to the procedure for synthesis of Intermediate S.
Reaction SMILES: C(OC([NH:8]/[C:9](/[NH:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:33][CH2:32][CH2:31][C@@H:26]2[C:27]([NH:29][CH3:30])=[O:28])=[CH:21][CH:20]=1)=[N:10]/C(OC(C)(C)C)=O)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[K+]>C(Cl)Cl>[CH3:30][NH:29][C:27]([C@H:26]1[CH2:31][CH2:32][CH2:33][N:25]1[C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:9]([NH2:10])=[NH:8])=[CH:20][CH:21]=1)=[O:28]
Reactant: CNC(=O)[C@H]1CCCN1c1ccc(N/C(=N\C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)[C@H]1CCCN1c1ccc(NC(=N)N)cc1
Reaction time: 4 h
Yield: 78.1 %

Procedure:
To 1-[4-({(E)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)phenyl]-N-methyl-D-prolinamide (Method 58; 1.9 g) was added DCM (60 ml) and TFA (20 ml). The reaction was stirred for 4 hours before removal of the solvent in vacuo. The reaction was basified with 2.0N KOH (20 ml) and extracted with DCM (2×50 ml). Product failed to extract in to DCM, the aqueous was reduced down to 90% of the initial volume and re-extracted with DCM (3×200 ml), dried and solvent removed in vacuo to yield the title compound as a brown solid (0.84 g, 78%). NMR (299.955 MHz) 7.79 (q, 1H), 7.57 (s, 1H), 7.18 (s, 2H), 7.03 (d, 2H), 6.48 (d, 2H), 3.91 (d, 1H), 3.58-3.54 (m, 1H), 3.17 (q, 1H), 2.56 (d, 3H), 2.19-2.09 (m, 2H), 2.01-1.89 (m, 2H); m/z 261.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([N:9]3[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:31][O:32][C:33](=[O:43])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41]Br)[CH:36]=1.O>CN(C)C=O>[CH3:31][O:32][C:33](=[O:43])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][N:14]([CH:11]2[CH2:12][CH2:13][N:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:28]=[CH:27][C:5]=4[N:6]=3)[CH2:10]2)[S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])(=[O:16])=[O:17])[CH:36]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CCN(c2nc3ccc(Cl)cc3s2)C1
Reactant: COC(=O)Cc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cccc(CN(C2CCN(c3nc4ccc(Cl)cc4s3)C2)S(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
N-[1(6-chlorobenzothiazole-2-yl)pyrrolidine-3-yl]-2-nitrobenzenesulfonamide (500 mg) was dissolved in dimethylformamide (5 mL). Sodium hydride (60%, oil, 50 mg) was added thereto and the mixture was stirred at room temperature for 1 hour. (3-bromomethylphenyl)acetic acid methyl ester (305 mg) was added thereto and the mixture was stirred for 16 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (412 mg). Yield: 60%.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[OH:14][CH2:15][C:16]([NH:18][CH3:19])=[O:17].C(N(C(C)C)CC)(C)C>ClCCl>[C:2](=[O:3])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[O:14][CH2:15][C:16]([NH:18][CH3:19])=[O:17]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CNC(=O)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)COC(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 16 h
Yield: 80.3 %

Procedure:
5.93 g (29.4 mmol) of 4-nitrophenyl chloroformate are added portionwise and at room temperature to a suspension of 2.62 g (29.4 mmol) of 2-hydroxy-N-methylacetamide and 16.5 g (58.7 mmol) of supported diisopropylethylamine (Ps-DIEA from Argonaut, charge=3.56 mmol/g) in 250 ml of dichloromethane. Orbital stirring is continued at room temperature for 16 hours. The resin is filtered off and rinsed with 150 ml of dichloromethane, and the filtrate is concentrated under reduced pressure. 6 g of product are obtained in the form of a pale yellow solid (purity estimated at 70%), and are used without further purification in the following step.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([CH:35]=1)[C:23]([N:25]=[S@@:26]([CH3:34])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>>[CH3:34][S@:26](=[N:25][C:23]([C:22]1[CH:35]=[C:18]([C:2]#[C:1][C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH:6]=[CH:7][CH:8]=2)[CH:19]=[N:20][CH:21]=1)=[O:24])(=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: C#Cc1cccc(NC(=O)OC(C)(C)C)c1
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Product: CC(C)(C)OC(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@@](C)(=O)c3ccccc3)c2)c1
Yield: 22.8 %

Procedure:
In a manner similar to that described in Example 449, tert-butyl 3-ethynylphenylcarbamate (0.098 g, 0.443 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (0.100 g, 0.295 mmol) reacted to give the title compounds as a white solid (32 mg, 23%).
Reaction SMILES: Cl[C:2]1[N:17]=[N:16][C:5]2[NH:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[BrH:18]>CCOC(C)=O.[OH-].[Na+]>[Br:18][C:2]1[N:17]=[N:16][C:5]2[NH:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: O=C1Nc2ccccc2Nc2nnc(Cl)cc21
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C1Nc2ccccc2Nc2nnc(Br)cc21
Temperature: 100 °C
Yield: 36 %

Procedure:
2-Chloro-5,10-dihydro-3,4,5,10-tetraaza-dibenzo[a,d]cyclohepten-11-one from Example 2 (400 mg, 1.62 mmol) was added to HBr (10 ml, 47% in water) and heated at 100° C. for 63 hours. The solution was cooled and diluted with EtOAc and NaOH (1M). The resultant precipitate was collected by filtration, washed with EtOAc and water and then dried under vacuum to give the title compound as a white solid (170 mg, 36%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([C:18]3[CH:19]=[CH:20][C:21]4[N:22]([CH:24]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[N:26]=4)[N:23]=3)[CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:31](=O)([O-])[O-].[K+].[K+].CN(C=O)C.IC>O>[CH3:31][N:11]([C:12]1[CH:13]=[C:14]([C:18]2[CH:19]=[CH:20][C:21]3[N:22]([CH:24]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[N:26]=3)[N:23]=2)[CH:15]=[CH:16][CH:17]=1)[S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:9])=[O:10]
Reactant: CC(=O)Nc1cn2nc(-c3cccc(NS(=O)(=O)c4ccc(C)cc4)c3)ccc2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CC(=O)Nc1cn2nc(-c3cccc(N(C)S(=O)(=O)c4ccc(C)cc4)c3)ccc2n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a round-bottomed flask was added N-(6-(3-(4-methylphenylsulfonamido)phenyl)imidazo[1,2-b]pyridazin-2-yl)acetamide (from Example 1, Step 5) (0.027 g, 0.064 mmol), potassium carbonate (0.013 g, 0.096 mmol), DMF (1.0 mL) and iodomethane (0.0044 mL, 0.071 mmol). The mixture was stirred at 25° C. for 14 h, then poured into water and extracted with EtOAc (3×30 mL). The combined extracts were washed with water (2×50 mL) and brine (50 mL) then dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (0 to 3% MeOH (2 M in NH3)/CH2Cl2) afforded the title compound as a light-yellow solid. MS (ESI positive ion) m/z: 436 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 10.92 (s, 1H), 8.27 (s, 1H), 8.07 (d, J=9.6 Hz, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.75 (t, J=1.9 Hz, 1H), 7.70 (d, J=9.6 Hz, 1H), 7.52 (t, J=7.9 Hz, 1H), 7.39-7.47 (m, 4H), 7.23 (dd, J=8.0 Hz, 1.4 Hz, 1H), 3.20 (s, 3H), 2.41 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:42])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](N(OC)C)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[CH:43]1([Mg]Br)[CH2:45][CH2:44]1.Cl>O1CCCC1>[CH:43]1([C:36](=[O:37])[CH2:35][O:34][C@H:31]2[CH2:32][CH2:33][C@H:28]([N:18]3[C:17](=[O:42])[C:16]([CH2:15][C:12]4[CH:11]=[CH:10][C:9]([C:4]5[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=5)=[CH:14][CH:13]=4)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]4[N:25]=[CH:26][N:27]=[C:19]34)[CH2:29][CH2:30]2)[CH2:45][CH2:44]1
Reactant: Br[Mg]C1CC1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)N(C)OC)CC2)c2ncnn12
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)C3CC3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-[(trans-4-{6-[(2′-Cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide (0.32 g) was dissolved in tetrahydrofuran (4 mL), cyclopropylmagnesium bromide (3.3 mL, 0.5M tetrahydrofuran solution) was added dropwise, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.23 g, 75%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[C:20]([CH2:25][OH:26])[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C1C=CN=CC=1.O=S(=O)=O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[C:20]([CH:25]=[O:26])[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(Br)c(CO)c2)[nH]1
Agent: O=S(=O)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(Br)c(C=O)c2)[nH]1
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
To the solution of 2-[5-(4-bromo-3-hydroxymethyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (196 mg, 0.46 mmol) in DMSO (3.5 ml) was added triethylamine (0.40 ml). The mixture was stirred for 30 minutes, and pyridine-sulfur trioxide (500 mg) was added. The mixture was stirred for 2 hours and was quenched with ice-water. The stirring was continued for additional 30 minutes and the mixture was extracted with EtOAc. The organic phase was washed with water and brine, and was dried with sodium sulfate. Concentration gave 2-[5-(4-Bromo-3-formyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (180 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:37]([O:39][C:40]1[CH:46]=[C:45]([N:47]2[CH2:52][CH2:51][CH:50]([N:53]3[CH2:58][CH2:57][N:56]([S:59]([CH3:62])(=[O:61])=[O:60])[CH2:55][CH2:54]3)[CH2:49][CH2:48]2)[CH:44]=[CH:43][C:41]=1[NH2:42])[CH3:38].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[CH:44][C:45]([N:47]4[CH2:52][CH2:51][CH:50]([N:53]5[CH2:58][CH2:57][N:56]([S:59]([CH3:62])(=[O:61])=[O:60])[CH2:55][CH2:54]5)[CH2:49][CH2:48]4)=[CH:46][C:40]=3[O:39][CH2:37][CH3:38])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1N
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: CCOc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OCC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 175 °C
Yield: 42.3 %

Procedure:
A mixture of 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (0.10 g, 0.20 mmol), 2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (0.076 g, 0.20 mmol) and para-toluenesulfonic acid (0.090 g, 0.47 mmol) in i-PrOH (5 mL) was heated in a microwave at 175° C. for 25 min. The reaction mixture was concentrated onto silica gel and purified by flash chromatography. Recrystallization from DCM and diethyl ether afforded N-(2,6-difluorophenyl)-2-(ethyloxy)-5-(3-{2-[(2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)benzamide (0.072 g, 43%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.76 (s, 1H), 9.35 (br. s., 1H), 8.36 (s, 1H), 8.24 (d, J=5.2 Hz, 1H), 8.06 (d, J=1.7 Hz, 1H), 7.66-7.81 (m, 2H), 7.35-7.48 (m, 3H), 7.15-7.32 (m, 3H), 6.89-7.01 (m, 1H), 6.67 (d, J=2.3 Hz, 1H), 6.54-6.60 (m, 1H), 6.44-6.53 (m, 1H), 4.23-4.33 (m, 2H), 4.07 (q, J=6.9 Hz, 2H), 3.66-3.80 (m, 2H), 3.05-3.13 (m, 4H), 2.87 (s, 3H), 2.56-2.73 (m, 5H), 2.36-2.46 (m, 2H), 1.78-1.89 (m, 2H), 1.49-1.61 (m, 2H), 1.44 (t, J=6.9 Hz, 3H), 1.25 (t, J=7.0 Hz, 3H). MS (M−H, ES−) 850.
Reaction SMILES: Cl.[C:2]1([C:8]2([NH:14][C:15](=[O:17])[CH3:16])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].CS(O[CH2:25][CH2:26][CH:27]([C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([Cl:46])[CH:40]=1)[CH2:28][N:29]([CH3:38])[C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=O)=O>O>[ClH:45].[CH3:38][N:29]([CH2:28][CH:27]([C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([Cl:46])[CH:40]=1)[CH2:26][CH2:25][N:11]1[CH2:12][CH2:13][C:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([NH:14][C:15](=[O:17])[CH3:16])[CH2:9][CH2:10]1)[C:30](=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(=O)NC1(c2ccccc2)CCNCC1
Reactant: CN(CC(CCOS(C)(=O)=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)NC1(c2ccccc2)CCN(CCC(CN(C)C(=O)c2ccccc2)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 70 °C

Procedure:
22.7 g of 4-phenyl-4-acetylaminopiperidine hydrochloride are dissolved in 20 ml of water. 10 ml of concentrated sodium hydroxide solution are added. The mixture is extracted twice with dichloromethane and the organic phase is dried over MgSO4, The solution obtained is added to the product obtained in step 8. The mixture is concentrated to dryness, 30 ml of DMF are added and the mixture is heated to 70° C. for 1 h 30 min. The solution is poured very slowly onto 30 ml of water+ice. The precipitate is filtered off, taken up several times in water and drained. It is purified by chromatography on silica; elution: pure dichloromethane, then dichloromethane with addition of methanol up to 10%.
Reaction SMILES: [O:1]=[C:2]([CH3:12])[CH2:3][CH:4]1[CH:6]([C:7]([OH:9])=[O:8])[C:5]1([CH3:11])[CH3:10].[C:13](=O)(O)[O-].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[O:1]=[C:2]([CH3:12])[CH2:3][CH:4]1[CH:6]([C:7]([O:9][CH3:13])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: O=C([O-])O
Reactant: CC(=O)CC1C(C(=O)O)C1(C)C
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)C1C(CC(C)=O)C1(C)C
Reaction time: 4 h
Yield: 96.4 %

Procedure:
10 g of 3-(2-oxopropyl)-2,2-dimethyl-cyclopropane carboxylic acid in 100 ml of acetone were heated to 30° C. to 34° C. in the presence of 7.35 g of potassium bicarbonate and 5 ml of dimethyl sulfate. After 4 hours of stirring, 0.85 ml of dimethyl sulfate were added and the reaction medium was held at 30° to 34° C. for 20 hours. After filtration, the product was taken up in ethyl ether and the solvent was evaporated. The residue was chromatographed on silica (eluant: hexane - ethyl acetate 8-2) to obtain 10.43 g of the expected product.
Reaction SMILES: [CH2:1]([NH:8][CH:9]([C:30]#[N:31])[CH2:10][C@H:11]1[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:14]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-:33].[K+].[K+].OO>CS(C)=O.O>[CH2:1]([NH:8][CH:9]([C:30](=[O:33])[NH2:31])[CH2:10][C@H:11]1[N:15]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C@H:14]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](CC(C#N)NCc2ccccc2)N1C(=O)OC(C)(C)C
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](CC(NCc2ccccc2)C(N)=O)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2.6 g of di-tert-butyl (2S,5S)-5-(2-benzylamino-2-cyanoethyl)pyrrolidine-1,2-dicarboxylate were dissolved in 6.5 ml of dimethyl sulfoxide. 373 mg of finely ground potassium carbonate and 1.08 ml of a 30% strength hydrogen peroxide solution were added thereto. The mixture was stirred at room temperature for 14 h and was then heated at 35° C. for 30 min. The solution was diluted with 60 ml of water and extracted 3 times with 100 ml of ethyl acetate each time. The combined organic phases were washed once with 120 ml of a saturated sodium chloride solution and dried with sodium sulfate. The solvents were removed in vacuo, and the residue was chromatographed on silica gel.