Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12][C:11]2[C:6](=[C:7]([OH:15])[CH:8]=[C:9]([CH:13]=[O:14])[CH:10]=2)[C:5](=[O:16])[CH2:4]1)[CH3:2].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([C:3]1([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:12][C:11]2[C:6](=[C:7]([O:15][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:8]=[C:9]([CH:13]=[O:14])[CH:10]=2)[C:5](=[O:16])[CH2:4]1)[CH3:2]
Reactant: CCC1(Cc2ccccc2)CC(=O)c2c(O)cc(C=O)cc2C1
Reactant: BrCc1ccccc1
Product: CCC1(Cc2ccccc2)CC(=O)c2c(cc(C=O)cc2OCc2ccccc2)C1

Procedure:
The product of Example 35 is benzylated with benzyl bromide as described in Example 15.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15])([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=1)=[O:15])([O-:11])=[O:10]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1cccc(F)c1
Product: O=C(Nc1cccc(F)c1)c1ccccc1[N+](=O)[O-]
Yield: 76.1 %

Procedure:
Using the procedure described in Example 93, Part A, 3-fluoroaniline-15.6 mmol) and 2-nitrobenzoyl chloride (17.2 mmol) yielded 3.09 g (76%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=1)\[C:13](O)=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[NH2:30][C@H:31]1[C@@H:34]([CH2:35][N:36]2[CH:40]=[N:39][C:38]([CH3:41])=[N:37]2)[NH:33][C:32]1=[O:42].CCN=C=NCCCN(C)C.N1C=CC=CC=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:25]([O:24][C:22]([NH:21][C:18]1[S:19][CH:20]=[C:16](/[C:12](=[N:11]/[O:10][C:7]([CH3:9])([CH3:8])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:29])/[C:13]([NH:30][C@@H:31]2[C:32](=[O:42])[NH:33][C@@H:34]2[CH2:35][N:36]2[CH:40]=[N:39][C:38]([CH3:41])=[N:37]2)=[O:14])[N:17]=1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)cs1
Reactant: Cc1ncn(C[C@H]2NC(=O)[C@H]2N)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: Cc1ncn(C[C@H]2NC(=O)[C@H]2NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c2csc(NC(=O)OC(C)(C)C)n2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.9 %

Procedure:
To a solution of (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (310 mg, 0.72 mmol), (3S,4R)-3-amino-4-((3-methyl-1H-1,2,4-triazol-1-yl)methyl)azetidin-2-one (130 mg, 0.72 mmol) and EDCI (150 mg, 0.79 mmol) in DMF (5 mL) at 0° C. was added pyridine (64 μL, 0.79 mmol). After stirring at rt for 24 h, more (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (310 mg, 0.72 mmol) and EDCI (150 mg, 0.79 mmol) were added, along with HOBt (110 mg, 0.79 mmol) and DIPEA (250 μL, 1.44 mmol). After an additional 16 h of stirring it was concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 5%), affording the title compound (230 mg, 54%) as a white solid. LCMS: m/z=593.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[N:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]([NH:18][C:19]3[N:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]4)=[CH:21][CH:20]=3)=[O:17])=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: Cc1cc(-c2ccc(CC(=O)O)cc2)ccn1
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: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(CC(=O)Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)cc2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(4-(2-methylpyridin-4-yl)phenyl)acetic acid 26-3 (1.1 g, 4.8 mmol), tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate 125-4 (1.3 g, 4.6 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (2.0 g, 5.3 mmol) in DMF (15 mL) was added DIEA (2.4 mL, 13.8 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted into ethyl acetate, washed with saturated NaHCO3 then brine, dried over Na2SO4. The solvent was removed by rotary evaporation to give tert-butyl 4-(6-(2-(4-(2-methylpyridin-4-yl)phenyl)acetamido)pyridin-3-yl)piperazine-1-carboxylate 125. MS m/z 488.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ10.55 (s, 1H), 8.56 (d, 1H), 8.03 (s, 1H), 7.93 (d, 1H), 7.81 (d, 1H), 7.74 (s, 1H), 7.66 (d, 1H), 7.51 (d, 2H), 7.42 (m, 1H), 3.75 (s, 2H), 3.08 (b, 2H), 2.57 (s, 2H), 2.54 (s, 4H), 2.51 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]=1)=[O:4].[I-:28].[Na+]>CC(C)=O>[I:28][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]=1)=[O:4]
Reactant: [I-]
Reactant: O=C(CCl)Nc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(CI)Nc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reaction time: 8 h
Yield: 60.4 %

Procedure:
A solution of 2-chloro-N-[3,4-bis(phenylmethoxy)phenyl]acetamide (8.98 g, 23.5 mmol) and sodium iodide (3.53 g, 23.5 mmol) in acetone (75 ml) was refluxed for two hours and allowed to stand overnight at room temperature. The reaction was filtered hot to remove the sodium iodide and a precipitate formed in the cold filtrate which was collected and washed with cold acetone to give, upon drying, 6.71 g (14.2 mmol) of the title compound. A second crop was obtained from cold acetone (1.0 g).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:24]2[CH2:28][CH2:27][C:26]([F:30])([F:29])[CH2:25]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15](C3C=CC=CC=3Cl)=[O:16])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC([C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([Cl:61])[CH:56]=1)=O>>[C:1]([C:5]1[N:6]=[C:7]([N:24]2[CH2:28][CH2:27][C:26]([F:29])([F:30])[CH2:25]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]([C:55]3[CH:60]=[CH:59][CH:58]=[C:57]([Cl:61])[CH:56]=3)=[O:16])[N:13]=2)[N:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C(CBr)c1cccc(Cl)c1
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CC(=O)c3ccccc3Cl)nc2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CC(=O)c3cccc(Cl)c3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 2-[5-tert-Butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl]-1-(2-chloro-phenyl)-ethanone (example 47), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-bromo-1-(3-chlorophenyl)ethanone and isolated as yellow solid. MS (m/e): 435.3 (MH+).
Reaction SMILES: [OH:1][C@@H:2]([P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9])[CH:3]=[C:4]([CH3:6])[CH3:5]>CO.[Pd]>[OH:1][C@@H:2]([P:7](=[O:12])([O:8][CH3:9])[O:10][CH3:11])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: COP(=O)(OC)[C@H](O)C=C(C)C
Agent: [Pd]
Solvent: CO
Product: COP(=O)(OC)[C@H](O)CC(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
Dimethyl (S)-1-hydroxy-3-methyl-2-butenylphosphonate obtained in Example 31 (68% e.e., 54 mg) was dissolved in 10 ml of methanol, and 10% Pd/C (16 mg) was added thereto. The mixture was stirred at room temperature for 3 hours under hydrogen atmosphere. The reaction mixture was filtered through Celite and the filter cake was washed with ethyl acetate. The solvent was distilled under reduced pressure and the residue was purified by flash column chromatography (acetone/hexane=1/4, on SiO2) to obtain dimethyl (S)-1-hydroxy-3-methylbutylphosphonate as a final product in a yield of 98%. This compound is known to be useful as a raw material for medicines and the like. The chemical reaction in this Reference Example is shown in chemical formula 49. ##STR43##
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[CH:14]=[C:15]([CH:33]=[CH:34][C:35]=1[OH:36])[O:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20]([NH:24][C:25](=[O:31])[C:26]([O:28]CC)=[O:27])=[CH:19][C:18]=1[CH3:32])[CH:9]([CH3:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1.O>[CH2:1]([N:8]([CH2:12][C:13]1[CH:14]=[C:15]([CH:33]=[CH:34][C:35]=1[OH:36])[O:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20]([NH:24][C:25](=[O:31])[C:26]([OH:28])=[O:27])=[CH:19][C:18]=1[CH3:32])[CH:9]([CH3:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)Nc1cc(C)c(Oc2ccc(O)c(CN(Cc3ccccc3)C(C)C)c2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(NC(=O)C(=O)O)cc(C)c1Oc1ccc(O)c(CN(Cc2ccccc2)C(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl {[4-(3-{[benzyl(isopropyl)amino]methyl}-4-hydroxyphenoxy)-3,5-dimethylphenyl]amino}(oxo)acetate (50 mg, 0,10 mmol) and NaOH (40 mg, 1.02 mmol) are dissolved in dioxane/water (0.5 1, 1:1 v/v) and stirred at room temperature for 1 h. The reaction mixture is partitioned between ethyl acetate and potassium dihydrogen phosphate/disodium hydrogen phosphate buffer solution (pH 7), and the organic phase is salted out with NaCl, filtered and evaporated. The resulting crude product is purified by preparative RP-HPLC with a water/acetonitrile/TFA eluent.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[CH:3]([N:29]1[CH2:33][CH2:32][C@H:31]([NH:34]C(=O)OC(C)(C)C)[CH2:30]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([C:23](=[O:28])[NH:24][CH:25]([CH3:27])[CH3:26])=[CH:18][CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1.[ClH:44]>C(Cl)Cl.CC(O)C>[ClH:44].[ClH:44].[NH2:34][C@H:31]1[CH2:32][CH2:33][N:29]([CH:3]([C:4]2[CH:5]=[CH:6][C:7]3[N:8]([C:10]([C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][C:17]([C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:28])=[CH:18][CH:19]=5)[N:14]=4)=[N:11][N:12]=3)[CH:9]=2)[C:2]([F:43])([F:42])[F:1])[CH2:30]1
Reactant: CC(C)NC(=O)c1ccc2ccc(-c3nnc4ccc(C(N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc2c1
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)NC(=O)c1ccc2ccc(-c3nnc4ccc(C(N5CC[C@H](N)C5)C(F)(F)F)cn34)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.4 %

Procedure:
To a solution of tert-butyl (3S)-1-(2,2,2-trifluoro-1-(3-(7-(isopropylcarbamoyl)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (0.023 g, 0.039 mmol) in DCM (0.5 mL) was added 5 N HCl (0.39 mL, 1.92 mmol) in IPA. The mixture was stirred at ambient temperature for 1 hour. The solvent was removed under reduced pressure to give 2-(6-(1-((S)-3-aminopyrrolidin-1-yl)-2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-N-isopropylquinoline-7-carboxamide dihydrochloride (0.023 g, 95.7%) as a solid. LCMS APCI (+) m/z 498 (M+H).
Reaction SMILES: C[C@@H:2]1CCC[CH2:4][NH:3]1.[C:8]([C:12]1[CH:13]=[C:14]([NH:27][C:28]([NH:30][C@@H:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C@H:34]([O:41][C:42]3[CH:43]=[CH:44][C:45]4[N:46]([C:48]([N:51]5[CH2:56][CH2:55][CH2:54][CH2:53][C@@H:52]5[CH3:57])=[N:49][N:50]=4)[CH:47]=3)[CH2:33][CH2:32]2)=[O:29])[N:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25]O)[CH:18]=2)[N:16]=1)([CH3:11])([CH3:10])[CH3:9]>>[C:8]([C:12]1[CH:13]=[C:14]([NH:27][C:28]([NH:30][C@@H:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C@H:34]([O:41][C:42]3[CH:43]=[CH:44][C:45]4[N:46]([C:48]([N:51]5[CH2:56][CH2:55][CH2:54][CH2:53][C@H:52]5[CH3:57])=[N:49][N:50]=4)[CH:47]=3)[CH2:33][CH2:32]2)=[O:29])[N:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][N:3]([CH3:4])[CH3:2])[CH:18]=2)[N:16]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: C[C@@H]1CCCCN1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12
Product: C[C@@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCN(C)C)c4)c4ccccc43)cn12

Procedure:
The title compound was prepared from (R)-2-methyl piperidine using analogous procedures to those described for the preparation of Intermediate 95e. LCMS (Method 3): Rt 3.63 min, m/z 679 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.[NH2:12][CH2:13][C:14]([N:16]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15]>CN(C)C1C=CN=CC=1.ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:12][CH2:13][C:14]([N:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:23][C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])=[O:15])=[O:7]
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)CN(C(=O)CN)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)CN(C(=O)CNC(=O)c1ccc(Cl)c(Cl)c1)c1ccccc1
Temperature: 20 °C
Reaction time: 3 h
Yield: 34.3 %

Procedure:
4-Dimethylaminopyridine (5 mg) and then N,N'-carbonyldiimidazole (1.78 g) are added to a solution of 3,4-dichlorobenzoic acid (1.91 g) in anhydrous 1,2-dichloroethane (50 cc). The solution obtained is stirred for 2 hours at a temperature in the region of 20° C., tert-butyl 2-(2-amino-N-phenylacetamido)acetate (2.64 g) is then added and the mixture is stirred for 3 hours at a temperature in the region of 20° C. The reaction mixture is then washed with water (3×75 cc), and the organic phase is separated, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by chromatography on silica gel (0.04-0.063 mm; 250 g) contained in column 4.2 cm in diameter [eluant: dichloromethane/methanol (98:2 by volume)], using an excess pressure of 40 kPa of nitrogen and collecting 20-cc fractions. Fractions 7 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. and the residue is recrystallized in a mixture of cyclohexane and 2-propanol (80:20 by volume). tert-Butyl N-[N- (3,4-dichlorobenzoyl)glycyl]-N-phenylglycinate (1.5 g), m.p. 95° C., is thereby obtained.
Reaction SMILES: C([NH:5][C:6]([NH:8][CH:9]([CH2:12][N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)[CH2:10]O)=[S:7])(C)(C)C.[ClH:20]>>[ClH:20].[ClH:20].[ClH:20].[CH3:19][N:16]1[CH2:17][CH2:18][N:13]([CH2:12][CH:9]2[CH2:10][S:7][C:6]([NH2:5])=[N:8]2)[CH2:14][CH2:15]1
Reactant: CN1CCN(CC(CO)NC(=S)NC(C)(C)C)CC1
Agent: Cl
Product: CN1CCN(CC2CSC(N)=N2)CC1
Temperature: 100 °C

Procedure:
A suspension of 0.42 g de N-(tert-butyl)-N′-[2-hydroxy-1-(4-methyl-piperazin-1-ylmethyl)ethyl]-thiourea in 3.9 mL of an aqueous 6N hydrochloric acid is heated at a temperature of about 100° C. for 5 hours. After cooling, the reaction medium is concentrated under reduced pressure (2 kPa) at a temperature of about 55° C. The residue obtained is dried in an oven under vacuum (2 kPa) for 4 hours. About 0.47 g of 4-(4-methyl-piperazin-1-ylmethyl)-4,5-dihydro-thiazol-2-ylamine, trihydrochloride are obtained in the form of a very hygroscopic off-white paste. [1H NMR spectrum (300 MHz, (CD3)2SO d6 with addition of a few drops of CD3COOD d4. δ in ppm): from 2.55 to 2.90 (mf, 4H); 2.80 (s, 3H); from 2.95 to 3.30 (mf, 4H); from 3.30 to 3.60 (mf, 2H); 3.40 (dd, J=11.5 and 5.5 Hz, 1H); 3.69 (dd, J=11.5 and 7.5 Hz, 1H); 4.51 (mt, 1H)].
Reaction SMILES: C[NH:2]C.[C:4](Cl)(=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>>[C:4]([NH2:2])(=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CNC
Reactant: CCCCCCCC(=O)Cl
Product: CCCCCCCC(N)=O
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
135.03 g of Dimethyl Amine solution is charged at room temperature and cooled to 10±2° C., then Octanoyl Chloride obtained in EXAMPLE 4 is charged at 8 to 12° C. over a period of 2 hours, and the reaction mixture is stirred at 10 to 15° C. for 30 minutes and then stirred at room temperature for 1 hour and the upper organic layer is separated from lower aqueous layer and 29.80 g of Sodium Chloride (20% solution) is added to the organic layer. This organic layer is washed and 9.94 g of Sodium Sulphate is added to the organic layer to take up water, and the mixture is filtered to obtain crude Octanamide.
Reaction SMILES: [C:1]1([C:7]2([C:12]#[N:13])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]1([C:7]2([CH2:12][NH2:13])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC1(c2ccccc2)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1(c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
To a stirred solution of 1-phenyl-cyclopentanecarbonitrile (4 g, 23.5 mmol) in tetrahydrofuran (50 mL) was added lithium aluminium hydride slowly (1M in tetrahydrofuran, 70 ml, 70.6 mmol) and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was quenched with saturated aqueous Na2SO4 solution slowly at 0° C. It was then filtered and the residue was washed with ethyl acetate. The organic part was concentrated to get C-(1-phenyl-cyclopentyl)-methylamine (8) (2.5 g, crude) as a liquid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)OC1>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>[CH3:28][N:27]1[C:23]([C:2]2[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=2)=[CH:24][CH:25]=[N:26]1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
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: O
Solvent: C1COCCO1
Product: Cn1nccc1-c1ccc(C(=O)O)s1
Temperature: 80 °C

Procedure:
To a solution of 5-bromo-2-thiophenecarboxylic acid (100 mg, 0.48 mmol) in dioxane/H2O (5:1, 6 mL) was added K2CO3 (267 mg, 1.93 mmol), tetrakistriphenylphosphine Pd(0) (28 mg, 24 umol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (94 mg, 0.48 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 12 h and was then partitioned between 6N NaOH and DCM. The pH of the aqueous phase was adjusted to ˜3 with 3M HCl and washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (−100 mg, quant.): LC-MS (ES) m/z=209 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]1([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:18]=2[CH2:36][OH:37])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>C(Cl)Cl.C(N(CC)CC)C>[C:11]1([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([S:26]([C:29]3[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=3)(=[O:27])=[O:28])[C:18]=2[CH:36]=[O:37])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(CO)c(-c3ccccc3)c3ccccc32)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)n2c(C=O)c(-c3ccccc3)c3ccccc32)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of oxalyl chloride (1.37 g, 10.8 mmol) in DCM (30 mL) at −78° C. and under a nitrogen atmosphere was added DMSO (1.50 mL, 21.6 mmol). After stirring for 10 min at −78° C., a solution of [3-phenyl-1-(toluene-4-sulfonyl)-1H-indol-2-yl]methanol (2.27 g, 6.01 mmol) in DCM (20 mL) was added and stirring was continued for 1.5 h. Triethylamine was added and, after stirring for 10 min at −78° C., the mixture was slowly warmed to RT. The reaction mixture was poured into a 1.0M aq HCl solution and extracted with DCM (×3). The combined organic layers were washed with water, then brine, dried (Na2SO4) and concentrated in vacuo affording the title compound as a gum which then solidified on standing to give an off-white solid (2.26 g, 100%). 1H NMR (CDCl3, 400 MHz): δ 10.22 (1H, s), 8.31 (1H, d, J=8.56 Hz), 7.86-7.81 (2H, m), 7.60-7.41 (7H, m), 7.33-7.21 (3H, m), 2.37 (3H, s)
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[C:7]1(=[O:17])[O:12][C:10](=O)[CH:9]2[CH2:13][CH2:14][CH2:15][CH2:16][CH:8]12>C(O)C>[C:10]([O:6][CH:3]([CH2:4][O:5][C:7](=[O:17])[CH:8]=[CH2:16])[CH2:2][N:1]1[C:7](=[O:17])[CH:8]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:9]2[C:10]1=[O:12])(=[O:12])[CH:9]=[CH2:13]
Reactant: O=C1OC(=O)C2CCCCC12
Reactant: NCC(O)CO
Solvent: CCO
Product: C=CC(=O)OCC(CN1C(=O)C2CCCCC2C1=O)OC(=O)C=C
Yield: 109.7 %

Procedure:
A 500-ml, two necked flask was equipped a magnetic stirring bar, heating mantle and condenser. The flask was charged with 46 g of 3-amino-1,2-propanediol (0.50 mol.) and 300 ml of ethanol. Next, 77 g of hexahydrophthalic anhydride (0.50 mol.) was slowly added to the flask after which the reaction was refluxed for 12 hours. The imide formation was confirmed by IR. The ethanol was removed by a rotoevaporator to yield 92 g (81%) of the N-[2,3-di(hydroxy)propyl]hexahydrophthalimide.
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]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH2:34]([O:36][C:37]1[CH:42]=[C:41]([N:43]2[CH2:48][CH2:47][N:46]([CH:49]([CH3:51])[CH3:50])[CH2:45][CH2:44]2)[CH:40]=[CH:39][C:38]=1[NH2:52])[CH3:35].Cl.O1CCOCC1.C[O-].[Na+]>FC(F)(F)CO.CO.C(Cl)Cl.CCCCCC>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][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:52][C:38]3[CH:39]=[CH:40][C:41]([N:43]4[CH2:48][CH2:47][N:46]([CH:49]([CH3:50])[CH3:51])[CH2:45][CH2:44]4)=[CH:42][C:37]=3[O:36][CH2:34][CH3:35])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: CCOc1cc(N2CCN(C(C)C)CC2)ccc1N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCCCCC
Solvent: OCC(F)(F)F
Product: CCOc1cc(N2CCN(C(C)C)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 175 °C
Yield: 63.6 %

Procedure:
To 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (100 mg, 0.22 mmol) and {2-(ethyloxy)-4-[4-(1-methylethyl)-1-piperazinyl]phenyl}amine (57 mg, 0.22 mmol) in 2,2,2-trifluoroethanol (1.1 mL) was added 4 M HCl in dioxane (108 μL, 0.43 mmol). The mixture was stirred and heated on a Biotage microwave at 175° C. for 30 min, then cooled to rt. The mixture was neutralized with 0.5M sodium methoxide in MeOH. The mixture was concentrated under vacuum and the residue purified by silica gel chromatography to give a yellow oil. The oil was dissolved in minimal DCM, then hexane was added until a precipitate was formed. The slurry was cooled at −10° C. for 30 min, then poured through a Teflon filter, washing the solids with cold hexanes. The solids were dried under vacuum to give the title compound (98 mg, 0.14 mmol, 66%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.24 (s, 1H), 9.38 (brs, 1H), 8.36 (d, 2H, J=14.66 Hz), 8.23 (d, 1H, J=5.13 Hz), 8.05 (d, 1H, J=7.88 Hz), 7.81 (d, 1H, J=7.88 Hz), 7.73 (d, 1H, J=9.16 Hz), 7.61 (t, 1H, J=7.70 Hz), 7.36-7.49 (m, 3H), 7.21 (t, 2H, J=8.06 Hz), 6.97 (t, 1H, J=6.87 Hz), 6.65 (s, 1H), 6.45-6.50 (m, 2H), 4.06 (q, 2H, J=7.03 Hz), 3.08-3.14 (m, 4H), 2.64-2.69 (m, 1H), 2.54-2.61 (m, 4H), 1.24 (t, 3H, J=6.96 Hz), 1.00 (d, 6H, J=6.23 Hz). MS (ESI): 689 [M+H]+.