Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[C:29]([F:36])[CH:30]=[CH:31][CH:32]=2)[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[C:29]([F:36])[CH:30]=[CH:31][CH:32]=5)[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: Fc1cccc2ccc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ccc5cccc(F)c5n4)cc3CC[C@@H]12
Yield: 50.5 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-8-fluoroquinoline (84 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 78 mg (50%) of the title compound as an amorphous foam. FDMS: m/e=406. α[D]589 =+63.29 (c=0.56, chloroform).
Reaction SMILES: C[O:2][C:3]1[CH:17]=[CH:16][C:6]2[N:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:9][C:5]=2[CH:4]=1.Br>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>[N:10]1([C:8]2[S:9][C:5]3[CH:4]=[C:3]([OH:2])[CH:17]=[CH:16][C:6]=3[N:7]=2)[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1
Reactant: COc1ccc2nc(N3CCOCC3)sc2c1
Agent: Br
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: Oc1ccc2nc(N3CCOCC3)sc2c1
Temperature: 100 °C
Yield: 92.9 %

Procedure:
A mixture of 6-methoxy-2-morpholin-4-yl-benzothiazole (12.20 g, 48.7 mmol), tetrabutylphosphonium bromide (1.65 g, 4.87 mmol) and 48% HBr (80 mL) was stirred at 100° C. for twenty hours before it was cooled to room temperature, neutralized with 10N NaOH (60 mL) to pH=5-6. The mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo to give the title compound as a white solid (10.69 g): 1H NMR (CDCl3, 200 MHz): δ=7.28 (m, 1H), 7.15 (m, 1H), 6.75 (m, 1H), 3.70 (m, 4H), 3.43 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[CH:21]=[N:22][C:23]([O:29][CH2:30][CH3:31])=[CH:24][C:25]=3[O:26][CH2:27][CH3:28])=[N:9]2)=[CH:4][CH:3]=1.[C:32](Cl)([Cl:34])=[O:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:32]([Cl:34])=[O:33])[C:10]([C:20]3[CH:21]=[N:22][C:23]([O:29][CH2:30][CH3:31])=[CH:24][C:25]=3[O:26][CH2:27][CH3:28])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(OCC)c(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2)cn1
Reactant: O=C(Cl)Cl
Product: CCOc1cc(OCC)c(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)Cl)cn1

Procedure:
Using the procedure as described in example 1, cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4,6-diethoxy-pyridin-3-yl)-4,5-dihydro-1H-imidazole was reacted with phosgene to give cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4,6-diethoxy-pyridin-3-yl)-4,5-dihydro-imidazole-1-carbonyl chloride. The carbonyl chloride was then coupled with 2-piperazinone (Alfa) to give cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4,6-diethoxy-pyridin-3-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C@@H:9]3[C@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1.[F:22][CH2:23][C:24](OCC)=[O:25]>>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C@@H:9]3[C@H:14]([NH:15][C:24](=[O:25])[CH2:23][F:22])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)CF
Reactant: N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Product: O=C(CF)N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Yield: 39 %

Procedure:
trans-7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (10 mg, 0.03 mmol) was dissolved in 1 mL of ethyl fluoroacetate. The resulting mixture was heated to reflux for 2 h. Evaporation followed by crystallisation from methanol gave trans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2-fluoroacetamide (4.7 mg, 39%). Data: (m/z)=361 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](Br)[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:10]=2)=[O:5])[CH3:2].[CH3:26][N:27](C)C(=O)C>C(OCC)(=O)C.[Cl-].[NH4+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Zn].[C-]#N.[Zn+2].[C-]#N>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:26]#[N:27])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:10]=2)=[O:5])[CH3:2]
Reactant: CC(=O)N(C)C
Reactant: CCOC(=O)c1nc(Br)c2cc(OCc3ccccc3)ccc2c1O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(C#N)c2cc(OCc3ccccc3)ccc2c1O
Reaction time: 3 h

Procedure:
7-Benzyloxy-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester was prepared by heating a mixture of 1.76 g (4.4 mmol) of 7-benzyloxy-1-bromo-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester, 201 mg (0.2.0 mmol) tris(dibenzylideneacetone)dipalladium(0), 243 mg (0.44 mmol) 1,1′-bis(diphenylphosphino) ferrocene, 34 mg (0.53 mmol) zinc dust, 309 mg (2.64 mmol) zinc cyanide, and 9.0 mL of N,N-dimethylacetamide at 115 deg C. for 3 hours. The resultant mixture was diluted with ethyl acetate and saturated aqueous ammonium chloride and filtered through a celite pad. The organic fraction was washed with saturated ammonium chloride, water, brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography, eluting from silica gel with a 10 to 90 percent gradient of ethyl acetate in hexanes to give 1.18 g of the title compound; MS (ESI+): 349.3 e/z (M+1)
Reaction SMILES: [C:1](O)(=O)C.[NH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][N:18]=[CH:17]3)=[O:13])[CH2:6]1.C=O.C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[CH3:1][N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][N:18]=[CH:17]3)=[O:13])[CH2:6]1
Reactant: CC(=O)O
Reactant: O=C(NC1CCCNC1)c1ccc2[nH]ncc2c1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCCC(NC(=O)c2ccc3[nH]ncc3c2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
Acetic acid (0.12 ml, 2.1 mmol) was added to a suspension of the N-(3-piperidinyl)-1H-indazole-5-carboxamide (0.100 g, 0.409 mmol) obtained in Example 139 and paraformaldehyde (0.101 g, 3.34 mmol) in methanol (3 ml), and the resulting mixture was stirred for 15 minutes and then ice-cooled. Sodium cyanoborohydride (0.128 g, 2.04 mmol) was added thereto and the resulting mixture was slowly warmed up to room temperature and stirred overnight. After a 1N-aqueous sodium hydroxide solution was added thereto, the solvent was distilled off under reduced pressure and the residue was dried up and then purified by a silica gel chromatography (eluent: chloroform/methanol/30% aqueous ammonia=100/10/1). Ethyl acetate was added thereto to precipitate a solid and the resulting suspension was stirred to wash the solid. The solid was collected by filtration and dried under reduced pressure to obtain N-(1-methylpiperidin-3-yl)-1H-indazole-5-carboxamide (0.0718 g, 68%).
Reaction SMILES: CC1C=CC(C2C=CC=CN=2)=C(C=1)C(OC)=O.Br[C:19]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:20]=1[C:21]([N:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([CH3:29])[C@H:24]1[CH2:30][N:31]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]1=[O:41])=[O:22].C([Sn](CCCC)(CCCC)[C:52]1[N:57]=[CH:56][CH:55]=[CH:54][N:53]=1)CCC>>[F:46][C:43]1[CH:44]=[CH:45][C:19]([C:52]2[N:57]=[CH:56][CH:55]=[CH:54][N:53]=2)=[C:20]([CH:42]=1)[C:21]([N:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([CH3:29])[C@H:24]1[CH2:30][N:31]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]1=[O:41])=[O:22]
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2Br)[C@@H]1CN1C(=O)c2ccccc2C1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: COC(=O)c1cc(C)ccc1-c1ccccn1
Product: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-c2ncccn2)[C@@H]1CN1C(=O)c2ccccc2C1=O

Procedure:
The title compound was prepared following the same general protocol as described for methyl 5-methyl-2-(pyridin-2-yl)benzoate in Example A9, using 2-(((2S,3R)-1-(2-bromo-5-fluorobenzoyl)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione and 2-(tributylstannyl)pyrimidine. ESI-MS (m/z): 445 [M+1]+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([I:11])=[CH:7][CH:8]=2)[C@@H:3]1[NH:12][C:13](=[O:19])OC(C)(C)C.Cl.[OH-].[Na+].[F:23][C:24]1[CH:32]=[CH:31][C:27](C(Cl)=O)=[CH:26][CH:25]=1>O1CCOCC1>[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:13]([NH:12][C@H:3]2[C:4]3[C:9](=[CH:8][CH:7]=[C:6]([I:11])[CH:5]=3)[CH2:10][C@@H:2]2[OH:1])=[O:19])=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1c2cc(I)ccc2C[C@@H]1O
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(N[C@H]1c2cc(I)ccc2C[C@@H]1O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a solution of tert-butyl N-[(1S,2S)-2-hydroxy-6-iodo-indan-1-yl]carbamate (39.6 mmol, 14.9 g) in 1,4-dioxane (200 mL), add a solution of 4 M hydrogen chloride in dioxane (100 mL) at room temperature and stir for 2 hr. Concentrate the resulting suspension in vacuo and dry in a vacuum oven for 48 hr. Dissolve the residue in THF (25 mL) and cool in an ice bath for 30 min. Add 5 M aqueous sodium hydroxide (17.4 mL, 87.2 mmol) and 4-fluorobenzoyl chloride (3.78 mL, 40.4 mmol) dropwise. Warm the solution to room temperature and stir for one hour. Concentrate the black solution in vacuo and dilute with water (50 mL). Collect the solid by filtration and dry at 40° C. in a vacuum oven overnight to obtain the title compound (14.4 g, 91%). LC-ES/MS m/z 398 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6][CH2:5]2.[CH3:12][O:13][C:14]1[CH:24]=[CH:23][C:17]([CH2:18][CH2:19][C:20](Cl)=O)=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:20][CH2:19][CH2:18][C:17]1[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:24][CH:23]=1)[CH2:6][CH2:5]2
Reactant: Oc1ccc2c(c1)CCNC2
Reactant: COc1ccc(CCC(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CCCN2CCc3cc(O)ccc3C2)cc1

Procedure:
5.4 g of 6-hydroxy-1,2,3,4-tetrahydroisoquinoline are acylated twice with 14.2 g of 4-methoxydihydrocinnamoyl chloride in methylene chloride in the presence of 7.5 g of triethylamine, the mixture is extracted by shaking with water, and the organic phase is dried and evaporated in a rotary evaporator. The crude product is dissolved, without further purification, in tetrahydrofuran, and added dropwise, with cooling, to a solution of 1.5 g of lithium aluminum hydride in dry tetrahydrofuran. After destroying the reagent with water, inorganic material is filtered off and the filtrate is dried. The residue from filtration is dried, extracted twice by boiling with methanol, and the methanol and tetrahydrofuran are evaporated together in a rotary evaporator. After triturating the oily residue with ethyl acetate, 3.5 g of colorless product (33% of theory) are obtained. Melting point: 163°-164°.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[C:13](Cl)(=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl>O.C(O)(C)C>[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCCCCCCCC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Reaction time: 1 h

Procedure:
69.1 g (0.5 mol) of para-hydroxybenzoic acid were first dissolved in 200 ml of water and 300 ml of isopropanol and this solution was adjusted to a pH of 10.5 at 20 to 25° C. using 87.4 g of NaOH solution (32% strength by weight aqueous solution, 0.7 mol). Metered in to this solution at a pH of 10.5 subsequently, over the course of three hours, were 95.4 g (0.5 mol) of decanoyl chloride. The pH was held at 10.5 using 40.5 g of NaOH solution (32% strength by weight aqueous solution, 0.324 mol) and the temperature was held at 20 to 25° C. The batch was stirred for one hour thereafter. Subsequently the reaction mixture was adjusted to a pH of 1.5 to 3 at 20 to 25° C. using 65.3 g of HCl solution (32% strength by weight aqueous solution). The reaction mixture was filtered on a suction filter. Here there were considerable problems, since the suction filter/filtration unit clogged up, owing to the size of the product crystals. The experiment had to be terminated at this point. The same occurs if the product is precipitated at 65° C. and the reaction mixture is filtered at 35 to 65° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6].[CH2:15]([Li])CCC.IC.Cl>C1COCC1>[F:1][C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:12])([F:13])[F:14])[C:5]([OH:7])=[O:6]
Reactant: [Li]CCCC
Reactant: O=C(O)c1ccc(C(F)(F)F)c(F)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(C(=O)O)ccc(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
25.0 g (120.1 mmol) of 3-fluoro-4-trifluoromethylbenzoic acid were dissolved in 250 ml of THF, and 100.9 ml (2.5M in hexane, 252.3 mmol) of n-butyllithium were added dropwise at −40° C. The mixture was stirred for 3.5 h, and a solution of 51.2 g (360.4 mmol) of iodomethane in 50 ml of dry THF was then added dropwise. The mixture was stirred for 16 h, and after half an hour the temperature slowly increased to room temperature (RT). For work-up, 150 ml of 1M HCl were added carefully. The mixture was extracted with diethyl ether, and the organic phase was then extracted with 1M NaOH. The aqueous phase was acidified and then extracted with diethyl ether. The organic phase was washed with water, dried and freed from the solvent. The residue was titrated with n-heptane and the solid was removed by filtration. What was isolated were 13.5 g of the pure product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:33])[C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=4[F:32])[CH2:20][CH2:19]3)[CH2:14][C:15]#[N:16])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[N:34]1([C:39]2[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=2)[CH:38]=[CH:37][N:36]=[CH:35]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.C(#N)C.O>[N:34]1([C:39]2[CH:40]=[CH:41][C:42]([NH:43][C:2]3[N:7]=[C:6]([C:8]4[CH:9]=[N:10][N:11]([CH:13]([CH2:17][CH:18]5[CH2:23][CH2:22][N:21]([C:24](=[O:33])[C:25]6[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=6[F:32])[CH2:20][CH2:19]5)[CH2:14][C:15]#[N:16])[CH:12]=4)[CH:5]=[CH:4][N:3]=3)=[CH:44][CH:45]=2)[CH2:38][CH2:37][N:36]=[CH:35]1
Reactant: N#CCC(CC1CCN(C(=O)c2ccc(F)cc2F)CC1)n1cc(-c2ccnc(Cl)n2)cn1
Reactant: Nc1ccc(-n2ccnc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Solvent: C1COCCO1
Product: N#CCC(CC1CCN(C(=O)c2ccc(F)cc2F)CC1)n1cc(-c2ccnc(Nc3ccc(N4C=NCC4)cc3)n2)cn1

Procedure:
A mixture of 3-(4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)-4-(1-(2,4-difluorobenzoyl)piperidin-4-yl)butanenitrile (30 mg, 0.06 mmol), 4-(1H-imidazol-1-yl)aniline (15.2 mg, 0.0956 mmol), and p-toluenesulfonic acid (9.3 mg, 0.054 mmol) in dry 1,4-dioxane (0.5 mL) was refluxed overnight. The mixture was diluted with acetonitrile and water, purified on RP-HPLC to give the desired product as a racemic mixture (25 mg, 71%). LCMS (M+H) 594.1.
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.[CH3:34][C:35]1[C:36]([N:44]2[CH2:49][CH2:48][N:47]([S:50]([CH3:53])(=[O:52])=[O:51])[CH2:46][CH2:45]2)=[CH:37][C:38]([O:42][CH3:43])=[C:39]([CH:41]=1)[NH2:40].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C(F)(F)F.N>CO.C(Cl)Cl>[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:40][C:39]3[CH:41]=[C:35]([CH3:34])[C:36]([N:44]4[CH2:49][CH2:48][N:47]([S:50]([CH3:53])(=[O:52])=[O:51])[CH2:46][CH2:45]4)=[CH:37][C:38]=3[O:42][CH3:43])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: COc1cc(N2CCN(S(C)(=O)=O)CC2)c(C)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: OCC(F)(F)F
Product: COc1cc(N2CCN(S(C)(=O)=O)CC2)c(C)cc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 100 °C
Yield: 51.1 %

Procedure:
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), 5-methyl-2-(methyloxy)-4-[4-(methylsulfonyl)-1-piperazinyl]aniline (Example 225, step B) (53 mg, 0.18 mmol), and p-toluenesulfonicacid (99 mg, 0.52 mmol) were weighed into a 20 mL vial. 1 mL of trifluoroethanol was added and the mixture was heated to 100° C. for 72 h. 2 mL of 2 N ammonia in MeOH was added. The solvent was rotovaped down. The residue was taken up in 3 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-absorbed solids were purified by flash chromatography to give the title compound (67 mg, 0.092 mmol, 52%). 1H NMR (400 MHz, DMSO-d6) d ppm 10.23 (s, 1H), 9.40 (s, 1H), 8.50 (s, 1H), 8.33 (s, 1H), 8.24 (d, J=5.50 Hz, 1H), 8.05 (d, J=7.70 Hz, 1H), 7.82 (d, J=8.07 Hz, 1H), 7.73 (d, J=9.17 Hz, 1H), 7.61 (t, J=7.70 Hz, 1H), 7.53 (s, 1H), 7.45-7.51 (m, 1H), 7.36-7.44 (m, 1H), 7.20 (t, J=8.07 Hz, 2H), 7.00 (t, J=6.97 Hz, 1H), 6.83 (s, 1H), 6.51 (d, J=5.13 Hz, 1H), 3.81 (s, 3H), 3.23-3.30 (m, 4H), 2.95-2.99 (m, 4H), 2.94 (s, 3H), 2.17 (s, 3H); MS (ESI): 725 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:18]C(=O)OC(C)(C)C)[CH:9]([OH:17])[CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>Cl.O1CCOCC1>[NH2:18][C@H:8]([CH:9]([OH:17])[CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(O)CN1CCCCC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](CC1CCCCC1)C(O)CN1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
600 mg (1.69 mmol) of t-butyl [(1S)-1-(cyclohexylmethyl)-2-hydroxy-3-piperidinopropyl]carbamate were dissolved in 6 ml of 5.2N hydrochloric acid in dioxan and subsequently stirred at room temperature for 2 hours. Thereafter, the reaction solution was evaporated under reduced pressure, made alkaline with 25% ammonia solution and extracted with ether. Drying and evaporation of the ether extract yielded 400 mg (93%) of α-[(S)-1-amino-2-cyclohexylethyl]-1-piperidineethanol (αR:αS=5:1) as a resin, MS: 236 (M-H2O)+.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3][CH:2]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[NH2:40][C:41]1([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:43][CH2:42]1>C1COCC1>[N:3]1[CH:4]=[C:5]([C:7]([NH:40][C:41]2([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:43][CH2:42]2)=[O:9])[CH:6]=[N:1][CH:2]=1
Reactant: CCOC(=O)C1(N)CC1
Reactant: O=C(O)c1cncnc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(NC(=O)c2cncnc2)CC1
Reaction time: 8 h

Procedure:
A solution of 6.80 g (54.8 mmol) of pyrimidine-5-carboxylic acid, 18.82 mL (135 mmol) of triethylamine and 19.27 g (60 mmol) of TBTU in 200 mL THF was stirred for 30 minutes at ambient temperature. Then 9.11 g (55 mmol) of ethyl 1-amino-cyclopropanecarboxylate hydrochloride were added and the mixture was stirred further overnight. Then the mixture was evaporated down, the residue was stirred with 200 mL water and the crude product was extracted with ethyl acetate. The intermediate product was purified by column chromatography (silica gel, dichloromethane+0-4% methanol).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:12]([NH:19][CH:8]1[CH2:9][CH2:10][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH2:7]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)N1CCC(=O)CC1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)N1CCC(NCc2ccccc2)CC1
Yield: 26.3 %

Procedure:
A solution of 1-tert-butyl-4-oxopiperidine (3.6 g, 23.1), benzylamine (5.1 ml, 46.8 mmol), acetic acid (1.5 ml) and sodium triacetoxyborohydride (7.38 g, 34.8 mmol) was stirred at ambient for 2 days. Reaction mixture reduced in vacuo, residue partitioned between aqueous K2CO3 and EtOAc. The organic portion was dried (Na2SO4), filtered and reduced in vacuo. The residue was subjected to chromatography using CH2Cl2/MeOH/NH4OH (87/12/1) as the eluent to yield N-benzyl-1-tert-butylpiperidin-4-amine (1.5 g) (LC/MS: Rt 0.45, [M+H]+ 247).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH:21]([CH3:23])[CH3:22])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1.[C:25](Cl)(=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29]>>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH:21]([CH3:22])[CH3:23])[N:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1)[C:25](=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: COC(=O)[C@@H](NCc1ccc(-c2ccccc2C#N)cc1)C(C)C
Reactant: CCCCC(=O)Cl
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@H](C(=O)OC)C(C)C

Procedure:
condensation of N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester compound of Formula II or its hydrochloride salt with the valeryl chloride compound of Formula III in the presence of an inorganic base and a suitable solvent to give the (N-[(2′-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine methyl ester compound of Formula IV;
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[Br:14][C:15]1[C:20](F)=[C:19]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:17][C:16]=1[F:25]>C1COCC1.O>[Br:14][C:15]1[C:16]([F:25])=[CH:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[C:20]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: Nc1ccccn1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(Br)c1Nc1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
Potassium tert-butoxide (2.82 g, 25.2 mmol) was added to a solution of 2-aminopyridine (1.25 g, 13.2 mmol) in THF (40 mL) at 0° C. and the reaction mixture stirred at 0° C. for 30 min. 2-Bromo-1,3-difluoro-4-nitrobenzene (3 g, 12.6 mmol) was added as a solution in THF (10 mL) and the reaction mixture stirred at 0° C. for 2 h. The reaction mixture was diluted with water and the product extracted with EtOAc (3×40 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to yield the title compound as a yellow solid (2.38 g, 60%). 1H NMR 400 MHz δ (CDCl3): 8.16 (1H, ddd, J=5.1, 2.0, 1.0 Hz), 8.08 (1H, dd, J=9.3, 5.6 Hz), 7.82 (1H, br s), 7.62 (1H, ddd, J=8.1, 7.3, 1.8 Hz), 6.99 (1H, dd, J=9.2, 7.1 Hz), 6.91 (1H, ddd, J=7.3, 5.0, 1 Hz), 6.82 (1H, dt, J=8.3, 1.0 Hz).