Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:13])([CH3:12])[C:6]1[N:7]([CH3:11])[CH:8]=[CH:9][N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.[Cl:19][C:20]1[CH:54]=[CH:53][C:23]([C:24]([C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[N:32]([CH2:36][CH:37]2[CH2:39][CH2:38]2)[C:31](=[O:40])[CH:30]=[C:29]3[C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([C:47]#[C:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[CH:42]=2)=[O:25])=[CH:22][CH:21]=1>C1COCC1>[C:1]([Si:5]([CH3:13])([CH3:12])[C:6]1[N:7]([CH3:11])[C:8]([C:24]([C:23]2[CH:53]=[CH:54][C:20]([Cl:19])=[CH:21][CH:22]=2)([OH:25])[C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[N:32]([CH2:36][CH:37]2[CH2:39][CH2:38]2)[C:31](=[O:40])[CH:30]=[C:29]3[C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([C:47]#[C:48][Si:49]([CH3:51])([CH3:52])[CH3:50])[CH:42]=2)=[CH:9][N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)C#Cc1cccc(-c2cc(=O)n(CC3CC3)c3ccc(C(=O)c4ccc(Cl)cc4)cc23)c1
Reactant: Cn1ccnc1[Si](C)(C)C(C)(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: Cn1c(C(O)(c2ccc(Cl)cc2)c2ccc3c(c2)c(-c2cccc(C#C[Si](C)(C)C)c2)cc(=O)n3CC2CC2)cnc1[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
A solution of 2-(tert-butyl-dimethyl-silanyl)-1-methyl-1H-imidazole (1.71 g, 8.7 mmol) in THF (40 mL) at −78° C. was treated with sec-butyllithium (1.3 M in cyclohexane, 8.4 mL, 10.9 mmol). The reaction mixture was warmed to 0° C., stirred for 3 hours, and cooled to −78° C. A solution of 6-(4-Chloro-benzoyl)-1-cyclopropylmethyl-4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2-one (3.47 g, 6.8 mmol) (2.87 g, 6.4 mmol) in THF (20 mL) was cannulated into the reaction mixture, slowly warmed to room temperature, and stirred overnight. The reaction mixture was quenched with ammonium chloride (12 mL), diluted with ether (200 mL), and washed with H2O (200 mL) and brine (200 mL). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo to give 6-[[2-(tert-Butyl-dimethyl-silanyl)-3-methyl-3H-imidazol-4-yl]-(4-chloro-phenyl)-hydroxy-methyl]-1-cyclopropylmethyl4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2one (4.50 g) as a yellow foam. The crude material was used in the next step without any further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([OH:8])[CH:7]=1.I[CH2:11][CH3:12].[H-].[Li+]>>[Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([O:9][CH2:11][CH3:12])[CH:3]=1
Reactant: CCI
Reactant: Oc1cc(O)cc(Br)c1
Agent: [H-]
Agent: [Li+]
Product: CCOc1cc(O)cc(Br)c1
Yield: 32 %

Procedure:
A similar procedure as described in Example 43, step 2 was used, starting from 5-bromo-benzene-1,3-diol (9.2 g, 48.67 mmol), iodoethane (8.13 g, 51.1 mmol), and lithium hydride (720 mg, 97.34 mmol) to afford 3-bromo-5-ethoxy-phenol (3.38 g, 32%) as a light yellow oil: ES(+)-HRMS m/e calcd for C8H9BrO2 (M+Na)+ 217. found 217.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:4](=[O:22])[C:3]=1[C:23](=O)[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.O.[NH2:37][NH2:38].C(=O)([O-])O.[Na+]>CN(C=O)C>[F:32][C:31]([F:33])([F:34])[C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C:23]2[C:3]3[C:4](=[O:22])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:38][N:37]=2)=[CH:26][CH:27]=1
Reactant: O=C(Cc1ccc(C(F)(F)F)cc1)c1c(O)c2cccnc2n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3ccc(C(F)(F)F)cc3)n[nH]c2c2cccnc2n1-c1cccc(C(F)(F)F)c1
Temperature: 105 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
To a suspension of 4-hydroxy-1-(3-trifluoromethylphenyl)-3-(4-trifluoromethylphenylacetyl)-1,8-naphthyridin-2(1H)-one (985 mg, 2.0 mmol) produced in Synthesis Example 16 in DMF (10 mL) was added hydrazine monohydrate (purity of 80%, 388 μL), and the mixture was stirred at 100 to 110° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, recrystallized from ethanol, and dried to give 3-(4-trifluoromethylbenzyl)-5-(3-trifluoromethylphenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one (342 mg, yield 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[C:8]([C:17](O)=[O:18])=[CH:7]1.Cl.[CH3:24][NH:25][O:26][CH3:27].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(#N)C>[CH3:27][O:26][N:25]([CH3:24])[C:17]([C:8]1[C:9](=[O:16])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]([CH2:5][C:4]2[CH:20]=[CH:21][CH:22]=[C:2]([Cl:1])[CH:3]=2)[CH:7]=1)=[O:18]
Reactant: CNOC
Reactant: O=C(O)c1cn(Cc2cccc(Cl)c2)c2ccccc2c1=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cn(Cc2cccc(Cl)c2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Step 5 of Example 60, from crude 1-(3-Chloro-benzyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 2.21 g (22.6 mmol) of N,O-dimethylhydroxylamine hydrochloride, 14.3 mL (10.4 g, 103 mmol) of triethylamine and 14.6 mL (15.6 g, 24.5 mmol) of 50% 1-propanephosphonic acid cyclic anhydride in 100 mL acetonitrile to give 3.10 g of the product as an off-white solid.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:30]([CH:32]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([O:50][CH3:51])=[O:49])=[CH:44][CH:43]=1)[CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=O.O>C1COCC1>[CH3:51][O:50][C:48]([C:45]1[CH:46]=[CH:47][C:42]([CH2:41][CH:32]([CH:30]=[CH:6][C:5]2[CH:26]=[CH:27][CH:28]=[CH:29][C:4]=2[O:3][CH3:2])[CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:43][CH:44]=1)=[O:49]
Reactant: COC(=O)CCCCC(C=O)Cc1ccc(C(=O)OC)cc1
Reactant: COc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCCCC(C=Cc1ccccc1OC)Cc1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 77.4 mg (0.17 mmol) of 2-methoxybenzyltriphenylphosphonium bromide from Ex. IVj are suspended under argon in 20 ml of THF, and 0.115 ml of buthyl-lithium (0.18 mmol, 1.6 M solution in hexane) are added. The deep-orange solution is stirred at 0° C. for 30 min. At this temperature, a solution of 51.2 mg (0.17 mmol) of methyl 6-formyl-7-(4-methoxycarbonylphenyl)heptanoate (synthesis analogously to EP-A-0 341 551, p. 32, Ex. 44) in 15 ml of THF is added dropwise. The mixture is stirred at 0° C. for 30 min. At 0° C., water is added and the mixture is warmed to room temperature and extracted with ethyl acetate. The organic phase is washed with sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. For purification, the substance is chromatographed on silica gel 60 (particle size 0.040-0.063 mm) using cyclohexane/ethyl acetate 9:1 to 1:1 as mobile phase.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:11][CH3:12])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[CH2:13](N)[CH2:14][NH2:15]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:9]2[NH:15][CH2:14][CH2:13][N:10]=2)[CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(C#N)c1cccc(Cl)c1
Reactant: NCCN
Product: CCC(C1=NCCN1)c1cccc(Cl)c1

Procedure:
rac-2-[1-(3-Chloro-phenyl)-propyl]-4,5-dihydro-1H-imidazole was prepared from 2-(3-chloro-phenyl)-butyronitrile and ethylene diamine in analogy to Example 22: colourless powder;MS (ISP): 223.0 ((M+H)+.).
Reaction SMILES: C[Al](C)C.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11].[Si:12]([O:19][CH:20]1[CH2:23][N:22]([CH2:24][C@H:25]([O:30][C:31]2[N:36]=[CH:35][N:34]=[C:33]3[N:37]([C:40]4[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][C:41]=4[Cl:47])[N:38]=[CH:39][C:32]=23)[C:26](OC)=[O:27])[CH2:21]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O.C(Cl)Cl>[Si:12]([O:19][CH:20]1[CH2:21][N:22]([CH2:24][C@H:25]([O:30][C:31]2[N:36]=[CH:35][N:34]=[C:33]3[N:37]([C:40]4[C:41]([Cl:47])=[CH:42][CH:43]=[CH:44][C:45]=4[Cl:46])[N:38]=[CH:39][C:32]=23)[C:26]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=2)=[O:27])[CH2:23]1)([C:15]([CH3:17])([CH3:18])[CH3:16])([CH3:13])[CH3:14]
Reactant: Nc1ccccn1
Reactant: COC(=O)[C@H](CN1CC(O[Si](C)(C)C(C)(C)C)C1)Oc1ncnc2c1cnn2-c1c(Cl)cccc1Cl
Agent: C[Al](C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CN(C[C@H](Oc2ncnc3c2cnn3-c2c(Cl)cccc2Cl)C(=O)Nc2ccccn2)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 68.2 %

Procedure:
Trimethylaluminium (0.362 mL, 0.72 mmol) was added to a solution of pyridin-2-amine (68.1 mg, 0.72 mmol) in toluene (8 mL) at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 20 mins and then (S)-methyl 3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-(1-(2,6-dichlorophenyl)-1H-pyrazolo [3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate BJ1) (200 mg, 0.36 mmol) in toluene (4 mL) was added. The reaction mixture was allowed to warm to room temperature and then heated at reflux under nitrogen for 4 hours. The reaction mixture was allowed to cool to room temperature and the concentrated. The residue was neutralised to pH 7 with citric acid (1M, aq) and then diluted with water and DCM (50 mL). The organic layer was separated and the aqueous layer re-extracted with DCM (30 mL). The combined organics were dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane to afford the product (151 mg, 67.9%).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](O)=[O:41])=[CH:33][C:32]=2[CH3:43])=[C:28]([CH:44]([CH3:46])[CH3:45])[NH:27][N:26]=1)(=O)C.Cl.[NH2:48][C@@H:49]([CH2:53][CH2:54][CH2:55][CH2:56][NH:57]C(OCC1C=CC=CC=1)=O)[C:50]([NH2:52])=[O:51].C(N1CCNCC1)C1C=CC=CC=1>>[NH2:57][CH2:56][CH2:55][CH2:54][CH2:53][C@H:49]([NH:48][C:40]([CH2:39][CH2:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:44]([CH3:46])[CH3:45])=[C:32]([CH3:43])[CH:33]=1)=[O:41])[C:50](=[O:51])[NH2:52]
Reactant: NC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Agent: c1ccc(CN2CCNCC2)cc1
Product: Cc1cc(OCCC(=O)N[C@@H](CCCCN)C(N)=O)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 99 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and (S)-2-amino-6-(benzyloxycarbonylamino)hexanamide hydrochloride instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole and 1-benzylpiperazine, respectively.
Reaction SMILES: [SH:1][C:2]([CH:5]1[O:10][C:8](=[O:9])[CH:7]([CH2:11][SH:12])[CH2:6]1)([CH3:4])[CH3:3]>C(Cl)Cl.C(Br)C=C.CCOCC>[CH2:4]([S:1][C:2]([CH:5]1[O:10][C:8](=[O:9])[CH:7]([CH2:11][S:12][CH2:7][CH:6]=[CH2:5])[CH2:6]1)([CH3:4])[CH3:3])[CH:2]=[CH2:3]
Reactant: CC(C)(S)C1CC(CS)C(=O)O1
Solvent: ClCCl
Solvent: CCOCC
Solvent: C=CCBr
Product: C=CCSCC1CC(C(C)(C)SCC=C)OC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-mercapto-1-methylethyl)-2-mercaptomethyl-4-butanolide (0.24 g) in methylene chloride (3 ml), allyl bromide (1.0 ml) and N,N-(diisopropyl)ethylamine (1.0 ml) were added under nitrogen atmosphere. The mixture was stirred overnight at room temperature. The mixture was diluted with ether (50 ml) and washed with 2N hydrochloric acid and saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue was purified by silica gel column chromatography to give 0.142 g (43%) of cis-form (compound No.12-1) and 0.170 g (51%) of transform (compound No.12-2) of the titled compound.
Reaction SMILES: [CH2:1]([Li])[CH3:2].[CH3:4][C:5]([CH:10]=[CH:11][CH2:12][CH:13]([CH3:21])[CH2:14][CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][C:7]([OH:9])=O.[Cl-].[NH4+]>C1C=CC=CC=1.CCOCC>[CH3:4][C:5]([CH:10]=[CH:11][CH2:12][CH:13]([CH3:21])[CH2:14][CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][C:7](=[O:9])[CH2:1][CH3:2]
Reactant: CC(C=CCC(C)CCCC(C)(C)C)=CC(=O)O
Reactant: [Li]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCC(=O)C=C(C)C=CCC(C)CCCC(C)(C)C
Reaction time: 3 h

Procedure:
To a stirred solution of 9.5 ml. of a one molar solution of ethyllithium in benzene and 50 ml ether, under nitrogen is added at 0° 1.0 g. of 3,7,11,11-tetramethyldodeca-2,4-dienoic acid in 10 ml. ether. The reaction mixture is stirred for three hours and then is poured into a rapidly stirred saturated aqueous ammonium chloride solution followed by the addition of 50 ml. of ether. The organic layer is separated and then is washed with saturated sodium chloride. The solution is dried over magnesium sulfate and the solvent is removed to yield 5,9,13,13-tetramethyltetradeca-4,6-dien-3-one.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[Cl-].[C:14]([C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22]([CH2:24][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:21][C:20]=2[CH:44]=1)#[N:15].C1CCN2C(=NCCC2)CC1>O1CCCC1.CO>[C:14]([C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22]([CH:24]=[CH:1][C:3]3[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=3)=[CH:21][C:20]=2[CH:44]=1)#[N:15]
Reactant: N#Cc1ccc2oc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2c1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: COC(=O)c1ccc(C=Cc2cc3cc(C#N)ccc3o2)cc1

Procedure:
5.17 g of methyl 4-formylbenzoate and 13.97 g of (5-cyano-2-benzofuranyl)methyltriphenylphosphonium chloride were dissolved in a solvent mixture of 50 ml of tetrahydrofuran and 50 ml of methanol. A 5.02 g of 1,8-diazabicyclo[5.4.0]-7-undecene was added to the thus prepared solution while stirring under ice cooling, followed by stirring at room temperature for 2 hours. By collecting the precipitated crystals through a filter, methyl 4-[2-(5-cyano-2-benzofuranyl)vinyl]benzoate was obtained as a mixture of E and Z forms. The thus obtained crystals were dissolved in a solvent mixture of 300 ml of tetrahydrofuran and 100 ml of ethanol, and the solution was subjected to catalytic hydrogenation under normal pressure for 2 hours in the presence of 2.0 g of palladium oxide.1H2O.barium sulfate. After removing the catalyst by filtration and concentrating the resulting filtrate, the thus obtained residue was purified by subjecting it to silica gel column chromatography using benzene as an elution solvent to obtain 8.1 g of methyl 4-[2-(5-cyano-2-benzofuranyl)ethyl]benzoate in the form of prism crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([N+:15]([O-])=O)=[CH:13][N:12]=[C:11]([O:18][C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:28])[CH3:27])[CH:22]=[CH:23][CH:24]=3)[CH:10]=2)=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[NH2:15][C:14]1[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)=[CH:10][C:11]([O:18][C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:28])[CH3:27])[CH:22]=[CH:23][CH:24]=2)=[N:12][CH:13]=1
Reactant: [H][H]
Reactant: CC(=O)Nc1cccc(Oc2cc(Nc3ccc(O)cc3)c([N+](=O)[O-])cn2)c1
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1cccc(Oc2cc(Nc3ccc(O)cc3)c(N)cn2)c1
Yield: 78.9 %

Procedure:
The product of Step 2 (2.9 g, 7.6 mmol) was hydrogenated in methanol (50 mL) in the presense of 5% Pd/C (250 mg) with a balloon of hydrogen overnight. The reaction mixture was filtered through Celite and concentrated to give the title compound (2.1 g, 79%) as a dark orange solid. MS (ES+) m/e 351 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6](C)[CH:5]=[CH:4][N:3]=1.[NH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:11]1.[C:23](OCC)(=O)C.C(=O)(O)[O-].[Na+]>O>[CH2:16]([N:13]1[CH2:14][CH2:15][CH:10]([NH:9][C:2]2[CH:7]=[CH:6][C:5]([CH3:23])=[CH:4][N:3]=2)[CH2:11][CH2:12]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccnc(Br)c1
Reactant: CCOC(C)=O
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1ccc(NC2CCN(Cc3ccccc3)CC2)nc1
Temperature: 180 °C
Reaction time: 9 h

Procedure:
To 2-bromo-4-methylpyridine (15.5 g) was added 4-amino-1-benzylpiperidine (68.5 g). The resulting solution was stirred at 180° C. for 9 hours and then at 150° C. for 6 hours. Ethyl acetate and water were then added to the solution followed by addition of saturated aqueous sodium bicarbonate solution. After separating liquid layers, the organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then, concentrated under reduced pressure. The resulting residue was purified by chromatography [silica gel, ethyl acetate-methanol-aqueous ammonia (90:10:0.1)] to give the title compound (11.5 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[C:11]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:10]=1)#[N:2].[NH2:28][CH2:29][C@@H:30]1[NH:34][C:33](=[O:35])[CH2:32][CH2:31]1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:28][CH2:29][C@H:30]2[CH2:31][CH2:32][C:33](=[O:35])[NH:34]2)=[O:15])=[C:11]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:10]=1)#[N:2]
Reactant: NC[C@H]1CCC(=O)N1
Reactant: N#Cc1ccccc1-c1ccc(C(=O)O)c(NCCc2cccc(F)c2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-c1ccc(C(=O)NC[C@H]2CCC(=O)N2)c(NCCc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a mixture of 6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinic acid (110 mg, 0.30 mmol), (R)-5-(aminomethyl)pyrrolidin-2-one (52 mg, 0.46 mmol), HOBT (62 mg, 0.46 mmol), and HBTU (174 mg, 0.46 mg) in RB flask was added DMF and the mixture was stirred at r.t. for 1 h. LC/MS indicated the reaction was complete and the mixture was filtered and purified on RP-HPLC using a mixture of acetonitrile and water to give (R)-6-(2-cyanophenyl)-2-(3-fluorophenethylamino)-N-((5-oxopyrrolidin-2-yl)methyl)nicotinamide (91.6 mg, 67%). LRMS (M+H+) m/z 458.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Br[CH2:15][CH2:16][CH2:17][Cl:18].C(N(CC)CC)C>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][Cl:18])[CH2:10][CH2:9]1
Reactant: ClCCCBr
Reactant: Cc1ccccc1N1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccccc1N1CCN(CCCCl)CC1
Yield: 64.7 %

Procedure:
A mixture of 35.2 g (0.2 mole) of 1-(2-methyl-phenyl)-piperazine, 31.4 g (0.2 mole) of 1-bromo-3-chloropropane, 40.4 g (0.4 mole) of triethylamine and 100 ml of tetrahydrofurane is refluxed for five hours. After cooling it is filtered, the filtrate is concentrated and the residue is fractionally distilled under vacuum. There are obtained 32.7 g of 3-[4-(2-methyl-phenyl)-piperazino]-propyl chloride (65% of theory) of boiling point 138°-140° C/0.1 mm Hg.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:70][CH2:71][C:72]([NH2:74])=[O:73]>CN(C=O)C>[NH2:74][C:72](=[O:73])[CH2:71][NH:70][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:35]([CH3:36])=[C:27]([C:10]2[C:11]3[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]4[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=4[F:25])[C:12]=3[N:13]=[C:8]([NH:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:37][CH3:38])[N:9]=2)[CH:28]=1
Reactant: NCC(N)=O
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NCC(N)=O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.2 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and glycinamide (11.1 mg, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (9 mg, 31%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][S:14]([C:17]1[CH:18]=[C:19]([CH2:23][NH2:24])[CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15].C(N(C(C)C)CC)(C)C.ClC1N=C(NCC2C=CC=C(S(C)(=O)=O)C=2)C(C(F)(F)F)=CN=1.ClC1C(C(F)(F)F)=CN=C(NCC2C=CC=C(S(C)(=O)=O)C=2)N=1.[NH2:80][C:81]1[CH:95]=[CH:94][C:84]([CH2:85][P:86](=[O:93])([O:90][CH2:91][CH3:92])[O:87][CH2:88][CH3:89])=[CH:83][CH:82]=1.C(O)(C(F)(F)F)=O>>[CH3:13][S:14]([C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[CH2:23][NH:24][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:80][C:81]2[CH:82]=[CH:83][C:84]([CH2:85][P:86](=[O:93])([O:87][CH2:88][CH3:89])[O:90][CH2:91][CH3:92])=[CH:94][CH:95]=2)[N:7]=1)(=[O:15])=[O:16]
Reactant: CS(=O)(=O)c1cccc(CN)c1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Agent: CS(=O)(=O)c1cccc(CNc2nc(Cl)ncc2C(F)(F)F)c1
Agent: CS(=O)(=O)c1cccc(CNc2ncc(C(F)(F)F)c(Cl)n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(NCc3cccc(S(C)(=O)=O)c3)n2)cc1)OCC

Procedure:
Reaction of 2,4-dichloro-5-(trifluoromethyl)pyrimidine XL with commercially available 1-[3-(methylsulfonyl)phenyl]methanamine and diisopropylethylamine at 0° C. overnight affords a mixture of 2-chloro-N-[3-(methylsulfonyl)benzyl]-5-(trifluoromethyl)pyrimidin-4-amine and 4-chloro-N-[3-(methylsulfonyl)benzyl]-5-(trifluoromethyl)pyrimidin-2-amine XLIVa/XLIVb. The crude mixture was crystallized from methylene chloride to afford a sample of the pure, undesired 2-substituted isomer XLIVb. The mother liquors were chromatographed over silica gel eluting with 1:1 hexane:ethyl acetate to yield a further pure sample of the 2-substituted isomer plus a sample of the desired 2-chloro-N-[3-(methylsulfonyl)benzyl]-5-(trifluoromethyl)pyrimidin-4-amine XLIVa. Reaction of this latter isomer with anilines such as diethyl (4-aminobenzyl)phosphonate in the presence of TFA and TFE under microwave irradiation yields the desired product (e.g. diethyl (4-{[4-{[3-(methylsulfonyl)benzyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate, Ex. 25).