Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C1([Mg]Br)C=CC=CC=1.[CH:22](=[O:26])[CH:23]([CH3:25])[CH3:24]>C1COCC1>[N+:11]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH:22]([OH:26])[CH:23]([CH3:25])[CH3:24])([O-:13])=[O:12]
Reactant: CC(C)C=O
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1I
Agent: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CC(C)C(O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 30 %

Procedure:
To a solution of 1-iodo-2,6-dinitrobenzene (Smith and Ho, 1990), which is incorporated herein by reference) (1.55 g, 5.27 mmol) in anhydrous THF (18 mL) at minus 50° C. under a nitrogen atmosphere, phenylmagnesium bromide (2 M in THF, 3.2 mL, 6.4 mmol) was added dropwise at a rate such that the temperature would not exceed minus 45° C. Upon completion of the addition, the mixture was stirred at minus 50° C. for five min, followed by addition of isobutyraldehyde (0.96 mL, 11 mmol). The mixture was gradually warmed up to room temperature, quenched with saturated NH4Cl solution (10 mL), and then diluted with water (50 mL). The mixture was extracted with CH2Cl2 (100 mL) three times. The combined organic phase was washed with brine (50 mL), dried over Na2SO4, concentrated in vacuo, and the residue was purified by silica gel column chromatography to yield (R/S)-1-(2,6-dinitrophenyl)-2-methyl-1-propanol (0.375 g, 30%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.82 (d, 2H, J=8.0 Hz, Ph-H), 7.59 (t, 1H, J=8.0 Hz, Ph-H), 4.83 (dd, 1H, J=9.2 and 7.6 Hz, Ph-CH), 2.87 (d, 1H, J=7.6 Hz, OH), 2.19 (m, 1H, CH), 1.12 (d, 3H, J=6.4 Hz, CH3), 0.76 (d, 3H, J=6.8 Hz, CH3).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[NH2:11])([O-:3])=[O:2].CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1>CC(O)=O>[N+:1]([C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[CH:18][CH:17]=[CH:16]2)[CH:7]=[CH:6][C:5]=1[NH2:11])([O-:3])=[O:2]
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: Nc1ccc(-n2cccc2)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 2-nitro-1,4-phenylenediamine (20 g, 131 mmol), 2,5-dimethoxytetrahydrofuran (18.3 mL, 135 mmol) in HOAc (37 mL) at 95° C. for 3 h according to the general procedure F. Obtained as a red solid (13.5 g).
Reaction SMILES: Cl.[F:2][C:3]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]=2[C:8]([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])=[N:7]1.[C:28]([O:32][CH2:33][C:34](O)=[O:35])([CH3:31])([CH3:30])[CH3:29].C(N(CC)C(C)C)(C)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>>[C:28]([O:32][CH2:33][C:34]([N:11]1[CH2:12][CH2:13][C:14]2[N:6]([CH2:5][C:4]3[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:3]=3[F:2])[N:7]=[C:8]([C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[C:9]=2[CH2:10]1)=[O:35])([CH3:31])([CH3:30])[CH3:29]
Reactant: N#Cc1cccc(-c2nn(Cc3ccc(F)cc3F)c3c2CNCC3)c1
Reactant: CC(C)(C)OCC(=O)O
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OCC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2Cc2ccc(F)cc2F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.6 %

Procedure:
To a 0° C. cold mixture of 3-[1-(2,4-Difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (7c) (0.4 g, 1.142 mmol) and 2-tert-butoxyacetic acid (196 mg, 1.485 mmol) was added N,N-diisopropylethylamine (0.59 g, 4.57 mmol) and TOTU (O-(Cyano(ethoxycarbonyl)methylenamino)-1,1,3,3-tetramethyluronium tetrafluoroborate, 562 mg, 1.71 mmol) and the mixture was stirred at 25° C. for 1 h. The crude product was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 120 mg of 3-[5-(2-tert-Butoxy-acetyl)-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (8d).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=O.[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12][C:13]([O-])=[O:14].C(O)C.N1CCCCC1>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:3]=1[CH:4]=[C:12]([C:11]([O:17][CH2:18][CH3:19])=[O:16])[C:13](=[O:14])[O:10]2
Reactant: O=Cc1c(O)cccc1Cl
Reactant: CCOC(=O)CC(=O)[O-]
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cc2c(Cl)cccc2oc1=O
Yield: 57.8 %

Procedure:
15 g (0.0958 mole) of 2-chloro-6-hydroxy-benzaldehyde, 16.7 g (0.105 mole) ethyl malonate, 40 mL ethanol, 0.6 mL piperidine and 0.1 mL acetic acid are refluxed for 5 hours. After cooling the resultant product is dried. After drying, 14 g of ethyl 5-chlorocoumarin-3-carboxylate are obtained. (Yield=58%). Melting pointG =142°-144° C.
Reaction SMILES: O1[C:5]2([CH2:9][CH2:8][N:7]([C@H:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]3[O:16][CH2:17][CH2:18][C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])[CH2:6]2)[O:4]CC1.Cl>CC(=O)CC.O>[ClH:25].[O:4]=[C:5]1[CH2:9][CH2:8][N:7]([C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[O:16][CH2:17][CH2:18][C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:26])[CH2:6]1
Reactant: Clc1cccc(Cl)c1CCO[C@H]1CCCC[C@@H]1N1CCC2(C1)OCCO2
Agent: Cl
Solvent: CCC(C)=O
Solvent: O
Product: O=C1CCN([C@H]2CCCC[C@@H]2OCCc2c(Cl)cccc2Cl)C1

Procedure:
A mixture of (1R,2R)/(1S,2S)-2-[1,4-dioxa-7-azaspiro[4.4]non-7-yl]-1-(2,6-dichlorophenethoxy)cyclohexane (15.85 g, 38.9 mmol, step ix) and 6M HCl aqueous solution (100 mL) in 2-butanone (400 mL) was refluxed for 16 hours. The cooled reaction mixture was diluted with water (100 mL) and the organic solvent was evaporated in vacuo. The organic layer was further diluted with water (400 mL), extracted with diethyl ether (500 mL) and with dichloromethane (2×600 mL). The combined dichloromethane extracts were dried over sodium sulfate and the solvent was evaporated in vacuo. Azeotropic distillation with toluene provided the title compound which was further dried under high vacuum for 15 min. The hydrochloride salt was crystallized by triturating in diethyl ether, the crystals were collected and recrystallized from a mixture of ethanol-diethyl ether to yield 11.85 g of pure product (77% yield), having the elemental analysis indicated in Table 1.
Reaction SMILES: [C:1]([C:8]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:9]=1[C:10]([O:12]C)=O)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.[CH3:21][NH:22][O:23][CH3:24].[Li]CCCC>>[C:1]([C:8]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:9]=1[C:10]([N:22]([CH3:21])[O:23][CH3:24])=[O:12])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CNOC
Reactant: CCCCCC#Cc1cc(OC)ccc1C(=O)OC
Agent: Cl
Agent: [Li]CCCC
Product: CCCCCC#Cc1cc(OC)ccc1C(=O)N(C)OC
Yield: 78 %

Procedure:
Treatment of methyl 2-(1-heptyn-1-yl)-4-(methyloxy)benzoate (110) (0.67 g, 2.57 mmol) with a mixture of N,O-dimethylhydroxylamine hydrochloride and nBuLi gave 0.58 g (78%) of the title compound (111) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 0.93 (t, J=7.0 Hz, 3H), 1.30-1.50 (m, 4H), 1.60-1.70 (m, 2H), 2.41 (t, J=7.1 Hz, 2H), 3.31 (br s, 3H), 3.64 (br s, 3H), 3.83 (s, 3H), 6.86 (dd, J1=8.5 Hz, J2=2.5 Hz, 1H), 6.96 (d, J=2.6 Hz, 1H), 7.27 (d, J=8.6 Hz, 1H). LCMS (ESI): m/z 290 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:14][C:13]([NH2:15])=[N:12][C:11]2[C:7]=1[N:8]=[CH:9][N:10]=2.O[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>CN(C=O)C.C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:14]=[C:13]([NH2:15])[N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: Nc1nc2ncnc-2c(-c2ccco2)[nH]1
Reactant: OCCc1ccccn1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccco2)c2ncn(CCc3ccccn3)c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47 %

Procedure:
A mixture of 6-(2-furyl)-1H-purine-2-amine (50 mg, 0.25 mmol) and triphenylphosphine polystyrene (0.21 g, 0.62 mmol) in anhydrous DMF (0.5 mL) and anhydrous THF (2 mL) was treated with 2-(2-hydroxyethyl)pyridine (61 mg, 0.50 mmol), shaken at room temperature for 10 min, treated with di-tert-butyl azodicarboxylate (0.115 g, 0.50 mmol), shaken for 16 h, filtered and the filtrate concentrated in vacuo and purified by chromatography [SiO2; CH2Cl2-MeOH (100:5)] to give the title compound (36 mg, 47%) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:46])[C@@H:4]([NH:23][C:24](=[O:45])[C:25]1[C:30]([Cl:31])=[CH:29][C:28]([O:32][CH2:33][CH2:34][CH2:35][NH:36]C(OC(C)(C)C)=O)=[CH:27][C:26]=1[Cl:44])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:21])=[CH:8][CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][O:2][C:3](=[O:46])[C@@H:4]([NH:23][C:24](=[O:45])[C:25]1[C:26]([Cl:44])=[CH:27][C:28]([O:32][CH2:33][CH2:34][CH2:35][NH2:36])=[CH:29][C:30]=1[Cl:31])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:22])[C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:21])=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1c(Cl)cc(OCCCNC(=O)OC(C)(C)C)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1c(Cl)cc(OCCCN)cc1Cl
Reaction time: 15 h
Yield: 118.5 %

Procedure:
To a solution of (S)-2-[4-(3-tert-butoxycarbonylaminopropoxy)-2,6-dichlorobenzoylamino]-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid methyl ester (7.5 g, 7.98 mmol) in dichloromethane (100 mL) was added an excess of TFA (9.12 g, 5.9 mL, 80 mmol) at room temperature. The resulting solution was stirred for 15 h. Then, the solvent was removed under vacuum and the residue was azeotrophed one time with toluene. After drying under high vacuum, 5.8 g (99%) of (S)-2-[4-(3-aminopropoxy)-2,6-dichlorobenzoylamino]-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid methyl ester was obtained as a white solid. ES(+)-HRMS m/e calcd. for C27H25Cl4N3O5 (M+H)+ 612.0621, obsd. 612.0619.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[CH:8][N:9]=1)(=[O:3])[CH3:2].C([Li])CCC.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][C@H:25]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:26]2[O:31][C:30](=[O:32])[C:29]3[CH:33]=[CH:34][CH:35]=[C:36]([C:37]([F:40])([F:39])[F:38])[C:28]=3[N:27]=2)=[CH:16]1>O1CCCC1.CCCCCC>[O:32]=[C:30]([C:29]1[CH:33]=[CH:34][CH:35]=[C:36]([C:37]([F:38])([F:39])[F:40])[C:28]=1[NH:27][C:26]([C@@H:25]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:24][C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:15][CH:16]=1)=[O:31])[CH2:2][C:1](=[O:3])[NH:4][C:5]1[S:6][CH:7]=[CH:8][N:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Reactant: CC(=O)Nc1nccs1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F
Yield: 106.1 %

Procedure:
Using the procedure of Step B of Example 7, a solution of 18.34 g of 2-acetylaminothiazole in 565 ml of tetrahydrofuran, 184 ml of a solution of n-butyllithium in hexane and 20.3 g of the product of Step A in 150 ml of tetrahydrofuran were reacted to obtain 28 g of 1,1-dimethylethyl N-[(S) 1-[[2-[1,3-dioxo-3-(2-thiazolylamino)-propyl]-6-(trifluoromethyl)-phenyl]-aminocarbonyl]-2-(1H-indol-3-yl)-ethyl]-carbamate as an orange oil which was used as is in the following step.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[C:16]([NH2:17])=[C:15]([C:18]([CH3:20])=[CH2:19])[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=1)[CH3:3].C(O)(=O)C>C(O)C.[Pd].[Pt]>[CH:2]([C:4]1[C:16]([NH2:17])=[C:15]([CH:18]([CH3:20])[CH3:19])[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=1)([CH3:3])[CH3:1]
Reactant: C=C(C)c1cc2c(sc3ccccc32)c(C(=C)C)c1N
Agent: [Pd]
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)c1cc2c(sc3ccccc32)c(C(C)C)c1N
Yield: 82.2 %

Procedure:
2,4-di(prop-1-en-2-yl)dibenzo[b,d]thiophen-3-amine (9 g, 32.2 mmol) was dissolved in ethanol (150 mL) and 9 mL of acetic acid was added. To the flask, 10% Pd/C (9.0 g) and 5% Pt/C (9.0 g) were added and hydrogenated at 40 psi of H2 for over night. GC indicated complete conversion of olefin to alkane. The reaction mixture was filtered through a Celite pad and washed with methylene chloride. The filtrate was concentrated to produce 7.5 g (82%) of desired product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1>CN1CCCC1=O.O>[C:34]([O:33][C:31]([N:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=3[F:19])=[CH:6][N:5]=2)[CH2:26][CH2:27]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CCS(=O)c1ncc(C(=O)c2c(OC)ccc(F)c2F)c(N)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc1N
Yield: 80 %

Procedure:
A solution of (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone (7.7 g, 23 mmol, Example 165) and 4-amino-1N-Boc-piperidine (6.8 g, 34 mmol, Astatech) in 30 mL of 1-methyl-2-pyrrolidinone was heated at 70° C. for 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The dried (Na2SO4) organic solution was evaporated and the residue was chromatographed on silica gel. Elution with 3:2 ethyl acetate/hexane provided 80% yield of 4-[4-amino-5-(2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester as a colorless solid, mp 114 dec., identical to material prepared in Example 106. Mass Spectrum (LR-ES) M+: 463.
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.O.[NH2:16][NH2:17].O>C(OCC)(=O)C>[C:1]([NH:16][NH2:17])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccccc1
Reactant: NN
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccccc1
Temperature: 78 °C
Yield: 66 %

Procedure:
Into a 200 mL three-neck flask was put 25 g (0.17 mol) of ethyl benzoate, 60 mL of ethanol was added thereto, and the mixture was stirred. After that, 20 mL of hydrazine monohydrate was added to the mixture, and this mixture was stirred while being heated at 78° C. for 8 hours. After the reaction, the reaction solution was added to about 500 mL of water, and ethyl acetate was added to this aqueous solution. An organic layer was separated from an aqueous layer, and washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution in that order. Magnesium sulfate was added to the organic layer, so that the organic layer was dried. This mixture was suction filtered, so that the magnesium sulfate was removed, whereby a filtrate was obtained. The obtained filtrate was concentrated to give a solid. The solid was recrystallized with a mixed solvent of ethanol and hexane, whereby 15 g of a white solid of benzohydrazide, which was the object of the synthesis, was obtained in a yield of 66% (synthesis scheme (b-1)).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([CH:28]=[CH:29][N:30]=2)[CH:5]=[C:6]([C:8]2[C:9]([CH3:27])=[C:10]([NH:14][C:15](=[O:26])[C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=3)[CH:11]=[CH:12][CH:13]=2)[CH:7]=1.C(N(C(C)C)CC)(C)C.[C:40](Cl)(=[O:42])[CH3:41]>ClCCl>[C:40]([NH:1][C:2]1[C:3]2[N:4]([CH:28]=[CH:29][N:30]=2)[CH:5]=[C:6]([C:8]2[C:9]([CH3:27])=[C:10]([NH:14][C:15](=[O:26])[C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:23])[CH3:24])=[CH:18][CH:17]=3)[CH:11]=[CH:12][CH:13]=2)[CH:7]=1)(=[O:42])[CH3:41]
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cc(N)c2nccn2c1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2cccc(NC(=O)c3ccc(C(C)(C)C)cc3)c2C)cn2ccnc12
Temperature: 0 °C

Procedure:
To N-[3-(8-Amino-imidazo[1,2-a]pyridin-6-yl)-2-methyl-phenyl]-4-tert-butyl-benzamide (185 mg, 0.414 mmol) in dichloromethane (10 mL) was added diisopropylethylamine (0.24 mL, 3 eq). The resulting mixture was cooled to 0° C. and with stirring was added acetyl chloride (31 μL, 0.95 eq) and the resulting mixture was stirred from 0° C. to room temperature overnight. The next day the solvent was removed under reduced pressure at 55° C. and ethyl acetate (35 mL) and water (25 mL) were added to the residue. The organic layer was concentrated. Then added THF (5 mL) and 1N NaOH (5 mL) and stirred vigorously at room temperature overnight to hydrolize significant bis-amide. The next day added ethyl acetate (150 mL) and water (50 mL) and added 1N HCl to pH=2 and stirred vigorously for 10 minutes. The layers were separated, and the organic layer was washed with brine (1×50 mL), and then dried over magnesium sulfated, filtered and concentrated. The crude product was purified by Thin Layer Chromatography, eluting with 5% methanol in dichloromethane to give the title compound as an off-white powder (31 mg), ((M+H)+=441).
Reaction SMILES: CCCCCCCCCCCCCCC[CH2:16][CH2:17][C:18]([O:20]CCCCCCCCCCCCCC(C)C)=[O:19].C(O)CCCCCO.C(CC(C)(C)C(O[O-])=O)(C)(C)C.C([O-])(=O)C(C)=C.[CH:63]([N:65]1[CH2:69][CH2:68][CH2:67][C:66]1=[O:70])=[CH2:64]>O>[CH:63]([N:65]1[CH2:69][CH2:68][CH2:67][C:66]1=[O:70])=[CH2:64].[C:18]([OH:20])(=[O:19])[CH:17]=[CH2:16]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCC(C)C
Agent: C=C(C)C(=O)[O-]
Agent: C=CN1CCCC1=O
Agent: CC(C)(C)CC(C)(C)C(=O)O[O-]
Solvent: O
Product: C=CC(=O)O
Temperature: 65 °C
Reaction time: 1 h

Procedure:
Into a 1-liter, four-necked glass kettle, equipped with 2 feeding pumps an anchor agitator, a thermocouple and a condenser, was charged 300 g of CERAPHYL 494 (iso-cetyl stearate) and 60 g of hexylene glycol and heated to 65° C. for 30 minutes. The solution was purged with nitrogen throughout the ensuing reaction process. T-butylperoxypivalate was added as well as a mixture of 15 g of methyl methacrylate, 36.75 g of butyl methacrylate, 32.25 of stearyl methacrylate and 0.2 g PETE was added to the kettle over a period of 3 hours. The resulting solution was held at 65° C. for 1 hour and then heated to 90° C. Five times every 2 hours, 0.1 g of the initiator was added and the resulting solution was held at 90° C. for 2 additional hours after the last initiator charge. The resulting crosslinked acrylate polymer mixture was then cooled to 65° C. and Solution I of 50 g of vinylpyrrolidone and Solution II of 50 g of acrylic acid were prepared and fed into the kettle at a constasnt rate over a 4 hour period. The resulting solution was held at 65° C. for 1 hour before raising the temperature to 80° C. T-butylperoxypivalate (0.1 g) was added 4 times every 2 hours. The resulting solution containing the polymeric, crosslinked methacrylate polymer network penetrated with the vinyl pyrrolidone polymer was held for an additional 2 hours after which 1 g of water was added and stirred for another 5 hours at 100° C. and then cooled and a homogenized product was recovered.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([NH2:19])([CH2:14][O:15][CH2:16][O:17][CH3:18])[CH2:9][O:10][CH2:11][O:12][CH3:13])[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:26][CH2:27][C:28](Cl)=[O:29]>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:19][C:28](=[O:29])[CH2:27][Cl:26])([CH2:9][O:10][CH2:11][O:12][CH3:13])[CH2:14][O:15][CH2:16][O:17][CH3:18])[CH:5]=[CH:4][CH:3]=1
Reactant: COCOCC(N)(COCOC)c1cccc(Br)n1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COCOCC(COCOC)(NC(=O)CCl)c1cccc(Br)n1
Reaction time: 0.17 h

Procedure:
To a solution of 1-(6-bromo-pyridin-2-yl)-2-methoxymethoxy-1-methoxymethoxymethyl-ethylamine (15.0 g, 44.75 mmol) in DCM (150 ml) was added aqueous Na2CO3 solution (10.91 g, 102.925 mmmol in water, 30 ml) was added at 0° C. and stirred for 10 min. Chloroacetylchloride (5.56 g, 49.225 mmol) was added to the resultant reaction mixture at 0° C. stirring continued for 1 h at ambient temperature. Reaction mixture was diluted with DCM (˜1 l), and worked up the reaction mixture by washing with water, brine and dried over anhy. Na2SO4. Organic layer was separated and concentrated under reduced pressure to obtain title compound as a brown liquid. Yield=9.0 g (48%). TLC (50% ethyl acetate in hexane) Rf=0.54; LCMS: RtH7=1.341, [M+1]=411.0 and 413.0; HPLC: RtH9=4.27 min (50.4%); 1H NMR (400 MHz, CDCl3): δ 8.11 (d, 1H), 7.57-7.52 (m, 1H), 7.46-7.37 (m, 2H), 4.59-4.52 (m, 4H), 4.23-4.17 (m, 4H), 4.09-4.04 (m, 2H), 3.21 (s, 6H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[N:16]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:15]=[C:14]2[C:27]([OH:29])=[O:28])C1C=CC=CC=1.CC1C=C(C)C(C)=C(C)C=1C.CCOCC>FC(F)(F)C(O)=O>[OH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[N:16]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:15]=[C:14]2[C:27]([OH:29])=[O:28]
Reactant: O=C(O)c1cn(S(=O)(=O)c2ccccc2)c2c(OCc3ccccc3)cccc12
Agent: Cc1cc(C)c(C)c(C)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: O=C(O)c1cn(S(=O)(=O)c2ccccc2)c2c(O)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
To a solution of 1.0 g of 7-benzyloxy-1-phenylsulfonyl-1H-indole-3-carboxylic acid in 5 mL of trifluoroacetic acid, 1.0 g of 1,2,3,4,5-pentamethylbenzene was added, and the resulting mixture was stirred at room temperature overnight. 20 mL of ether was added to the solution, insoluble matter was removed, the solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate to obtain 0.25 g of 7-hydroxy-1-phenylsulfonyl-1H-indole-3-carboxylic acid as a gray solid. FAB−:316
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([NH2:15])=O)[CH2:6][CH2:5]1)[CH2:2][CH3:3].O=P(Cl)(Cl)Cl>CN(C=O)C.O>[CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]#[N:15])[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCN1CCC(c2cccc(C(N)=O)c2)CC1
Solvent: O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCN1CCC(c2cccc(C#N)c2)CC1
Yield: 39.1 %

Procedure:
A solution of 3-(1-propyl-piperidin-4-yl)-benzamide (350 mg) and POCl3 (326 μL) in dry DMF (6 ml) was heated at 80° C. for 3 h under an argon atmosphere. Evaporation of the solvent yielded a dark, oily residue, which was dissolved in water. The solution was basified and extracted with CH2Cl2. The combined organic phases were dried (MgSO4), filtered and evaporated. The oily residue was chromathographed on a silica column with MeOH:CH2Cl2 (1:19 (v/v)) as eluent. Collection of the fractions containing pure product and evaporation of the solvent afforded pure 3-(1-Propyl-piperidin-4-yl)-benzonitrile (127 mg). The amine was converted into the fumarate salt and recrystallized from ethanol/diethylether: m.p. 122° C.; MS m/z (relative intensity, 70 eV) 228 (M+, 2), 199 (42), 129 (26), 70 (bp) 56 (53).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9](Cl)=[O:10])=[CH:4][N:3]=1.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[CH2:17][NH2:18]>>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([NH:18][CH2:17][C:16]2[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=[C:14]([C:13]([F:12])([F:26])[F:27])[CH:15]=2)=[O:10])=[CH:4][N:3]=1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(Cl)c1cnc(Cl)nc1Cl
Product: O=C(NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)nc1Cl
Yield: 61 %

Procedure:
The title compound was prepared as described in Example 1, but employing 2,4-dichloropyrimidine-5-carbonylchloride (0.10 g, 0.40 mmol) and 3,5-bistrifluoromethylbenzylamine (0.10 g, 0.45 mmol) to give the compound in a 61% yield (0.12 g); m.p. 144°-145° C.