Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[N:18]1[CH:20]=[CH:21][CH:22]=[C:17]1[C:16]2=[O:23])=O>C(O)(=O)C>[N:1]1[C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[NH:8][C:9]=1[C:11]1[C:19]2[N:18]3[CH:20]=[CH:21][CH:22]=[C:17]3[C:16](=[O:23])[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccncc1NC(=O)c1cccc2c1-n1cccc1C2=O
Solvent: CC(=O)O
Product: O=C1c2cccc(-c3nc4ccncc4[nH]3)c2-n2cccc21
Temperature: 200 °C
Yield: 46.1 %

Procedure:
In a 20 ml microwave reactor, a mixture of 256 mg of 9-oxo-9H-pyrrolo[1,2-a]indole-5-carboxylic acid (4-aminopyridin-3-yl)amide obtained according to the preceding stage, in 20 ml of glacial acetic acid, is heated at 200° C. for 30 minutes. The reaction medium is filtered through clarcel, washing being carried out with glacial acetic acid. The filtrate is evaporated to dryness under vacuum and the residue is taken up twice with toluene and each time re-evaporated to dryness under vacuum. The solid is triturated from isopropyl ether, filtered, and dried under vacuum at 40° C. overnight. 111 mg of 5-(3H-imidazo[4,5-c]pyridin-2-yl)pyrrolo[1,2-a]indol-9-one are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([F:23])[CH:16]=2)=[CH:11][N:10]=[C:9]1SC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.Cl>O1CCOCC1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([F:23])[CH:16]=2)=[CH:11][N:10]=[C:9]1[NH:31][C:30]1[CH:32]=[CH:33][C:27]([F:26])=[CH:28][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: COc1ccc(-c2cnc(SC)n(Cc3ccccc3)c2=O)cc1F
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(-c2cnc(Nc3ccc(F)cc3)n(Cc3ccccc3)c2=O)cc1F
Temperature: 25 °C
Yield: 71 %

Procedure:
3-benzyl-5-(3-fluoro-4-methoxyphenyl)-2-(methylthio)pyrimidin-4(3H)-one (697.4 mg, 1.957 mmol) was dissolved in 1,4-dioxane (10 ml) and 4-fluoroaniline (1.50 ml, 15.6 mmol) and concentrated hydrochloric acid (0.040 ml, 1.1 mmol) were added. The flask was fitted with a reflux condenser and placed in a preheated oil bath (125 C) and stirred under nitrogen. After stirring for 70 hours, the reaction was cooled to room temperature and concentrated. It was then treated with Et2O, and filtered, and the solid was washed with Et2O and dried in vacuo to afford the desired 3-benzyl-5-(3-fluoro-4-methoxyphenyl)-2-(4-fluorophenylamino)pyrimidin-4(3H)-one (582.7 mg, 1.39 mmol, 96% purity, 67% yield over two steps). MS (ESI pos. ion) m/z: 420 (MH+). Calc'd exact mass for C24H19F2N3O2: 419. 1HNMR (400 MHz, CDCl3): 7.89 (br s, 1H), 7.53-7.37 (m, 8H), 7.13 dd, J=9.2 Hz, 4.0 Hz, 2H), 7.01 (t, J=8.0 Hz, 3H), 5.47 (s, 2H), 3.93 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH:19]([CH3:23])[CH2:20][O:21][CH3:22])=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:24][CH3:25])=[C:5]([CH3:26])[O:4][N:3]=1.[N:27]([CH2:30][CH2:31][NH:32]C(=O)OC(C)(C)C)=[C:28]=S.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:24][CH3:25])=[CH:9][C:10]3[C:11]4[N:18]([CH:19]([CH3:23])[CH2:20][O:21][CH3:22])[C:28]([NH:27][CH2:30][CH2:31][NH2:32])=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: COCC(C)Nc1c(N)cnc2cc(-c3c(C)noc3C)c(OC)cc12
Reactant: CC(C)(C)OC(=O)NCCN=C=S
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCC(C)n1c(NCCN)nc2cnc3cc(-c4c(C)noc4C)c(OC)cc3c21
Reaction time: 1 h
Yield: 5.4 %

Procedure:
From 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-(1-methoxypropan-2-yl)quinoline-3,4-diamine (70 mg) and 1,1-dimethylethyl (2-isothiocyanatoethyl)carbamate (50 mg). The crude product isolated was treated with TFA (2 ml) in DCM (10 ml), the mixture stirred for 1 h, then evaporated in vacuo. The residue was dissolved in DMSO (1 ml) and purified by MDAP (HpH) to give the title compound as a beige solid (4.5 mg, 4%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:21]=[C:22]([OH:27])[CH:23]=[CH:24][C:25]=1[F:26].[Cl-].[NH4+]>CN(C)C=O>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([O:27][C:22]2[CH:23]=[CH:24][C:25]([F:26])=[C:20]([F:19])[CH:21]=2)[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH3:12]
Reactant: Oc1ccc(F)c(F)c1
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(Oc2ccc(F)c(F)c2)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 66.1 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-butynyloxy)pyrimidine, 0.23 g of potassium carbonate, and 0.17 g of 3,4-difluorophenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.2 g of 4-(2-butynyloxy)-6-(3,4-difluorophenoxy)pyrimidine (the present compound (10)), m.p.: 109.7° C.
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[Cl:31][C:32]1[CH:45]=[CH:44][C:35]([CH:36]([NH2:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:34][CH:33]=1>>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([CH:36]([NH:43][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]2)=[CH:6][CH2:7]4)=[O:30])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:44][CH:45]=1
Reactant: NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Yield: 70 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5 -diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 4-chlorobenzhydrylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 70%.
Reaction SMILES: Cl[CH2:2][CH:3]1[C:15](=[O:16])[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH3:17])[C:6]=2[CH2:5][CH2:4]1.[CH3:18][C:19]1[NH:20][CH:21]=[CH:22][N:23]=1>CN(C=O)C>[CH3:17][N:7]1[C:6]2[CH2:5][CH2:4][CH:3]([CH2:2][N:20]3[CH:21]=[CH:22][N:23]=[C:19]3[CH3:18])[C:15](=[O:16])[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: Cc1ncc[nH]1
Reactant: Cn1c2c(c3ccccc31)C(=O)C(CCl)CC2
Solvent: CN(C)C=O
Product: Cc1nccn1CC1CCc2c(c3ccccc3n2C)C1=O
Reaction time: 1 h
Yield: 76 %

Procedure:
A solution of 3-(chloromethyl)-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one (0.50 g) and 2-methyl-1H-imidazole (1.60 g) in dry DMF was stirred under nitrogen at 90° for 3.75 h, and then poured onto water (25 ml). The suspension was stirred for 1 h, and the solid filtered off, washed with water (3×20 ml) and dried in vacuo at 50°. Column chromatography of this solid (0.53 g) eluting with a mixture of dichloromethane, ethanol and 0.88 aqueous ammonia (150:10:1) afforded the title compound (0.45 g) m.p. 228°-229°. This material was identical to the product from Example 7 by t.l.c. and n.m.r.
Reaction SMILES: [CH3:1][C:2]1[O:6][CH:5]=[C:4]([C:7]([O:9]CC)=[O:8])[CH:3]=1.[OH-].[K+].Cl>O>[CH3:1][C:2]1[O:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1
Reactant: CCOC(=O)c1coc(C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C(=O)O)co1
Temperature: 10 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
A mixture of 31.7 g (206 mmol) of ethyl 5-methylfuran-3-carboxylate, 40 ml of 45% strength potassium hydroxide and 100 ml of water was refluxed for 4 h, then cooled to 10° C. and acidified to pH 1 with 15% strength hydrochloric acid. The resulting mixture was left at this temperature for 2 h, and the precipitate was filtered off and dried to constant weight at 45-50° C., resulting in 23.7 g (188 mmol, 91%) of 5-methylfuran-3-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][CH:10]3[CH2:14][CH2:13][NH:12][CH2:11]3)[O:8][C:4]=2[CH:3]=1.Cl.ClC1OC2C=C(Cl)C=CC=2N=1>>[ClH:1].[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C@@H:10]3[CH2:14][CH2:13][NH:12][CH2:11]3)[O:8][C:4]=2[CH:3]=1
Reactant: Clc1ccc2nc(NC3CCNC3)oc2c1
Agent: Cl
Agent: Clc1ccc2nc(Cl)oc2c1
Product: Clc1ccc2nc(N[C@@H]3CCNC3)oc2c1

Procedure:
In analogy to the procedure described for the synthesis of (6-Chloro-benzooxazol-2-yl)-pyrrolidin-3-yl-amine; hydrochloride (example 1, step 1) the title compound was prepared from 2,6-dichloro-benzoxazole (commercially available) and R-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (commercially available) and subsequent cleavage of the tert-butyl oxy carbonyl protecting group under acidic conditions. (MH+) 238.0.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]([O:8]CC)=[CH2:7])CCC.Cl[C:20]1[N:25]=[C:24]2[CH:26]=[CH:27][N:28](C(OC(C)(C)C)=O)[C:23]2=[CH:22][CH:21]=1>CN(C=O)C.CCOC(C)=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>[NH:28]1[C:23]2[C:24](=[N:25][C:20]([C:6](=[O:8])[CH3:7])=[CH:21][CH:22]=2)[CH:26]=[CH:27]1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)n1ccc2nc(Cl)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2[nH]ccc2n1
Temperature: 100 °C
Reaction time: 48 h
Yield: 63.9 %

Procedure:
A high-pressure tube was charged with tributyl(1-ethoxyvinyl)stannane (7.75 g, 21.45 mmol) and tert-butyl 5-chloropyrrolo[3,2-b]pyridine-1-carboxylate (4.17 g, 16.50 mmol) in degassed DMF (64.0 mL) and Pd(PPh3)4 (1.9 g, 1.65 mmol) was added in one batch. The tube was closely tightly and the reaction mixture was stirred at 100° C. under N2 for 2 d. The reaction mixture was cooled, diluted with EtOAc (350 mL), and filtered through a pad of Celite® to remove solid Pd. The filtrate was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was dissolved in anhydrous THF (80.2 mL), and 2N HCl (41 mL) was added. The reaction mixture was stirred at RT under N2 for 16 h, poured into 10% aq. NaOH solution (100 mL) and then extracted with EtOAc (3×150 mL). The combined organic phases were washed with water and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by SiO2chromatography eluting with EtOAc/heptane to afford 1.69 g (64.1%) of 1-(1H-pyrrolo[3,2-b]-pyridin-5-yl)ethanone as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 7.99 (d, J=8.5 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.54 (t, J=3.0 Hz, 1H), 6.86 (s, 1H), 2.80 (s, 3H); MS (ESI) m/z: 161.3 [M+1]+.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:4].CN(C)CCN(C)C.C([Li])CCC.[I:27]I>O.O1CCCC1>[I:27][C:11]1[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:13])([CH3:12])[CH3:1])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(C)C(=O)Nc1ccccn1
Reactant: II
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(=O)Nc1ncccc1I
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of 2,2-dimethyl-N-pyridin-2-yl-propionamide described in Preparation Example 1-1-1 (3.0 g, 17 mmol), N,N,N′,N′-tetramethyl ethylenediamine (6.3 mL, 42 mmol) and tetrahydrofuran (60 mL) was added n-butyl lithium (1.6M n-hexane solution, 30 mL, 47 mmol) dropwise at −78° C, which was stirred overnight at 0° C. To the reaction mixture was added iodine (6.8 g, 27 mmol) at −78° C, which was stirred at 0° C for 1.5 hours. To the reaction mixture were added water and a saturated aqueous solution of sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride water, and the solvent thereof was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=2:1) to obtain the title compound (2.9 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][OH:15])[CH:10]=[N:9]2)=[N:6][CH:7]=1.[F:16][C:17]1[CH:18]=[CH:19][C:20]([I:26])=[C:21]([CH:25]=1)[C:22]([OH:24])=O>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([I:26])=[C:21]([C:22]([N:6]2[CH2:5][CH2:4][CH2:3][O:15][CH:14]2[CH2:13][C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)[CH:12]=2)=[O:24])[CH:25]=1
Reactant: O=C(O)c1cc(F)ccc1I
Reactant: OCCc1cnn(-c2ccc(F)cn2)c1
Product: O=C(c1cc(F)ccc1I)N1CCCOC1Cc1cnn(-c2ccc(F)cn2)c1

Procedure:
By using 2-[1-(5-fluoropyridin-2-yl)-1H-pyrazol-4-yl]ethanol obtained in Reference Example 22 (0.21 g, 1.0 mmol) and 5-fluoro-2-iodobenzoic acid (0.16 g, 0.60 mmol), the same procedure as in Reference Example 25 was carried out to obtain the title compound (0.15 g) (pale yellow oil).
Reaction SMILES: FC(F)(F)C(O)=O.ClCCl.C(OC([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][C:28]#[N:29])=[CH:21][CH:20]=1)=O)(C)(C)C>>[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH2:27][C:28]#[N:29])=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCCC#N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCCCc1ccc(N)cc1
Reaction time: 0.5 h
Yield: 117.5 %

Procedure:
A 0.25 M solution of trifluoroacetic acid in dichloromethane (5 mL, 1.25 mmol) was added to 4-[4-(t-Butoxycarbonylamino)phenyl]butanenitrile (98) (0.22 g, 0.85 mmol). After 30 min, reaction was quenched with 1 N NaOH solution. The mixture was partitioned with ethyl acetate (30 mL) and water (20 mL). The organic layer was dried over MgSO4, concentrated to give 4-(4-Aminophenyl)butanenitrile (97) (0.16 g, 99%) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:7][CH2:6][C:5](=O)[CH2:4][O:3]1.[NH3:10]>[Ni]>[CH3:1][C:2]1([CH3:9])[O:7][CH2:6][CH:5]([NH2:10])[CH2:4][O:3]1
Reactant: N
Reactant: CC1(C)OCC(=O)CO1
Agent: [Ni]
Product: CC1(C)OCC(N)CO1

Procedure:
6.1 g (47 mmol) of 2,2-dimethyl-1,3-dioxan-5-one (D. Enders, B. Bockstiegel, Synthesis 1989, 493, incorporated herein by reference) were subjected to reductive amination in 50 ml of ammonia—saturated methanol in an autoclave at 50° C. under a hydrogen pressure of 100 bar, using Raney nickel as the catalyst. After the catalyst had been filtered off and the filtrate concentrated, 4.8 g of a brown oil were obtained, this being further reacted without purification.
Reaction SMILES: [C:1]1([O:11][CH:12]([CH3:27])[C:13]([NH:15][C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.B#B.Cl>O1CCCC1>[C:1]1([O:11][CH:12]([CH3:27])[CH2:13][NH:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(C)Oc2cccc3ccccc23)cc1
Agent: B#B
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(NCC(C)Oc2cccc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A solution of 8.29 g. ethyl 4-[2-(1-naphthyloxy)propionamido]benzoate in 75 ml. tetrahydrofuran is reacted with 34 ml. 1 M diborane in tetrahydrofuran. After stirring at room temperature for 5 days, the solution is poured into 750 ml. 5% HCl, stirred for about 1/2 hour until foaming stopped, and extracted three times with 250 ml. portions of methylene chloride. The combined extracts are washed with 200 ml. brine, dried and condensed to nearly colorless oil. Crystallization from acetonitrile yield white solid, m.p. 110°-111.5° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9][C@H:8]1[CH:20]=O)=[O:6])[CH:2]=[CH2:3].C1(P(=[CH:41][C:42]([O:44][CH3:45])=[O:43])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[CH2:9][C@H:8]1[CH:20]=[CH:41][C:42]([O:44][CH3:45])=[O:43])=[O:6])[CH:2]=[CH2:3]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=CC(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-formylpyrrolidine (30.0 g) in tetrahydrofuran (300 ml) was added methyl (triphenylphosphoranylidene)acetate (35.2 g) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was chromatographed on a 300 g of silica gel to give (2S,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-(3-methoxy-3-oxo-1-propenyl)pyrrolidine (29.8 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].C1C=CC(CC(NCN[C@H](C(O)=O)CC2C=CC([N+]([O-])=O)=CC=2)=O)=CC=1.[Cl:51][C:52]1[CH:59]=[CH:58][C:55]([CH2:56][NH2:57])=[CH:54][CH:53]=1.C(N(CC)C(C)C)(C)C.C(CN)O.FC(F)(F)C(O)=O>CS(C)=O.O>[NH2:1][C:2]1[N:23]=[C:22]([NH:57][CH2:56][C:55]2[CH:58]=[CH:59][C:52]([Cl:51])=[CH:53][CH:54]=2)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Reactant: NCc1ccc(Cl)cc1
Agent: O=C(Cc1ccccc1)NCN[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Solvent: NCCO
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(NCc2ccc(Cl)cc2)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Temperature: 140 °C
Reaction time: 60 h
Yield: 24 %

Procedure:
To a solution of 2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Example A-101 (35 mg, 0.10 mmol) in dimethylsulfoxide (1mL) were added 4-chlorobenzylamine (234 μl, 1.92 mmol) and N,N-diisopropylethylamine (1.0 mL, 5.74 mmol), and the solution was stirred at 140° C. for 2.5 days. Ethanolamine (116 μl, 1.92 mmol) and N,N-diisopropylethylamine (1.0 mL, 5.74 mmol) were added to the reaction mixture, which was then further stirred at 140° C. for 2.5 days. Water was added to the reaction mixture, which was then extracted with ethyl acetate, the organic layer was sequentially washed with water and brine, dried over anhydrous sodium sulfate, and then, concentrated in vacuo. The obtained residue was purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), and the title compound (13.8 mg, 0.024 mmol, 24%) was obtained as a trifluoroacetic acid salt.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[N:9]2[CH:22]=[CH:23][CH:24]=[C:8]2[C:7]=1[OH:25])=[O:5])C.[NH2:26][CH2:27][C:28]([O-:30])=[O:29].[Na+]>>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH2:13][N:10]1[C:11](=[O:12])[C:6]([C:4]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:5])=[C:7]([OH:25])[C:8]2=[CH:24][CH:23]=[CH:22][N:9]12
Reactant: CCOC(=O)c1c(O)c2cccn2n(Cc2ccc(F)cc2F)c1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cccn2n(Cc2ccc(F)cc2F)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 1-(2,4-difluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 378 (M+H)+.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]([OH:13])=[O:12])[CH2:3]1>[Pd].CO>[CH:4]1([C:11]([OH:13])=[O:12])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:2][CH2:3]1
Reactant: O=C1CC(C(=O)O)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: O=C(O)C1CCc2ccccc21
Yield: 94.6 %

Procedure:
A MeOH (1 mL) solution of 3-oxo-indancarboxylic acid (85.5 mg, 0.485 mmol) was mixed with Pd/C (16.5 mg) and hydrogenated at room temperature under 55 psi H2 pressure for 18 h. The crude mixture was filtered and concentrated to give 1-indanecarboxylic acid (74.4 mg, 95%). MS Found: (M−H)·=161.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:26])[CH:9]([NH:14][C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][CH3:24])[N:18]=[C:17](Cl)[N:16]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])[CH3:2].Cl.Cl.[O:29]1[C:33]2[CH:34]=[CH:35][C:36]([N:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)=[CH:37][C:32]=2[O:31][CH2:30]1.C(N(CC)C(C)C)(C)C>CS(C)=O.C(OCC)(=O)C>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:26])[CH:9]([NH:14][C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][CH3:24])[N:18]=[C:17]([N:41]2[CH2:42][CH2:43][N:38]([C:36]3[CH:35]=[CH:34][C:33]4[O:29][CH2:30][O:31][C:32]=4[CH:37]=3)[CH2:39][CH2:40]2)[N:16]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])[CH3:2]
Reactant: c1cc2c(cc1N1CCNCC1)OCO2
Reactant: CCCCc1cc(NC(CC(C)C)C(=O)NCCCOCC)nc(Cl)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1cc(NC(CC(C)C)C(=O)NCCCOCC)nc(N2CCN(c3ccc4c(c3)OCO4)CC2)n1
Temperature: 25 °C
Yield: 15.3 %

Procedure:
2-(6-Butyl-2-chloro-pyrimidin-4-ylamino)-4-methylpentanoic acid (3-ethoxypropyl)amide (10 mg), 1-benzo[1,3]dioxol-5-yl-piperazine dihydrochloride (25 mg), and N,N-diisopropylethylamine (50 μL) were stirred for 24 h in 1 mL methyl sulfoxide at 100° C. The solution was cooled to room temperature and diluted with ethyl acetate (30 mL), then washed 4 times with 30 mL aliquots of a saturated aqueous solution of sodium chloride. Semi-preparative HPLC followed by silica gel chromatography (gradient: 2–4% methyl alcohol in methylene chloride) provided 2.2 mg of 2-[2-(4-benzo[1,3]dioxol-5-yl-piperazin-1-yl)-6-butylpyrimidin-4-ylamino]-4-methylpentanoic acid (3-ethoxypropyl) amide. ESI-MS (m/z) 555 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[C:30]1([CH3:39])[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1>C(Cl)Cl>[CH3:39][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]3[CH:26]=[CH:27][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)[CH2:21][CH2:22]2)=[O:38])=[CH:32][CH:31]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)N2CCN(C(=O)c3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)cc1
Yield: 93 %

Procedure:
To a suspension of 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine (2 g, 0.005 mol) in 15 ml of methylene chloride is added dropwise a solution of p-tolyl isocyanate in 10 ml of methylene chloride under nitrogen at room temperature. After complete addition, the resultant suspension is stirred at room temperature for 2 hours. This suspension is then filtered and the white residue is washed with methylene chloride and dried. This is re-crystallized from methanol/methylene chloride to give 2.5 g (93%) of white crystalline 1-[[(4-methylphenyl)amino]carbonyl]-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine of melting point 280°-282° C.