Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=2[F:19])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27](O)=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=2[F:19])[C:4]=1[F:20])=[O:28]
Reactant: Cc1nc(Cl)c(C(=O)O)[nH]1
Reactant: N#Cc1ccc(Oc2c(Cl)ccc(CN)c2F)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3ccc(C#N)cc3F)c2F)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 22.1 %

Procedure:
To a solution of 4-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-3-fluorobenzonitrile (40.0 mg, 0.136 mmol), 4-chloro-2-methyl-1H-imidazole-5-carboxylic acid (21.79 mg, 0.136 mmol) and HATU (51.6 mg, 0.136 mmol) in DMF (3 ml) was added diisopropylethyl amine (0.047 ml, 0.271 mmol) and the reaction mixture was stirred at rt for 15 minutes. The reaction mixture was purified via reverse phase HPLC and neutralized to give 4-chloro-N-({4-chloro-3-[(4-cyano-2-fluorophenyl)oxy]-2-fluorophenyl}methyl)-2-methyl-1H-imidazole-5-carboxamide (13 mg, 0.030 mmol, 22% yield) 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.73 (d, 1H), 7.47 (d, 1H), 7.29-7.42 (m, 2H), 6.87 (t, 1H), 4.52-4.73 (m, 2H), 2.34 (s, 3H). LC-MS (ES+) m/z 437.11, [M+H].
Reaction SMILES: [C:1]12([CH2:11][N:12]3[CH:16]=[CH:15][CH:14]=[N:13]3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:17]([Li])CCC.IC.O>O1CCCC1>[C:1]12([CH2:11][N:12]3[C:16]([CH3:17])=[CH:15][CH:14]=[N:13]3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: [Li]CCCC
Reactant: c1cnn(CC23CC4CC(CC(C4)C2)C3)c1
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ccnn1CC12CC3CC(CC(C3)C1)C2
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
A solution of EXAMPLE 3A (869 mg) in tetrahydrofuran (10 mL) was chilled to −45° C. n-Butyllithium (2.3 M solution in hexanes, 2.10 mL) was added dropwise over 5 minutes. The reaction was stirred for 1.5 hours, during which time the temperature increased to −20° C. Iodomethane (0.305 mL) was added dropwise over 3 minutes. The reaction was stirred for 30 minutes between −20 and −15° C. Water (25 mL) was added and the mixture was extracted with ethyl acetate (3×25 mL). The extracts were dried (Na2SO4), filtered, and concentrated to provide the title compound.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([CH:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13](COCC[Si](C)(C)C)[CH:12]=2)=[O:10])[CH3:7])[N:3]=[CH:2]1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[O:1]1[CH:5]=[C:4]([CH:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[NH:13][CH:12]=2)=[O:10])[CH3:7])[N:3]=[CH:2]1
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1cocn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: CC(NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1cocn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-oxazol-4-yl-ethyl)-amide (110 mg, 0.205 mmol) was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (0.63 ml, 8.2 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (1 ml) and ethylenediamine (0.83 ml, 12.3 mmol) was added. The yellow solution was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resulting suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 58 mg (70%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-oxazol-4-yl-ethyl)-amide as a light yellow powder. MS: (M+H)+=406; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.83 (br. s., 1H), 9.12 (s, 1H), 8.42-8.51 (m, 2H), 8.32-8.42 (m, 2H), 8.20 (s, 1H), 7.68 (dd, J=9.8, 1.9 Hz, 1H), 7.04 (td, J=9.3, 1.9 Hz, 1H), 5.28-5.46 (m, 1H), 4.14 (s, 3H), 1.58 (d, J=6.8 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(N(C(C)C)CC)(C)C>C(#N)C>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[N:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: FC(F)(F)c1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)nn2)CC1
Yield: 98.7 %

Procedure:
A mixture of 6-chloro-3-trifluoromethylpyridazine (0.666 g, 5.09 mmol) (prepared by following the procedure described in Goodman, A. J.; Stanforth, S. P; Tarbit B. Tetrahedron 1999, 55, 15067-15070), N-Boc-piperazine (1.138 g, 6.11 mmol) and diisopropylethylamine (1.95 ml, 1.12 mmol) in acetonitrile (10 ml) was stirred at 180° C. for 30 min., under microwave irradiation. The solvent was evaporated in vacuo and the residue was purified by column chromatography (silica gel; hexane/ethyl acetate) to yield D9 (1.67 g, 99%) as a light yellow solid. C14H19F3N4O2 requires 332; Found 333 (MH+).
Reaction SMILES: [Br-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2-].[Na+].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:35]=[C:34]([N:36]3[CH2:41][CH2:40][N:39]([CH2:42][C:43]([C:45]4[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=4)=O)[CH2:38][CH2:37]3)[S:33][N:32]=2)=[CH:27][CH:26]=1.O.CCOC(C)=O>C1COCC1>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[N:35]=[C:34]([N:36]3[CH2:41][CH2:40][N:39]([CH2:42][C:43]([C:45]4[CH:46]=[CH:47][C:48]([O:51][CH3:52])=[CH:49][CH:50]=4)=[CH2:2])[CH2:38][CH2:37]3)[S:33][N:32]=2)=[CH:29][CH:30]=1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C(=O)CN2CCN(c3nc(-c4ccc(Cl)cc4)ns3)CC2)cc1
Agent: [Br-]
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(CN1CCN(c2nc(-c3ccc(Cl)cc3)ns2)CC1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of methyltriphenylphosphonium bromide/sodium amide (57.7 mg, 146 μmol) was combined with THF (5 mL) to give a yellow suspension and stirred for 1 h at RT. 2-(4-(3-(4-chlorophenyl)-1,2,4-thiadiazol-5-yl)piperazin-1-yl)-1-(4-methoxyphenyl)ethanone (50 mg, 117 μmol) dissolved in THF (3 mL) was added drop-wise via syringe over 5 min. The resulting orange suspension was stirred over night at RT. Water (10 mL) and EtOAc (10 mL) was added and stirred for 10 min. The aqueous layer was separated and extracted with EtOAc (1×10 mL). The organic layers were washed with brine (1×10 mL), dried over Na2SO4, filtered off and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with a gradient formed from heptane and EtOAc to yield, after evaporation of the product containing fraction, 33 mg (66%) of the title compound as off-white solid. MS (m/e): 427.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[O:27]>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[Cl:17])=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Product: COc1ccc(NC(=O)Nc2ccc(Cl)cc2Cl)cc1-c1c(Cl)cnn1C
Yield: 24 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 2,4-dichlorophenyl isocyanate in a similar manner as described in Example 1.53, providing 16.4 mg (24%) of Compound 77 (Note: Compound 77 did not precipitate out. Therefore, the CH2Cl2 was removed under reduced pressure, the residue was dissolved in 5 mL DMSO, and purified by preparative HPLC): LCMS m/z (%)=427 (M+H37Cl, 72), 425 (M+H35Cl, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.85 (s, 1H), 8.26 (dd, J1=12 Hz, J2=4 Hz, 1H) 7.90 (s, 1H), 7.59 (dd, J1=8 Hz, J2=4 Hz, 1H), 7.38 (d, J=4 Hz, 1H), 7.36 (s, 1H), 7.36 (s, 1H), 7.24 (dd, J1=12 Hz, J2=4 Hz, 1H), 7.05 (d, J=8 Hz, 1H), 3.72 (s, 3H), 3.56 (s, 3H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C@H:10]2[CH2:14][CH2:13][CH2:12][NH:11]2)[CH:6]=[C:7]([F:9])[CH:8]=1.Br[C:16]1[CH:21]=[CH:20][N:19]2[N:22]=[CH:23][C:24]([C:25]([O:27]CC)=[O:26])=[C:18]2[CH:17]=1>>[F:9][C:7]1[CH:6]=[C:5]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:16]2[CH:21]=[CH:20][N:19]3[N:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[C:18]3[CH:17]=2)[CH:4]=[C:3]([F:2])[CH:8]=1
Reactant: Fc1cc(F)cc([C@H]2CCCN2)c1
Reactant: CCOC(=O)c1cnn2ccc(Br)cc12
Agent: Cl
Product: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cc(F)c3)cc12

Procedure:
The title compound was prepared by a method substantially similar to that mentioned in step-5 and step-6 of example-3 using (R)-2-(3,5-Difluorophenyl)pyrrolidine hydrochloride (step-1) and Ethyl 5-bromo-pyrazolo[1,5-a]pyridine-3-carboxylate to afford the product as white solid. MS (ESI): m/z 344.1 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][C:8]([CH2:9][S:10][C:11]2[O:12][C:13]3[C:18]([C:19](=[O:29])[C:20]=2[CH2:21][O:22]C2CCCCO2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.O>O1CCCC1>[C:1]([C:5]1[CH:31]=[CH:30][C:8]([CH2:9][S:10][C:11]2[O:12][C:13]3[C:18]([C:19](=[O:29])[C:20]=2[CH2:21][OH:22])=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CSc2oc3ccccc3c(=O)c2COC2CCCCO2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(CSc2oc3ccccc3c(=O)c2CO)cc1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
2-(4-Tertbutylbenzyl)thio-3-((2-tetrahydropyranyloxy)methyl) chromen-4-one (5.5 g, 12.55 mmol) is dissolved in tetrahydrofuran in a 50 mL round bottom flask. Acetic acid and water are then added such that the ratio of THF:Acetic acid:Water is 4:2:1 (28 mL). The flask is warmed to 45° C. and the mixture stirred for 3 hours. After cooling the flask the contents are poured into a separatory funnel and the aqueous layer extracted with ethyl acetate. The organic layer is then washed with water and brine and dried over sodium sulfate and filtered. The filtrate is concentrated in vacuo and the residue obtained is purified by silica gel flash chromatography (ethyl acetate:hexanes) to give the above-mentioned product.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH2:18])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.C([O:40][C:41](=O)[C:42]1[C:47]([CH2:48]Br)=[CH:46][CH:45]=[CH:44][C:43]=1[O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])C>C(#N)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][N:18]3[CH2:48][C:47]4[C:42](=[C:43]([O:50][Si:51]([C:54]([CH3:56])([CH3:55])[CH3:57])([CH3:52])[CH3:53])[CH:44]=[CH:45][CH:46]=4)[C:41]3=[O:40])[N:13]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN2Cc3sc(N)c(C(=O)OC(C)(C)C)c3CC2CN)cc1
Reactant: CCOC(=O)c1c(CBr)cccc1O[Si](C)(C)C(C)(C)C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2Cc3sc(N)c(C(=O)OC(C)(C)C)c3CC2CN2Cc3cccc(O[Si](C)(C)C(C)(C)C)c3C2=O)cc1
Reaction time: 12 h
Yield: 66.1 %

Procedure:
To a solution of 2-amino-5-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (3.00 g, 7.45 mmol) and diisopropyl ethylamine (1.93 ml, 11.2 mmol) in acetonitrile at room temperature was added a solution of 6-bromomethyl-2-(tert-butyl-dimethyl-silanyloxy)-benzoic acid ethyl ester (2.78 g, 7.45 mmol) in acetonitril over 48 hours. The solution was stirred for 12 hours after the addition was complete. The volatiles were evaporated in vacuo and the residue was taken into ethyl acetate (50 ml) and washed with water, 1 N hydrochloric acid, brine, dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was chromatographed on silica gel column eluted with a mixture of 20% ethyl acetate/Hexane, which afforded 3.2 g (66. %) of 2-amino-5-(7-(tert-butyl-dimethyl-silanyloxy)-1-oxo-1,3-dihydro-isoindol-2-ylmethyl]-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[O:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[Mg]Br>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]([C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)[OH:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1
Reactant: Br[Mg]c1cccs1
Reactant: COc1cc(C=O)ccc1-c1cccc(C)c1
Solvent: C1CCOC1
Product: COc1cc(C(O)c2cccs2)ccc1-c1cccc(C)c1
Reaction time: 2 h
Yield: 82.4 %

Procedure:
The aldehyde 5 were dissolved in dry THF and cooled to −20° C. thiphen-2-yl magnesium bromide (1.2 eq, 1.651 mM) was then added to the reaction and the reaction was stirred for an additional 2 hrs. After the completion of the reaction as determined by TLC, the reaction mixture was quenched with 0.1 N HCl, followed by washes with saturated sodium bicarbonate solution and brine. The product was purified by flash chromatography using 20% EtOAc/Hexanes as the solvent system to obtain a white solid. Yield=82.4% (Rf=0.26; 20% EtOAc/Hexanes) 1H NMR, 500 MHz Varian, CDCl3, δ 7.31 (d, J=2 Hz, 1H), 7.29 (d, J=4.00 Hz, 1H), 7.12 (d, J=9.50 Hz, 2H), 6.99 (m, J=9.50 Hz, 2H), 6.75 (s, 2H), 6.08 (d, J=4.00, 1H), 3.73 (s, 3H), 2.37 (s, 3H), MS: m/z (ESI, pos.)=333.5 ([M+23])
Reaction SMILES: [C-:1]#[N:2].[K+].CS([C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:10]([NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:9]=1)(=O)=O.O>CN(C)C=O>[CH2:24]([NH:23][C:10]1[N:9]=[C:8]([C:1]#[N:2])[N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)c1nc(NCCc2ccccc2)c2ncn(C3CCCCO3)c2n1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1nc(NCCc2ccccc2)c2ncn(C3CCCCO3)c2n1
Reaction time: 70 h
Yield: 67.9 %

Procedure:
Potassium cyanide (5.6 g, 86.2 mmol) was added to a stirred solution of 2-(methylsulfonyl)-N-phenethyl-9-tetrahydro-2H-pyran-2-yl-9H-purin-6-amine (21.0 g, 43.1 mmol) (preparation 43) in N,N-dimethylformamide (100 ml). The reaction mixture was heated at 110° C. for 74 hr with extra potassium cyanide being added at 44 hr (3.3 g, 50.8 mmol) and 68 hr (1.2 g, 18.5 mmol). The reaction mixture was allowed to stand at room temperature for 70 hr, then poured into water (500 ml), extracted with diethyl ether (1000 ml) and the aqueous layer washed with diethyl ether (500 ml). The combined organic layers were washed with water (3×500 ml). The solvent was removed under reduced pressure from the combined organic layers to give a residue which was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (99:1) to give the title compound (10.2 g) as a brown solid. MS: 349 (MH+).
Reaction SMILES: C[O-].[Na+].[Br-].[NH2:5][C:6]1[N:11]=[CH:10][CH:9]=[CH:8][N+:7]=1[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Br:20]>CO>[NH:5]=[C:6]1[N:11]=[CH:10][CH:9]=[CH:8][N:7]1[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Br:20]
Reactant: Nc1nccc[n+]1CCc1ccccc1Br
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Product: N=c1ncccn1CCc1ccccc1Br
Reaction time: 2 h
Yield: 81.3 %

Procedure:
To a solution of 3.3 g of sodium methoxide in 120 ml of anhydrous methanol is added 10.8 g of 2-amino-1-(o-bromophenethyl)pyrimidinium bromide, prepared as described in example 1 (G). The solution is stirred under nitrogen for 2 hours and then heated under reflux for 5 hours. The solvent is removed in vacuo and the residue is treated with 200 ml of anhydrous ether. The ether solution is washed, dried, and concentrated in vacuo to give about 6.8 g of yellow solid. This is recrystallized from hexane to give the name product, mp about 97°-98°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]#[N:14])([O-:3])=[O:2].O[CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:13]([C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:9]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:8]=1)#[N:14]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: N#Cc1c[nH]c2ccc([N+](=O)[O-])cc12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(C#N)c3cc([N+](=O)[O-])ccc32)CC1
Temperature: 25 °C
Reaction time: 32 h
Yield: 32.8 %

Procedure:
To a solution of 5-nitro-1H-indole-3-carbonitrile (2.0 g, 10.69 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (4.30 g, 21.37 mmol) and triphenylphosphine (5.61 g, 21.37 mmol) in 90 ml THF was slowly added DEAD (3.38 mL, 21.37 mmol) in 50 ml of THF over 3 hrs. The mixture was stirred 32 hrs at 25° C. The mixture was concentrated and purified on silica: 100% DCM 500 ml, then (5-60% EtOAc in Hexanes) to give tert-butyl 4-(3-cyano-5-nitro-1H-indol-1-yl)piperidine-1-carboxylate (1.3 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=O)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].NCC1CCN(CC2C=CC(Cl)=C(Cl)C=2)C1.[NH2:31][CH2:32][C@@H:33]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[C:40]=2[Cl:46])[CH2:34]1>>[Cl:46][C:40]1[C:41]([Cl:45])=[CH:42][CH:43]=[CH:44][C:39]=1[CH2:38][N:35]1[CH2:36][CH2:37][C@@H:33]([CH2:32][NH:31][C:12](=[O:14])[CH2:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=2)[CH2:34]1
Reactant: NC[C@@H]1CCN(Cc2cccc(Cl)c2Cl)C1
Reactant: CC(=O)Nc1cccc(CC(=O)O)c1
Agent: NCC1CCN(Cc2ccc(Cl)c(Cl)c2)C1
Product: CC(=O)Nc1cccc(CC(=O)NC[C@@H]2CCN(Cc3cccc(Cl)c3Cl)C2)c1

Procedure:
Proceeding as described above but substituting 4-(2,5-dimethylphenyl)-4-oxobutyric acid with 2-(3-acetylaminophenyl)acetic acid and 3-aminomethyl-1-(3,4-dichlorobenzyl)pyrrolidine with 3-(S)-aminomethyl-1-(2,3-dichlorobenzyl)pyrrolidine gave N-[1-(2,3-dichlorobenzyl)pyrrolidin-3-(S)-ylmethyl]-2-(3-acetylaminophenyl)-acetamide.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([O:17]CC=C)=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:4]=1)#[N:2].N1CCOCC1>C1COCC1.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>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33]([CH3:36])(=[O:34])=[O:35])[CH:4]=1)#[N:2]
Reactant: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N[C@@H]1c1ccc(C#N)cc1S(C)(=O)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CC1=C(C(=O)O)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The reaction was carried out under argon. Allyl (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (800 mg, 1.54 mmol; Example 4) and morpholine (1.5 eq., 201 mg, 2.31 mmol) were initially charged in dry THF (25 ml) at RT. The reaction mixture was degassed repeatedly (evacuation followed by venting with argon). Under protective gas, tetrakis(triphenylphosphine)palladium(0) (0.05 eq., 89 mg, 0.077 mmol) was added, and the reaction mixture was stirred at RT for 90 min (HPLC control). The reaction mixture was then concentrated and the residue was taken up in ethyl acetate (500 ml). The organic phase was washed with saturated ammonium chloride solution (50 ml), with water (50 ml) and with conc. sodium chloride solution (50 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave a colorless amorphous solid (696 mg, purity 86%, 81% of theory).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C[Si]([N:15]=[C:16]=[O:17])(C)C>C(O)(C)C>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:16]([NH2:15])=[O:17])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: C[Si](C)(C)N=C=O
Solvent: CC(C)O
Product: NC(=O)N1CCC2(CC1)OCCO2
Reaction time: 8 h
Yield: 102.9 %

Procedure:
To a stirred solution of 1,4-dioxa-8-azaspiro[4,5]-decane (1.1 g, 7.67 mmol) in isopropanol (20 mL) at rt was added trimethylsilylisocyanate (1.5 mL, 10.6 mmol) and the resulting solution stirred overnight before the volatiles were removed in vacuo to give 1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid amide (1.47 g, quant.); 1H-NMR (300 MHz, d6-DMSO) 5.96 (2H, s), 3.88 (4H, s), 3.33 (4H, t), 1.51 (4H, t).
Reaction SMILES: [NH3:1].[Br:2][C:3]1[N:4]=[C:5]([CH:13]2[CH2:16][C:15]([CH3:18])([OH:17])[CH2:14]2)[N:6]2[CH:11]=[CH:10][N:9]=[C:8](Cl)[C:7]=12>CC(O)CC>[NH2:1][C:11]1[N:6]2[C:5]([CH:13]3[CH2:16][C:15]([CH3:18])([OH:17])[CH2:14]3)=[N:4][C:3]([Br:2])=[C:7]2[CH:8]=[N:9][CH:10]=1
Reactant: N
Reactant: CC1(O)CC(c2nc(Br)c3c(Cl)nccn23)C1
Solvent: CCC(C)O
Product: CC1(O)CC(c2nc(Br)c3cncc(N)n23)C1
Temperature: 90 °C

Procedure:
A 35% ammonia solution (132 ml, 2.9 moles) was added to a suspension of 3-(1-bromo-8-chloroimidazo[1,5-α]pyrazin-3-yl)-1-methylcyclobutanol (22.0 g, 0.06463 mol) in 2-butanol (81 ml). The mixture was heated at 90° C. in a pressure vessel for 15 hr then concentrated to 130 ml, cooled to room temperature and the solid collected by filtration. This material was washed with water (3×22 mL) and dried at 40° C. under vacuum. To afford the desired product. 1H NMR (DMSO-d6, 400 MHz): δ 7.5 (d, 1H), 7.0 (d, 1H), 6.6 (bs, 2H), 5.1 (s, 1H), 3.4 (pentet, 1H), 2.3-2.4 (m, 4H) and 1.4 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-])=O)[CH:8]=2)[N:3]=1.[F:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][CH2:21][CH:22]2[NH2:25])=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][CH2:21][CH:22]2[NH:25][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([NH2:12])[CH:8]=3)[N:3]=2)=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Reactant: NC1CCc2ccc(F)cc21
Product: Nc1ccc2nc(NC3CCc4ccc(F)cc43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method described in example 2 from 2-chloro-6-nitro-quinoline and rac-6-fluoro-indan-1-ylamine (CAS no: 168902-77-0); MS: m/e=294.3 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:8]([CH3:9])=[C:7]([F:10])[C:6]([F:11])=[CH:5][C:3]=1[NH2:4].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[F:1][C:2]1[C:8]([CH3:9])=[C:7]([F:10])[C:6]([F:11])=[CH:5][C:3]=1[NH:4][C:12](=[O:14])[CH3:13]
Reactant: Cc1c(F)c(N)cc(F)c1F
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(F)c(F)c(C)c1F
Temperature: 0 °C

Procedure:
To 2,4,5-trifluoro-3-methylaniline (1 g) is added acetic anhydride (3 ml) at room temperature with stirring and the mixture is stirred for 15 minutes. The reaction mixture is poured into ice-water, extracted with dichloromethane, and the extract is washed with water and dried. The solvent is distilled off to give 2,4,5-trifluoro-3-methyl-N-acetylaniline (1.14 g), as white crystals.