Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[C:21]([Cu])#[N:22]>>[F:1][C:2]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:21]#[N:22])=[CH:14][C:6]1=2
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1
Reactant: N#C[Cu]
Product: N#Cc1cnc2c(c1)N(Cc1cc(F)ccc1F)CCN2
Yield: 86 %

Procedure:
1-(2,5-Difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (394 mg) was reacted with CuCN as in General Procedure 6 to give the title compound as a brown solid (86% yield). M.p. 204-206° C., LCMS: m/z=287.07 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 3.23-3.37 (m, 2H), 3.44-3.50 (m, 2H), 4.49 (s, 2H), 6.82 (s, 1H), 7.09-7.22 (m, 2H), 7.25-7.33 (m, 1H), 7.62 (bs, 1H), 7.73 (d, J=1.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[OH:13].[H-].[Na+].[Cl:16][C:17]1[CH:22]=[C:21]([N+]([O-])=O)[CH:20]=[CH:19][N:18]=1>>[F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:16])[CH:22]=1
Reactant: CCOC(=O)c1ccc(F)c(O)c1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1ccc(F)c(Oc2ccnc(Cl)c2)c1
Yield: 88.8 %

Procedure:
Using the method of Example 3, Step A, ethyl 4-fluoro-3-hydroxybenzoate (2.90 g, 15.8 mmol), 60% sodium hydride in mineral oil (631 mg, 15.8 mmol), and 2-chloro-4-nitropyridine (2.50 g, 15.8 mmol) were reacted to provide ethyl 4-fluoro-3-(2-chloropyridin-4-yloxy)benzoate (4.15 g, 89% yield) as a clear oil. 1H NMR-(CDCl3) δ 8.27 (d, 1H), 8.02 (m, 1H), 7.90 (d, 1H), 7.30 (t, 1H), 6.78-6.83 (m, 2H), 4.39 (q, 2H), 1.40 (t, 3H).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH:3]=[CH:2]1>P(Cl)(Cl)(Cl)=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=c1cc[nH]c2ccccc12
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc2ncccc2c1
Yield: 79.4 %

Procedure:
3-butyryl-6-benzoyloxymethyl)-4(1H)-quinolone (30 g) was heated under reflux in phosphorus oxychloride (200 ml) for 30 minutes. The solvent was evaporated and the residue partitioned between dichloromethane and ammonia solution. The organic layer was washed successively with sodium hydrogen carbonate solution and 50% brine. Dried anhyd. MgSO4), filtered and evaporated to an oily solid which crystallized on trituration with petroleum ether to give 3-butyryl-4-chloro-6-benzyloxymethyl)quinoline (21.2 g, 67%), m.p. 85° C.-6° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:21](=[O:24])[CH2:22][CH3:23])=[C:3]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[NH:4]2)=[CH:9][CH:8]=1
Reactant: Nc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12
Reactant: CCC(=O)Cl
Product: CCC(=O)Nc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(3-chlorobenzoyl)indole (Example 30) and propionyl chloride. m.p.: 129-130° C. 1H-NMR (CDCl3): 9.95 (1H, br s), 8.30 (1H, d, J=9.2 Hz), 8.17 (1H, br s), 7.78-7.59 (3H, m), 7.51 (1H, t, J=7.7 Hz), 7.32 (1H, d, J=1.1 Hz), 7.11 (1H, dd, J=1.8, 8.8 Hz), 4.48 (2H, q, J=7.6 Hz), 1.30 (3H, t, J=7.6 Hz)
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([C:24](=[O:35])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=4)[CH:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]O)[CH2:15]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:42][C:43]1[CH:48]=[CH:47][C:46]([N:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)=[CH:45][CH:44]=1>>[CH3:34][O:33][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[O:31][CH3:32])[C:24]([N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:15][CH:16]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:52]1[CH2:51][CH2:50][N:49]([C:46]2[CH:45]=[CH:44][C:43]([F:42])=[CH:48][CH:47]=2)[CH2:54][CH2:53]1)=[O:35]
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: COc1ccc(C(=O)N2c3ccccc3C(n3c4ccccc4c4ccccc43)CC2CCCCCO)cc1OC
Product: COc1ccc(C(=O)N2c3ccccc3C(n3c4ccccc4c4ccccc43)CC2CCCCCN2CCN(c3ccc(F)cc3)CC2)cc1OC
Yield: 51.2 %

Procedure:
Starting with 5-[4-(9H-9-carbazolyl)-1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-2-quinolinyl]-1-pentanol (0.13 g, 0.22 mmol) prepared in Example 135 and 4-(4-fluorophenyl)piperazine (79 mg, 0.44 mmol), the same procedure as shown in Example 136 was repeated to give the titled compound (0.08 g, yield: 51%) as a white crystal (cis:trans=4:1).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH2:24].C(N(CC)CC)C>C(Cl)Cl>[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH:24][S:16]([C:14]1[S:15][C:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CN(C)CCN
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)NCCN(C)C)s2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step II of Example 1 (1000 mg; 2.97 mmol; 1 eq) is dissolved in anhydrous DCM (100 ml). The reaction is put under nitrogen. 2-Dimethylaminoethylamine (0.97 ml; 8.91 mmol; 3 eq), triethylamine (1.66 ml; 11.9 mmol; 4 eq) are added successively and the reaction mixture is stirred overnight at room temperature. After 15 hours, to complete the reaction, triethylamine (4 eq) and 2-dimethylaminoethylamine (3 eq) are added. After one hour the reaction is complete. The reaction mixture is then wash with NH4Cl sat. (twice) and brine. The organic layer is dried over MgSO4 and the solvents are evaporated. The resulting crude product is dissolved in DCM and extracted with HCl 1N. The aqueous phase is washed with DCM (3 times) and basified with NaOH 5N until pH 10. The desired product is extracted with EtOAc (3 times). Combined organic phases are dried over MgSO4, filtrated and evaporated, affording Compound (3) as a beige solid (480 mg; 40%).
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C@@H:14]([CH2:25][C:26]([O:28][CH2:29][CH2:30][OH:31])=[O:27])[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:32]([O:39][C:40]([NH:42][C:43]1[CH:51]=[CH:50][C:46]([C:47](O)=[O:48])=[CH:45][CH:44]=1)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:1]1[C:13]2[N:12]([C@@H:14]([CH2:25][C:26]([O:28][CH2:29][CH2:30][O:31][C:47](=[O:48])[C:46]3[CH:45]=[CH:44][C:43]([NH:42][C:40]([O:39][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:41])=[CH:51][CH:50]=3)=[O:27])[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)OCc1ccccc1
Reactant: O=C(C[C@@H](C(=O)OCc1ccccc1)n1c2ccccc2c2ccccc21)OCCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(C[C@@H](C(=O)OCc1ccccc1)n1c2ccccc2c2ccccc21)OCCOC(=O)c1ccc(NC(=O)OCc2ccccc2)cc1
Yield: 59.6 %

Procedure:
(S)-1-benzyl 4-(2-hydroxyethyl) 2-(9H-carbazol-9-yl)succinate 17 (0.500 g, 1.20 mmol) was added to a solution of 4-(benzoyloxycarbonylamino)benzoic acid 10 (0.389 g, 1.44 mmol), EDCHCl (0.304 g, 1.58 mmol) and DMAP (0.043 g, 0.35 mmol) in CH2Cl2 (10 mL). After the reaction mixture was refluxed for 24 h, the solution was extracted with CH2Cl2 (100 mL) and water (100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using CH3OH:CH2Cl2 (1:99) to afford (S)-1-benzyl 4-(2-(4-(benzyloxycarbonylamino)benzoyloxy)ethyl) 2-(9H-carbazol-9-yl)succinate 18 (0.480 g, 60%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]([CH3:12])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1.[C:15](OC(OC)=O)(OC)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(Cl)Cl>[CH3:15][NH:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH:3]([CH3:12])[C:2]([F:13])([F:14])[F:1])=[CH:10][CH:9]=1
Reactant: CC(Oc1ccc(N)cc1)C(F)(F)F
Reactant: COC(=O)OC(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Product: CNc1ccc(OC(C)C(F)(F)F)cc1

Procedure:
This material was prepared from (rac)-4-(2,2,2-trifluoro-1-methyl-ethoxy)-phenylamine by, first an standard methoxycarbonylation reaction with dimethyl dicarbonate in methylene chloride (at RT and 12 h stirring) followed by reduction with LiAlH4 according to standard literature procedures.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12](=[O:23])[NH:13][C:14]([C:17](=[O:22])N(OC)C)([CH3:16])[CH3:15])([CH3:10])([CH3:9])[CH3:8]>C(OCC)C>[C:7]([O:11][C:12](=[O:23])[NH:13][C:14]([CH3:16])([CH3:15])[CH:17]=[O:22])([CH3:10])([CH3:8])[CH3:9]
Reactant: CON(C)C(=O)C(C)(C)NC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C=O)NC(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 90.8 %

Procedure:
Lithium aluminum hydride (7.8 g) was added to a stirred solution of [1-(methoxy-methyl-carbamoyl)-1-methyl-ethyl]-carbamic acid tert-butyl ester (compound L; 42.0 g) in dry diethyl ether (1.5 L) at −40° C. Then stirred at that temperature for about 5 min. Excess LiAlH4 was quenched with a solution of potassium hydrogen sulfate in water. The resulting mixture was partitioned between EtOAc and 3M aqueous HCl. The organic layer was washed with sat. aqueous NaHCO3, dried over Na2SO4, filtered, and concentrated in vacuo to afford (1,1-dimethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (compound M; 29 g) sufficiently pure for the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([S:11]([NH2:14])(=[O:13])=[O:12])[C:4]=2[O:3]1.C[Al](C)C.[CH3:20][O:21][C:22]1[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH:29][C:30](=O)[O:31]C)[N:23]=1.C(O)(=O)C>C(Cl)Cl.Cl>[CH3:20][O:21][C:22]1[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH:29][C:30]([NH:14][S:11]([C:10]2[C:4]3[O:3][C:2]([CH3:15])([CH3:1])[O:6][C:5]=3[CH:7]=[CH:8][CH:9]=2)(=[O:13])=[O:12])=[O:31])[N:23]=1
Reactant: COC(=O)Nc1nc(C)nc(OC)n1
Reactant: CC1(C)Oc2cccc(S(N)(=O)=O)c2O1
Agent: C[Al](C)C
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2cccc3c2OC(C)(C)O3)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 7.2 %

Procedure:
To a solution of 1.0 g 2,2-dimethyl-1,3-benzodioxole-4-sulfonamide, prepared in Example 1, in 50 ml methylene chloride a room temperature under nitrogen was added 2.5 ml trimethylaluminum (2M in toluene). After stirring 15 minutes at room temperature, 0.7 g of methyl [4-methoxy-6-methyl-1,3,5-triazin-2-yl]carbamate, prepared according to the procedure of Example 5, was added and the reaction mixture was heated at reflux 72 hours. The reaction mixture was cooled to room temperature and 75 ml ice, 3 ml glacial acetic acid, and 10 drops of hydrochloric acid were sequentially added. The organic phase was separated, dried and the solvent removed under reduced pressure to give an oil. Crystallization of the oil from a mixture of ether, methylene chloride, and hexane gave 0.1 g of white solid, m.p. 160°-168° C. The infrared spectrum showed a carbonyl absorption at 1705 cm-1 indicative of the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12](OCC)=[O:13])=[C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:7]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:4][OH:3])=[C:7]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:8]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(CO)c(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 46.3 %

Procedure:
A 100 mL 3 neck round-bottom flask equipped with a condenser and an addition funnel was flushed with nitrogen and then loaded with diethyl-2,3-di(4-fluorophenyl)-1,4-benzenedicarboxylate (1.22 g, 2.98 mmol) in anhydrous THF (25 mL). Lithium aluminum hydride (1.0 M in THF, 11.4 mL, 11.4 mmol) was then added dropwise via the addition funnel to the reaction mixture and the mixture was then refluxed overnight. The mixture was cooled to room temperature and the excess lithium aluminum hydride was destroyed by dropwise addition of water. 15% NaOH (1 mL) was then added followed by more water (3 mL). The mixture was filtered and the solvent was removed by rotary evaporation. The product was then dissolved in chloroform and filtered. Removal of the chloroform gave a white solid (0.45 g, 46% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:14][N:15](C=O)C>[C-]#N.[Zn+2].[C-]#N>[Cl:1][C:2]1[C:3]([C:14]#[N:15])=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOC(=O)c1cnc(C#N)c(Cl)c1
Temperature: 100 °C

Procedure:
A solution of ethyl 5,6-dichloronicotinate (1 eq), zinc cyanide (0.75 eq) and tetrakis(triphenyl-phosphine)palladium (0.10 eq.) in DMF (0.3 M) was degassed and then heated at 100° C. for 3 hours. Solvent was removed en vaccuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give ethyl 5-chloro-6-cyanonicotinate as a white solid.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=2)[NH2:31])[CH2:24][CH2:23]1>>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:31][C:30]3[CH:32]=[CH:33][CH:34]=[C:28]([N:25]4[CH2:24][CH2:23][N:22]([CH3:21])[CH2:27][CH2:26]4)[CH:29]=3)[N:20]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccccc1CNc1cccn2nc(Cl)nc12
Reactant: CN1CCN(c2cccc(N)c2)CC1
Product: COc1ccccc1CNc1cccn2nc(Nc3cccc(N4CCN(C)CC4)c3)nc12

Procedure:
N(8)-(2-Methoxy-benzyl)-N(2)-[3-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methoxy-benzyl)-amine (100.00 mg, 0.34634 mmol) and 3-(4-methylpiperazin-1-yl)aniline (74.2 mg, 0.388 mmol) in a manner analogous to Example 2d. Product isolated as a brown foam (39.14 mg, 25.4%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.12 (s, 1H), 7.96 (d, J=6.4 Hz, 1H), 7.25 (m, 4H), 7.09 (t, J=15.9, 7.8 Hz, 1H), 7.03 (d, J=8.6 Hz, 1H), 6.88 (t, J=15.0, 7.9 Hz, 1H), 6.73 (t, J=14.5, 7.4 Hz, 1H) 6.46 (d, J=8.6 Hz, 1H), 6.32 (d, J=8.1 Hz, 1H), 6.10 (m, 1H), 4.48 (d, J=5.2 Hz, 2H), 3.87 (s, 3H), 3.12 (s, 4H), 2.45 (s, 4H), 2.22 (s, 3H). MS=444 (MH)+.
Reaction SMILES: C(=O)([O-])O.[K+].BrC[CH2:8][CH:9]1[CH2:11][CH2:10]1.[C:12]([O:16][C:17](=[O:22])[NH:18][CH2:19][CH2:20][NH2:21])([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[C:12]([O:16][C:17](=[O:22])[NH:18][CH2:19][CH2:20][NH:21][CH2:10][CH:11]1[CH2:8][CH2:9]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: BrCCC1CC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNCC1CC1
Temperature: 66 °C
Yield: 30.3 %

Procedure:
Potassium hydrogen carbonate (220 mg, 2.2 mmol) and (bromoethyl)cyclopropane (270 mg, 2.0 mmol) were added to a solution of tert-butyl-N-(2-aminoethyl)carbamate (320 mg, 2.0 mmol) in THF (10 ml). The mixture was heated at 66° C. for 20 h and solvents were concentrated in vacuo. The residue was dissolved in chloroform, washed with water, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 1% triethylamine:4% methanol:95% chloroform) to yield the title compound (130 mg, 30%).
Reaction SMILES: [C:1]([O:7][C:8]1[C:13](=[O:14])[N:12]([CH:15]([CH3:17])[CH3:16])[C:11](=[O:18])[N:10]2[CH:19]([CH2:32][CH2:33][O:34]CC3C=CC=CC=3)[CH2:20][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:22](=[O:23])[C:9]=12)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[H][H]>C(OCC)(=O)C>[C:1]([O:7][C:8]1[C:13](=[O:14])[N:12]([CH:15]([CH3:17])[CH3:16])[C:11](=[O:18])[N:10]2[CH:19]([CH2:32][CH2:33][OH:34])[CH2:20][N:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[C:22](=[O:23])[C:9]=12)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)n1c(=O)c(OC(=O)C(C)(C)C)c2n(c1=O)C(CCOCc1ccccc1)CN(Cc1ccc(F)cc1)C2=O
Solvent: CCOC(C)=O
Product: CC(C)n1c(=O)c(OC(=O)C(C)(C)C)c2n(c1=O)C(CCO)CN(Cc1ccc(F)cc1)C2=O
Reaction time: 48 h

Procedure:
A mixture of 4-[2-(benzyloxy)ethyl]-2-(4-fluorobenzyl)-7-isopropyl-1,6,8-trioxo-1,3,4,6,7,8-hexahydro-2H-pyrazino[1,2-c]pyrimidin-9-yl pivalate (918 mg, 1.62 mmol) and 10% Pd(C) (92 mg) in ethyl acetate (32 mL) was stirred under a balloon atmosphere of hydrogen for 24 h. The reaction mixture was filtered through Celite, fresh catalyst was added and the mixture subjected to balloon hydrogenation for an additional 24 h. Analysis by LCMS showed slow conversion to the alcohol, so the mixture was again filtered through Celite and the filtrate was concentrated. The residual solid was taken up in ethanol (32 mL) with a small amount of ethyl acetate added to aid dissolution of the material. 10% Pd(C) was added and the mixture subjected to balloon hydrogenation for 96 h, with fresh catalyst being added after the first 24 h. The reaction still appeared to be progressing slowly, so the mixture was filtered through Celite and Pearlman's catalyst was added to the filtrate. Hydrogenation (balloon) was complete after 48 h (fresh Pearlman's catalyst was added after the first 24 h). Filtration through Celite and concentration afforded the title compound as a foamy white solid. 1H NMR (CDCl3, 400 MHz): δ 7.28-7.26 (m, 2 H), 7.07-7.02 (m, 2 H), 5.21-5.14 (m, 1 H), 4.87-4.74 (m, 2 H), 4.48-4.36 (m, 1 H), 3.89-3.77 (m, 1 H), 3.49-3.25 (m, 3 H), 1.68-1.54 (m, 2H), 1.46 (d, J=6.8 MHz, 6 H), 1.40 (s, 9 H). ES MS (M+1): 476.5.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[CH:20][N:19]=[C:18]([O:22]C3C=CC(NC(=O)CC(NC4C=CC(F)=CC=4)=O)=CC=3F)[CH:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC1C=CC(CC(N=C=O)=O)=CC=1.COC1C=CC(CNC2N=CN=C(O[C:72]3[CH:77]=[CH:76][C:75]([NH:78][C:79]([NH:81][C:82](=[O:91])[CH2:83][C:84]4[CH:89]=[CH:88][C:87]([F:90])=[CH:86][CH:85]=4)=[O:80])=[CH:74][C:73]=3[F:92])C=2)=CC=1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[CH:20][N:19]=[C:18]([O:22][C:72]3[CH:77]=[CH:76][C:75]([NH:78][C:79]([NH:81][C:82](=[O:91])[CH2:83][C:84]4[CH:89]=[CH:88][C:87]([F:90])=[CH:86][CH:85]=4)=[O:80])=[CH:74][C:73]=3[F:92])[CH:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CC(=O)Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1)Nc1ccc(F)cc1
Reactant: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Agent: O=C=NC(=O)Cc1ccc(F)cc1
Solvent: C1CCOC1
Product: O=C(Cc1ccc(F)cc1)NC(=O)Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1
Yield: 90.7 %

Procedure:
The title compound was prepared from 6-(4-amino-2-fluorophenoxy)-N-(4-(benzyloxy)phenyl)pyrimidin-4-amine (Compound B of Example 29, 45 mg, 0.11 mmol) and a solution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound D of Example 11, 0.13 mmol) in THF using a similar procedure described for the preparation of Compound E of Example 11. The crude product was triturated with isopropyl ether to give the title compound (58 mg, 90%) as a pink solid. 1H NMR (DMSO-d6) δ 11.02 (s, 1H), 10.54 (s, 1H), 9.46 (s, 1H), 8.24 (s, 1H), 7.70 (dd, 1H, J=12.7, 2.4 Hz), 7.46-7.26 (m, 9H), 7.18 (dd, 2H, J=9.6, 8.3 Hz), 7.00 (d, 2H, J=9.6 Hz), 6.11 (s, 1H), 5.09 (s, 2H), 3.75 (s, 2H); MS(ESI+) m/z 582.3 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[CH2:15]([C:17]1([CH2:27][CH3:28])[C:22](=[O:23])[O:21][CH2:20][C:19]([CH3:26])([CH2:24][OH:25])[NH:18]1)[CH3:16]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:27]([C:17]1([CH2:15][CH3:16])[C:22](=[O:23])[O:21][CH2:20][C:19]([CH3:26])([CH2:24][O:25][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])[NH:18]1)[CH3:28]
Reactant: CCC1(CC)NC(C)(CO)COC1=O
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1(CC)NC(C)(COC(=O)C(C)(C)C)COC1=O
Reaction time: 20 h

Procedure:
2.4 ml (0.017 mol) of triethylamine and then 2.15 g 2 (0.018 mol) of pivaloyl chloride are added dropwise to a solution of 3.45 g (0.017 mol) of 3,3-diethyl-5-methyl-5-hydroxymethylmorpholin-2-one and 0.1 g of 4-dimethylaminopyridine in 20 ml dichloromethane at 15° C. After stirring for 20 hours, the precipitated triethylaminehydrochloride is removed by filtration and the filtrate is washed with water, dried over MgSO4 and concentrated by evaporation in a rotary evaporator. The residue is recrystallised from hexane. This gives 3.9 g (77%) of compound (217), m.p. 51-53° C.
Reaction SMILES: [C:1]1([C:9](O)=O)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:2]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][N:19]=2)[CH2:14][CH2:13]1>>[C:1]1([CH2:9][N:12]2[CH2:13][CH2:14][CH:15]([C:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][N:19]=3)[CH2:16][CH2:17]2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:2]=1
Reactant: O=C(O)C1=Cc2ccccc21
Reactant: c1ccc2c(C3CCNCC3)noc2c1
Product: C1=C(CN2CCC(c3noc4ccccc34)CC2)c2ccccc21

Procedure:
3-[1-(Benzocyclobuten-1-ylmethyl)-4-piperidyl]-1,2-benzisoxazole was prepared from benzocyclobutene-1-carboxylic acid and 3-piperid-4-yl-1,2-benzisoxazole according to the process described in Example 19, stages A and B.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:12][C:11]([CH2:13][CH2:14][CH2:15][CH3:16])=[N:10][C:5]2=[N+:6]([O-])[C:7]=1[CH3:8].C(O)(=[O:19])C>>[Br:1][C:2]1[CH:3]=[C:4]2[NH:12][C:11]([CH2:13][CH2:14][CH2:15][CH3:16])=[N:10][C:5]2=[N:6][C:7]=1[CH2:8][OH:19]
Reactant: CCCCc1nc2c(cc(Br)c(C)[n+]2[O-])[nH]1
Reactant: CC(=O)O
Product: CCCCc1nc2nc(CO)c(Br)cc2[nH]1
Temperature: 120 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
8.0 g (28.17 mmole) of the compound obtained in step 5 was dissolved in 20 ml of anhydrous acetic acid. The resulting solution was stirred for 1 hour at 120° C., and evaporated under reduced pressure to remove anhydrous acetic acid. Thereafter, the residue was dissolved in a mixture of 30 ml of methanol and 40 ml of 3N LiOH. The resulting solution was refluxed for 1 hour, evaporated under reduced pressure to remove methanol, neutralized with 1N HCl and extracted with ethyl acetate (50 ml×3). The organic layer was dried over Na2SO4, concentrated under reduced pressure and purified with column chromatography (hexane:ethyl acetate=1:2) to obtain 5.3 g of the title compound (yield 66%).