Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([N:11]1[CH2:15][C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:13][C:12]1=[O:24])[CH2:5][C@H:6]1[CH2:9][C@H:8]([CH3:10])[CH2:7]1.O.O.[OH-].[Li+]>O1CCCC1>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][C:14]1[CH2:15][N:11]([CH:4]([CH2:5][C@H:6]2[CH2:7][C@H:8]([CH3:10])[CH2:9]2)[C:3]([OH:25])=[O:2])[C:12](=[O:24])[CH:13]=1
Reactant: COC(=O)C(C[C@H]1C[C@H](C)C1)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1C[C@H](CC(C(=O)O)N2CC(Oc3ccccc3Cl)=CC2=O)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.5 %

Procedure:
In a flask was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(trans-3-methyl-cyclobutyl)-propionic acid methyl ester (107 mg, 0.29 mmol) dissolved in a 1:1 solution of tetrahydrofuran:water (8 mL). To this mixture was added lithium hydroxide monohydrate (25 mg, 0.58 mmol) and the resulting mixture stirred for 1.5 h at 25° C. After such time, the mixture was concentrated in vacuo to remove the tetrahydrofuran and partioned between 1N aqueous hydrochloric acid (10 mL) and ethyl acetate (10 mL). The organic layer was separated and dried over sodium sulfate and concentrated in vacuo to afford 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(trans-3-methyl-cyclobutyl)-propionic acid (102 mg, 100%) as a light amber semi-solid: HR-ES-MS m/z calculated for C18H20NO4Cl [M+H]+ 350.1154, observed 350.1154.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[S:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[C:27](O)(=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[OH:3][C:2]1[CH2:4][S:5][C:6](=[O:7])[C:1]=1[C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: O=C1CSC(=O)C1
Reactant: CCCCCCCCCCC/C=C\CCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC/C=C\CCCCC(=O)C1=C(O)CSC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.4 %

Procedure:
To a stirring solution of 1.71 g (14.7 mmol) of thiotetronic acid in 20 mL of dimethylformamide is added 2.22 mL (15.9 mmol) of triethylamine and 592 mg (4.85 mmol) of 4-dimethylaminopyridine at 0° C. Next, 3.38 g (17.6 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 5.0 g (17.7 mmol) of petroselinic acid are added and the reaction mixture is stirred overnight at room temperature. The reaction is acidified with 1.0N HCl and extracted three times with diethyl ether. The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue is subjected to HPLC chromatography (2 inch Dynamax silica gel column, 25 mL/min) eluting with 100% ethyl acetate to give 1.2 g (21%) of 4-hydroxy-3-[(Z)-1-oxo-6-octadecenyl]-2(5H)-thiophenone as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[NH:7])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:25][C:26](=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28]>CCO>[CH2:30]([O:29][C:27]([C:26]1[N:7]=[C:6]([C:5]2[CH:17]=[CH:18][C:2]([Br:1])=[CH:3][CH:4]=2)[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[CH:25]=1)=[O:28])[CH3:31]
Reactant: CCOC(=O)C(=O)CBr
Reactant: N=C(NCc1ccccc1Cl)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cn(Cc2ccccc2Cl)c(-c2ccc(Br)cc2)n1
Temperature: 175 °C
Yield: 13.3 %

Procedure:
A mixture of 4-bromo-N-(2-chlorobenzyl)-benzamidine (1.4 g, 4.3 mmol), sodium bicarbonate (0.72 g, 8.6 mmol) and ethyl bromopyruvate (0.98 mL, 7.8 mmol) in EtOH (14 mL) was heated in a microwave unit (Biotage Initiator™) at 175° C. for 12 min. The resulting mixture was decanted and the solids rinsed with EtOAc. The combined filtrates were concentrated and purified by chromatography (silica, EtOAc/Hex, 0:100 to 40:60) to give the title compound (0.24 g, 13%) as a pale brown residue. 1H-NMR (DCM-d2): 0.5-7.58-7.62 (m, 3H), 7.43-7.49 (m, 3H), 7.34 (m, 1H), 7.28 (m, 1H), 6.96 (d, 1H), 5.30 (s, 2H), 4.32 (q, 2H), 1.35 (t, 3H); MS (ES): 419, 421 [M+H]+.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:35])[C:27]3[CH:32]=[CH:31][C:30]([CH2:33]Cl)=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>C(Cl)Cl>[CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:35])[C:27]3[CH:32]=[CH:31][C:30]([CH2:33][N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C(Oc1ccc(S(=O)(=O)CCN2CC[C@H](Cc3ccccc3)[C@H](O)C2)cc1)c1ccc(CCl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1ccc(S(=O)(=O)CCN2CC[C@H](Cc3ccccc3)[C@H](O)C2)cc1)c1ccc(CN2CCOCC2)cc1
Yield: 31.6 %

Procedure:
To a solution of 200 mg (0.38 mmol) 4-chloromethyl-benzoic acid-(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl ester in 10 ml CH2Cl2 were added 53 □l (0.38 mmol) Et3N and 33 μl (0.38 mmol) morpholine. After 16 hours the reaction mixture was purified by chromatography over silica gel to give 70 mg (0.12 mmol, 32%) 4-morpholin-4-ylmethyl-benzoic acid (3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl ester as a colorless solid.
Reaction SMILES: [CH:1](=[C:8]1[CH2:12][N:11](C(OC(C)(C)C)=O)[C@H:10]([C:20]([OH:22])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([N:25]1[C:37]2[CH:36]=[CH:35][C:34]([NH2:38])=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH3:24]>>[CH:1](=[C:8]1[CH2:12][NH:11][C@H:10]([C:20]([NH:38][C:34]2[CH:35]=[CH:36][C:37]3[N:25]([CH2:23][CH3:24])[C:26]4[C:31]([C:32]=3[CH:33]=2)=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CC(C)(C)OC(=O)N1CC(=Cc2ccccc2)C[C@H]1C(=O)O
Product: CCn1c2ccccc2c2cc(NC(=O)[C@@H]3CC(=Cc4ccccc4)CN3)ccc21

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 53% purity by LC/MS. MS(ESI+): m/z=396.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:28])[CH2:17][N:18]3[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[C:20](I)=[N:19]3)[C@@H:12]([CH3:29])[CH2:11]2)=[C:4]([F:30])[CH:3]=1.[C:31]([Cu])#[N:32].CN(C=O)C>C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:28])[CH2:17][N:18]3[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[C:20]([C:31]#[N:32])=[N:19]3)[C@@H:12]([CH3:29])[CH2:11]2)=[C:4]([F:30])[CH:3]=1
Reactant: COc1cc(N2CCN(C(=O)Cn3nc(I)c4cccnc43)[C@@H](C)C2)c(F)cc1Cl
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(=O)Cn3nc(C#N)c4cccnc43)[C@@H](C)C2)c(F)cc1Cl
Temperature: 175 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
A mixture of 1-[(S)-4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-2-methyl-piperazin-1-yl]-2-(3-iodo-pyrazolo[3,4-b]pyridin-1-yl)-ethanone (2.2 g, 4.0 mmol, 1 eq), CuCN (3.6 g, 40 mmol, 10 eq), and DMF (25 ml) was stirred at 175° C. for 1 hrs. The reaction mixture was cooled to rt, diluted with ethyl acetate and filtered. The filtrate was washed with water, dried over Na2SO4, and purified by flash chromatography to provide 1-{2-[4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-oxo-ethyl}-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (1.6 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:12]=2)[CH2:4][C@H:3]1[O:18][CH3:19].[Cl:20][C:21]1[N:22]=[C:23]([C:27](O)=[O:28])[NH:24][C:25]=1[Cl:26].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C>[Cl:20][C:21]1[N:22]=[C:23]([C:27]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[S:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:12]=3)[CH2:4][C@H:3]2[O:18][CH3:19])=[O:28])[NH:24][C:25]=1[Cl:26]
Reactant: O=C(O)c1nc(Cl)c(Cl)[nH]1
Reactant: CCOC(=O)c1cnc(N2CC[C@H](N)[C@H](OC)C2)s1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CCOC(=O)c1cnc(N2CC[C@H](NC(=O)c3nc(Cl)c(Cl)[nH]3)[C@H](OC)C2)s1
Yield: 24 %

Procedure:
The same operation as in Example (1g) was performed using ethyl cis(±)-2-(4-amino-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylate obtained by the method described in Example (5d) (0.23 g, 0.81 mmol), 4,5-dichloroimidazole-2-carboxylic acid obtained in Example (7d) (84 mg, 0.46 mmol), WSC hydrochloride (0.24 g, 1.25 mmol) and DMAP (10 mg, 0.083 mmol), to obtain 49 mg of the title compound as a pale yellow solid (24%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:21]2[O:22][C:23]([CH2:26]Cl)=[N:24][N:25]=2)[CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(#N)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:21]2[O:22][C:23]([CH2:26][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[N:24][N:25]=2)[CH:3]=1
Reactant: C1COCCN1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(CCl)o4)cc(Br)cc32)cc1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(CN5CCOCC5)o4)cc(Br)cc32)cc1
Temperature: 80 °C

Procedure:
A stirred mixture of 6-bromo-4-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1-[(4-methylphenyl)sulfonyl]-1H-indazole (0.1 g, 0.214 mmol) and morpholine (0.056 ml, 0.641 mmol) in acetonitrile (2.5 ml) was heated at 80° C. in the microwave (biotage initiator) for 45 mins. The mixture was evaporated and the residual solid triturated with ether (10 ml) to afford the title compound as a cream coloured solid which was collected by filtration (0.07 g).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12](OCC)=O.NC1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+].CC(=O)OCC>O>[OH:24][CH:21]1[CH2:22][CH2:23][CH:12]([N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[CH2:19][CH2:20]1
Reactant: NC1CCC(O)CC1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C1CCC(O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
To a solution of ethyl 1,3-dioxoisoindoline-2-carboxylate (1.67 g, 7.19 mmol) in water (16 mL) was added 4-aminocyclohexanol (1.31 g, 8.63 mmol), followed by K2CO3 (1.59 g, 11.5 mmol). The mixture was stirred at room temperature for 2 h. TLC (PE:EA=1:1) showed the reaction was complete. The mixture was filtered and the solid was dried under vacuum to give 2-(4-hydroxycyclohexyl)isoindoline-1,3-dione (1 g, 56.82%) as a brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][C:12]1[N:13]=[CH:14][C:15]2[CH:21]=[C:20]([C:22]3[C:27]([Cl:28])=[C:26]([O:29][CH3:30])[CH:25]=[C:24]([O:31][CH3:32])[C:23]=3[Cl:33])[C:19](=[O:34])[N:18]([CH3:35])[C:16]=2[N:17]=1)([O-])=O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>CCOC(C)=O.O>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][C:12]1[N:13]=[CH:14][C:15]2[CH:21]=[C:20]([C:22]3[C:23]([Cl:33])=[C:24]([O:31][CH3:32])[CH:25]=[C:26]([O:29][CH3:30])[C:27]=3[Cl:28])[C:19](=[O:34])[N:18]([CH3:35])[C:16]=2[N:17]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3cnc(Nc4c(C)cccc4[N+](=O)[O-])nc3n(C)c2=O)c1Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(Cl)c(-c2cc3cnc(Nc4c(C)cccc4N)nc3n(C)c2=O)c1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A mixture of 2-(2-nitro-6-methylphenylamino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (10) (810 mg, 1.57 mmol) and tin(II) chloride hydrate (1.77 g, 7.86 mmol) in EtOAc (50 mL) was stirred at 60° C. for 2 hours. The reaction was monitored by LCMS. The reaction mixture was basified with saturated aqueous sodium bicarbonate to pH=8-9, diluted with H2O (100 mL), and then extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, filtered, and concentrated. The residue was recrystallized with dichloromethane/ethyl acetate/petroleum ether (DCM/EtOAc/PE)=1/1/2 to give 2-(2-amino-6-methylphenylamino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (11) (640 mg, 83% yield) as a grey solid. (MS (ES+) C23H21Cl2N5O3 requires: 485, 487. found: 486, 488 [M+H]+; 1H-NMR (500 MHz, CDCl3) δ ppm 8.54 (s, 1H), 7.45 (s, 1H), 7.08 (t, J=7.5 Hz, 1H), 6.71 (dd, J=3.5, 7.5 Hz, 2H), 6.65 (br s, 1H), 6.62 (s, 1H), 3.94 (s, 6H), 3.88 (br s, 2H), 3.62 (br s, 3H), 2.24 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1.O[C:15]1[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:17]([CH2:28][CH3:29])[CH:16]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.P(CCCC)(CCCC)CCCC>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([O:13][C:15]2[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:17]([CH2:28][CH3:29])[CH:16]=2)[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(O)c1cccc(Br)n1
Reactant: CCOC(=O)COc1ccc(O)cc1CC
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCCC(Oc1ccc(OCC(=O)OCC)c(CC)c1)c1cccc(Br)n1
Temperature: 25 °C
Yield: 66.8 %

Procedure:
To a stirred solution of 1-(6-bromo-2-pyridinyl)-1-pentanol (250 mg, 1.02 mmol) and ethyl (4-hydroxy-2-ethylphenoxy)acetate (230 mg, 1.02 mmol) in dry THF (21 mL) at 0° C. (ice/water bath) under nitrogen was added ADDP (517 mg, 2.04 mmol) followed by nBu3P (510 μL, 2.04 mmol) drop-wise. The mixture was stirred with slow warming to rt over 18 hours and then concentrated under vacuum, diluted with EtOAc (150 mL) and washed with water (3×75 mL), dried (MgSO4), filtered and reduced to give an oil. Purification by SPE (silica, 10 g Cartridge) eluting with cyclohexane:EtOAc (gradient 20:1 to 5:1) afforded the title compound (307 mg).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.O[NH:35][C:36](=[NH:55])[C:37]1[CH:54]=[CH:53][C:40]2[CH2:41][CH2:42][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:44][CH2:45][C:39]=2[CH:38]=1>CN(C=O)C>[F:18][C:2]([F:1])([F:19])[C:3]1[CH:8]=[C:7]([C:9]2[O:11][N:35]=[C:36]([C:37]3[CH:54]=[CH:53][C:40]4[CH2:41][CH2:42][N:43]([C:46]([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:47])[CH2:44][CH2:45][C:39]=4[CH:38]=3)[N:55]=2)[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C(=N)NO)cc2CC1
Reactant: O=C(O)c1ccc(-c2ccccc2)c(C(F)(F)F)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(C(F)(F)F)c4)n3)cc2CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 64.5 %

Procedure:
2-(Trifluoromethyl)-4-biphenylcarboxylic acid (Preparation 40) (284 mg, 1.07 mmol), HOBT (159 mg, 1.18 mmol) and EDC (225 mg, 1.18 mmol) were stirred in DMF (10 ml) under argon for 20 minutes. 1,1-Dimethylethyl 7-[(hydroxyamino)(imino)methyl]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (Preparation 41) (326 mg, 1.07 mmol) was added and the mixture stirred at room temperature for 2.5 h before it was heated to 80° C. for 16 h. The reaction mixture was partitioned between EtOAc (30 ml) and water (30 ml) and the organic layer washed with aqueous sodium bicarbonate and water before it was dried (phase separator) and evaporated. The residue was triturated with methanol to give the title compound as a white solid (370 mg, 0.69 mmol). The filtrate was purified by Biotage Horizon, reverse phase cartridge, eluting with 5-100% acetonitrile in water to give further title compound (70 mg, 0.13 mmol). δH (d6DMSO, 400 MHz): 8.52 (1H, s), 8.50 (1H, d), 7.93 (1H, s), 7.90 (1H, dd), 7.74 (1H, d) 7.56-7.48 (3H, m), 7.41-7.38 (3H, m), 3.55-3.47 (4H, m), 3.02-2.93 (4H, m), 1.41 (9H, s).
Reaction SMILES: [NH:1]1C[CH2:4][CH2:3][CH:2]1[CH2:6][S:7]([OH:10])(=[O:9])=[O:8].[OH2:11]>>[NH2:1][CH:2]([CH:3]([OH:11])[CH3:4])[CH2:6][S:7]([OH:10])(=[O:9])=[O:8]
Reactant: O=S(=O)(O)CC1CCCN1
Reactant: O
Product: CC(O)C(N)CS(=O)(=O)O

Procedure:
NMR (0.2 NaOD, t-BuOD, δ=1.23 ppm): δ1.17(3H,d,J=6.5 Hz), 2.83(1H,dd,J=9 Hz, 14 Hz), 3.10(1H,dd,J=2.5 Hz, 14 Hz), 3.11-3.17(1H,m), 3.77-3.84(1 H,m) 2-Pyrrolidinylmethanesulfonic acid (compound 23) m.p.: 307°-308° C. (decomposition) [α]24 : +33.4° (c=1.0, H2O) Elementary Analysis: C5H11NO3S
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+]>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.CC#N>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:12][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(-c2ccccc2)nc1
Temperature: 25 °C

Procedure:
Phenylboronic acid (732 mg, 6 mmol), 2-bromo-5-methylpyridine (1.03g, 5.99 mmol), and Pd (PPh3)4 (350 mg, 0.303 mmol) were heated in 0.4 M K2CO3 (30 mL, 12 mmol) and CH3CN (30 mL) at 90° overnight. The mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between brine and ethyl acetate. The organic layer was separated, dried (Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (9:1 hexanes:ethyl acetate) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.50 (m, 1H), 8.05 (m, 2H), 7.85 (d, J=8.4 Hz, 1H), 7.68–7.71 (m, 1H), 7.37–7.50 (m, 3 H), 2.34 (s, 3H); MS (APCI+) m/z 170 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH:25]1[CH2:28][CH:27]([OH:29])[CH2:26]1>>[F:15][C:14]([F:17])([F:16])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:3][C:2]([N:25]1[CH2:28][CH:27]([OH:29])[CH2:26]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Reactant: OC1CNC1
Product: Cc1nc2ccc(N3CC(O)C3)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 22 %

Procedure:
The title compound was prepared from 1-(6-Bromo-2-methyl-4-phenyl-quinolin-3-yl)-2,2,2-trifluoro-ethanone [example 3] and azetidin-3-ol according to the procedure of example 25, except that the reaction time was of 16 h. Yield: 22%; MS: m/z=387 (M+H).
Reaction SMILES: [C:1]([Si:5]([CH3:33])([CH3:32])[O:6][CH2:7][C@H:8]([CH2:19][N:20]1[CH:25]=[CH:24][C:23]([N:26]2C=NC=N2)=[N:22][C:21]1=[O:31])[C@H:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH3:10])([CH3:4])([CH3:3])[CH3:2]>N.CO>[C:1]([Si:5]([CH3:32])([CH3:33])[O:6][CH2:7][C@H:8]([CH2:19][N:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[N:22][C:21]1=[O:31])[C@H:9]([O:11][Si:12]([C:15]([CH3:17])([CH3:18])[CH3:16])([CH3:14])[CH3:13])[CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)Cn1ccc(-n2cncn2)nc1=O
Agent: N
Solvent: CO
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)Cn1ccc(N)nc1=O
Yield: 67.1 %

Procedure:
A solution of 43 (2.0 g, 4.05 mmol) in 60 ml of 6 M NH3/MeOH was heated at 100° C. in a Parr bomb for 2 days. The reaction was cooled, concentrated and chromatographed on silica eluting, first, with ethyl acetate and, second, with 5% MeOH in ethyl acetate. Concentration of the product-containing fractions afforded 1.2 g (67%) of 44 as a white solid. 1H NMR (DMSO-d6): δ 7.39 (d, J=7 Hz, 1H), 6.94 (br s, 2H), 5.60 (d, J=7 Hz, 1H), 4.00 (m, 1H), 3.65 (m, 1H), 3.53 (m, 3H), 2.02 (m, 1H), 1.13 (d, J=6 Hz, 3H), 0.86 (s, 9H), 0.84 (s, 9H), 0.04 (s, 6H), −0.01 (s, 3H), −0.02 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[N:12]([CH2:13][C:14]([C:16]3[S:20][CH:19]=[N:18][C:17]=3[CH3:21])=[O:15])[C@H:11]([C:22]([F:25])([F:24])[F:23])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.Cl.[C@H:27]12[CH2:33][C@H:30]([NH:31][CH2:32]1)[CH2:29][O:28]2.C(N(CC)CC)C>O>[CH3:21][C:17]1[N:18]=[CH:19][S:20][C:16]=1[C:14](=[O:15])[CH2:13][N:12]1[C:4]2=[N:3][C:2]([N:31]3[CH2:32][C@@H:27]4[CH2:33][C@H:30]3[CH2:29][O:28]4)=[CH:7][C:6](=[O:8])[N:5]2[CH2:9][CH2:10][C@H:11]1[C:22]([F:25])([F:24])[F:23]
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: Cc1ncsc1C(=O)CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ncsc1C(=O)CN1c2nc(N3C[C@@H]4C[C@H]3CO4)cc(=O)n2CC[C@H]1C(F)(F)F
Temperature: 130 °C
Yield: 51.6 %

Procedure:
170 mg (0.511 mmol) of (8S)-2-chloro-9-[2-(4-methylthiazol-5-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 70.42 mg (0.52 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride are mixed together. The powder obtained is placed in a tube and 151 μl (1.08 mmol) of triethylamine are added. The tube is sealed and heated at 130° C. in an oil bath for 3 hours. The crude product obtained is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 120 mg of (8S)-9-[2-(4-methylthiazol-5-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows:
Reaction SMILES: C([BH3-])#N.[Na+].[ClH:5].[O:6]([C:13]1([OH:24])[CH:23]=[CH:22][C:16]([C:17]([CH3:21])([CH3:20])[CH2:18][NH2:19])=[CH:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO.CCOCC>[ClH:5].[CH2:25]([NH:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]1[CH:15]=[CH:14][C:13]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([OH:24])[CH2:23][CH:22]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(CN)C1=CCC(O)(Oc2ccccc2)C=C1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CC(C)(CNCc1ccccc1)C1=CCC(O)(Oc2ccccc2)C=C1
Reaction time: 1 h

Procedure:
Sodium cyanoborohydride (10 mg, 0.17 mmol) was added to a solution of 83 (30 mg, 0.11 mmol) and benzaldehyde (12 μl, 0.12 mmol) in MeOH (2 ml). After 1 hour stirring, the reaction mixture was diluted with ether and washed with water. The aqueous was extracted with ether and then combined organic layers were washed with water, and brine, then dried over MgSO4. The crude product was purified via flash SiO2 (eluted with hexane/ethyl acetate (10:1)) to give the protected amine as a white solid. The protected amine was dissolved in 3 N HCl solution in ethylacetate (2 ml) and the reaction mixture was stirred at ambient temperature for 15 hours. The crude reaction mixture was concentrated in vacuo and dried under high vacuum pressure to give 84 as a white solid (25 mg, 61% yield). 1H-NMR (400 MHz, DMSO-d6) δ 8.83 (brd s, 2H), 7.52-7.32 (m, 10H), 7.15 (d, J=7.6 Hz, 1H), 7.02-6.95 (m, 3H), 4.09 (s, 2H), 3.34 (s, 2H), 1.35 (s, 6H).