Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:23]1[O:24][CH:25]=[CH:26][CH:27]=1)CCC>O1CCOCC1.C(OCC)C.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>[O:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccco2)cc1
Temperature: 25 °C
Yield: 40.7 %

Procedure:
To a solution of 0.5 g (1.6 mmol) of material from Example 27 and 0.6 g (1.7 mmol) of 2-(tributylstannyl)-furan in 5 mL of dioxane was added 0.1 g (0.1 mmol) of tetrakis(triphenylphosphine)palladium (0). The mixture was heated to reflux for 16 hours, cooled to ambient temperature and diluted with 5 mL of ethyl ether. The mixture was washed once with 5 mL of saturated aqueous potassium fluoride, the organic layer was separated and the aqueous portion was extracted three times with 5 mL each of ethyl ether. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography (25 g of silica gel, 25% ethyl acetate/hexane) of the residue afforded a yellow oil which was recrystallized from ethyl ether/hexane to afford 0.2 g (51%) of the title compound.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH:15]3[O:19][C:18]([NH2:20])=[N:17][CH2:16]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21](OCC)(=[O:24])[C:22]#[CH:23]>C(O)C>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH:15]3[O:19][C:18]4=[N:20][C:21](=[O:24])[CH:22]=[CH:23][N:17]4[CH2:16]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C#CC(=O)OCC
Reactant: NC1=NCC(CNc2ccc(C3CCCCC3)cc2)O1
Solvent: CCO
Product: O=c1ccn2c(n1)OC(CNc1ccc(C3CCCCC3)cc1)C2
Temperature: 25 °C
Yield: 217.7 %

Procedure:
To a solution of 5-[(4-cyclohexyl-phenylamino)-methyl]-4,5-dihydro-oxazol-2-ylamine (1.13 g, 4.14 mmol) in 50 ml of ethanol was added 0.42 ml (0.415 mmol) of ethyl propiolate. The mixture was stirred at reflux for 6 h under nitrogen after which it was allowed to cool to room temperature. The resulting white crystals were isolated by filtration, washed with ethanol, and dried at room temperature under high vacuum to provide 0.294 g of the title compound. The filtrate from the filtration was concentrated to 10 ml and allowed to stand for 6 h. The resulting white crystals were isolated by filtration and dried under high vacuum to provide an additional 0.059 g of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.[CH3:9][NH:10][O:11][CH3:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[CH3:12][O:11][N:10]([CH3:9])[C:6]([C:4]1[N:3]=[CH:2][S:1][CH:5]=1)=[O:8]
Reactant: CNOC
Reactant: O=C(O)c1cscn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1cscn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of thiazole-4-carboxylic acid (1 g, 7.74 mmol), N,O-dimethylhydroxylamine (1.51 g, 15.5 mmol), and HATU (3.83 g, 10.07 mmol) in CH2Cl2 (25 mL) was added TEA (4.84 mL, 34.85 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with CH2Cl2 and water. The organics were concentrated and purified by chromatography (60-70% EtOAc/hexanes) to yield N-methoxy-N-methylthiazole-4-carboxamide as a clear oil. 1H NMR (CDCl3) δ: 8.83 (s, 1H), 8.10 (s, 1H), 3.79 (s, 3H), 3.46 (s, 3H)
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[Cl:18][C:19]1[CH:30]=[CH:29][C:22]([C:23](N(OC)C)=[O:24])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:30]=[CH:29][C:22]([C:23]([C:2]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[O:24])=[CH:21][CH:20]=1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: CON(C)C(=O)c1ccc(Cl)cc1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)c2ccc(Cl)cc2)c(C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with 4-chloro-N-methoxy-N-methylbenzamide. It is used in crude form in the following reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[O-:18][C:19]#[N:20].[Na+].C(O)(=O)/C=C\C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:19]([NH2:20])=[O:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: COC1=Cc2ccccc2Nc2ccccc21
Reactant: N#C[O-]
Agent: O=C(O)/C=C\C(=O)O
Agent: [Na+]
Solvent: ClCCl
Product: COC1=Cc2ccccc2N(C(N)=O)c2ccccc21
Temperature: 25 °C

Procedure:
To a 1 L 4-necked round bottom flask was added 10.0 g (0.045 mol) of 10-methoxyiminostilbene, 150.0 ml of dichloromethane, 37.0 g (0.57 mol) of sodium cyanate and 15.0 g (0.13 moles) of maleic acid and stirred at room temperature. The contents were heated to reflux (40-45° C.) under vigorous stirring for about 6 to about 8 hours. After completion of the reaction (detected by TLC) the reaction mass was filtered and washed with 50.0 ml dichloromethane. The dichloromethane layer was washed with water (50.0 ml×2) and the layers were separated.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[C:5]([CH:10]=[O:11])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[CH3:1][C:2]1[CH2:7][C:6]([CH3:8])([CH3:9])[C:5]([CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: CC1=CC=C(C=O)C(C)(C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC1=CC=C(CO)C(C)(C)C1
Yield: 0.1 %

Procedure:
A solution of 20 g (133 mole) of 4,6,6-trimethyl-1,3-cyclohexadiene-1-carbaldehyde in 100 ml of diethylether was added to a suspension of 1.5 g (39 mmole) of LiAlH4 in diethylether, under stirring and cooling with an ice-bath. After 1 h of reaction time, the mixture was hydrolyzed, the organic layer was separated, washed and dried and concentrated. The crude product was then distilled in vacuo, b.p. 60°/20 hPa, to obtain 11.6 g (56%) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5](Cl)=[O:6].[NH2:14][C:15]1[S:16][C:17]([C:20]2([CH3:26])[S:25][CH2:24][CH2:23][CH2:22][S:21]2)=[N:18][N:19]=1>C1(C)C=CC=CC=1.CCCCC>[CH3:26][C:20]1([C:17]2[S:16][C:15]([NH:14][C:5](=[O:6])[C:4]3[C:3]([O:2][CH3:1])=[CH:11][CH:10]=[CH:9][C:8]=3[O:12][CH3:13])=[N:19][N:18]=2)[S:21][CH2:22][CH2:23][CH2:24][S:25]1
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: CC1(c2nnc(N)s2)SCCCS1
Solvent: Cc1ccccc1
Solvent: CCCCC
Product: COc1cccc(OC)c1C(=O)Nc1nnc(C2(C)SCCCS2)s1
Temperature: 25 °C

Procedure:
A solution of 1.0 g of 2,6-dimethoxybenzoyl chloride in 50 ml of toluene containing 1.0 g of 2-amino-5-(2-methyl-1,3-dithian-2-yl)-1,3,4-thiadiazole was heated at reflux for fifteen hours. The reaction mixture was then cooled to room temperature and diluted with pentane, whereupon a white precipitate formed. The precipitate was collected by filtration and identified as N-[5-(2-methyl-1,3-dithian-2-yl)-1,3,4-thiadiazol-2-yl]-2,6-dimethoxybenzamide.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][OH:12])=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:14][C:15]1[CH:16]=[C:17]([CH2:23][CH:24]([O:28][CH:29]([CH3:31])[CH3:30])[C:25]([O-:27])=[O:26])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][O:12][CH2:14][C:15]2[CH:16]=[C:17]([CH2:23][CH:24]([O:28][CH:29]([CH3:31])[CH3:30])[C:25]([OH:27])=[O:26])[CH:18]=[CH:19][C:20]=2[O:21][CH3:22])=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(CC(OC(C)C)C(=O)[O-])cc1CBr
Reactant: CCCCc1ccc(CO)nc1
Product: CCCCc1ccc(COCc2cc(CC(OC(C)C)C(=O)O)ccc2OC)nc1

Procedure:
Using (5-butyl-2-pyridyl)methanol and 3-[3-(bromomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 3-(3-[(5-butyl-2-pyridyl)methoxy]methyl-4-methoxyphenyl)-2-isopropoxypropanoic acid was obtained in the same method as in Example 247).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([NH:19][C@H:20]([C:27]([NH:29][C@@H:30]([CH2:54][CH:55]1[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1)[C@@H:31]([OH:53])[CH2:32][C@@H:33]([CH:50]([CH3:52])[CH3:51])[CH2:34][CH2:35][NH:36][C:37]([NH:39]C(=O)OCC1C=CC=CC=1)=[NH:38])=[O:28])[CH2:21][C:22]1[N:26]=[CH:25][NH:24][CH:23]=1)=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[ClH:61].N1C=CC=CC=1>CO.[Pd]>[ClH:61].[CH:55]1([CH2:54][C@H:30]([NH:29][C:27]([C@@H:20]([NH:19][C:17]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:18])[CH2:21][C:22]2[N:26]=[CH:25][NH:24][CH:23]=2)=[O:28])[C@@H:31]([OH:53])[CH2:32][C@@H:33]([CH:50]([CH3:52])[CH3:51])[CH2:34][CH2:35][NH:36][C:37]([NH2:39])=[NH:38])[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1
Reactant: CC(C)[C@@H](CCNC(=N)NC(=O)OCc1ccccc1)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)[C@@H](CCNC(=N)N)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 76.4 %

Procedure:
0.110 g (0.132 mmol) of benzyl [N-[(3S,5S,6S)-6-[[N-[N-(t-butoxycarbonyl)-3-phenyl-L-alanyl]-L-histidyl]amino]-7-cyclohexyl-5-hydroxy-3-isopropylheptyl]amidino]carbamate and 0.015 mg (0.132 mmol) of pyridine hydrochloride are dissolved in 2.4 ml of methanol and hydrogenated in the presence of 20 mg of palladium on charcoal (5%) for 3 hours at room temperature and atmospheric pressure. After completion of the hydrogen uptake the catalyst is filtered off and the filtrate is evaporated under reduced pressure. In this manner there is obtained 0.074 g of t-butyl [(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-6-guanidino-2-hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate hydrochloride as an amorphous solid, MS: 697 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:6]2=[CH:7][N:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:18][CH:17]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4][N:3]1[C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([OH:31])=[O:30].CO.[CH3:38][Si](C=[N+]=[N-])(C)C>O1CCCC1>[O:1]=[C:2]1[C:6]2=[CH:7][N:8]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:20][CH:21]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4][N:3]1[C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([O:31][CH3:38])=[O:30]
Reactant: O=C(O)c1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reaction time: 0.5 h

Procedure:
2-(3-Oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)benzoic acid (Example 611, 30 mg, 0.065 mmol) was dissolved in tetrahydrofuran (1 mL) and methanol (1 mL) and treated with (trimethylsilyl)diazomethane (0.065 mL, 2 M diethyl ether solution, 0.13 mmol, 2 equiv). After stirring for 30 minutes, the mixture was concentrated in vacuo and the residue was purified by preparative reverse phase HPLC (80:20 to 5:95; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.15 (1H s), 8.46 (1H, d, J=2.5 Hz), 8.21 (1H, dd, J=7.8, 1.4 Hz), 7.83 (2H, d, J=8.8 Hz), 7.79 (1H, m), 7.77 (1H, d, J=2.3 Hz), 7.73-7.61 (3H, m), 7.56 (1H, t, J=7.7 Hz), 7.46 (2H, d, 8.7 Hz), 7.41 (1H, td, J=7.7, 1.1 Hz), 6.53 (1H, dd, J=2.4, 1.8 Hz), 5.77 (2H, s), 3.67 (3H, s) ppm; low resolution mass spectrometry (ES+) m/z 476.0 [(M+H)+; calculated for C28H22N5O3: 476.2].
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:6]=[CH:7][N:8]=1.Cl[CH2:21][C:22]1[N:23]=[C:24](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=2)[O:25][CH:26]=1>>[CH3:35][C:31]1[CH:30]=[C:29](/[CH:28]=[CH:27]/[C:24]2[O:25][CH:26]=[C:22]([CH2:21][O:19][C:16]3[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][N:5]4[CH:6]=[CH:7][N:8]=[C:4]4[CH2:3][CH2:2][OH:1])=[CH:18][CH:17]=3)[N:23]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: Cc1cccc(/C=C/c2nc(CCl)co2)c1
Reactant: OCCc1nccn1CCCCc1ccc(O)cc1
Product: Cc1cccc(/C=C/c2nc(COc3ccc(CCCCn4ccnc4CCO)cc3)co2)c1
Yield: 63.5 %

Procedure:
Using 4-[4-[2-(2-hydroxyethyl)-1H-imidazol-1-yl]butyl]phenol (260 mg) and (E)-4-chloromethyl-2-[2-(3-methylphenyl)ethenyl]oxazole (257 mg), the same reaction as Example 1 was carried out to yield the titled compound (290 mg) as colorless crystals.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[NH:9]2)=[N:5][CH:4]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](OCC)=[O:19].Cl>C(O)C>[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]([C:18](=[O:19])[C:14]3[S:13][CH:17]=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9]2)=[N:5][CH:4]=1
Reactant: O=C1Cc2ncc(Cl)cc2N1
Reactant: CCOC(=O)c1cccs1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: O=C1Nc2cc(Cl)cnc2C1C(=O)c1cccs1
Temperature: 0 °C

Procedure:
Pellets of sodium metal (3.4 g, 0.15 mmol) were added to dry ethanol (90 mL) in a dry round-bottomed flask. When dissolution of the sodium was complete, solid 6-chloro-4-azaoxindole (5.0 g 29.7 mmol) was added followed by ethyl 2-thiophenecarboxylate (8 mL, 55 mmol). The mixture was heated under nitrogen at reflux overnight during which a precipitate formed. The mixture was cooled, poured into ice/water and acidified to pH 3 with 6N HCl solution. The solid azaoxindole (7.8 g, 94%) (m.p. 250°) was collected by filtration washing with water and ether and dried in vacuo with heating.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18](O)=[O:19])[N:14]3[CH3:17])=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1)[CH3:2].[I-].ClC1C=CC=C[N+]=1C.CCN(C(C)C)C(C)C.[NH:49]1[CH2:52][CH:51]([N:53]2[CH2:58][CH2:57][CH:56]([OH:59])[CH2:55][CH2:54]2)[CH2:50]1>CN(C=O)C>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]([N:49]4[CH2:52][CH:51]([N:53]5[CH2:58][CH2:57][CH:56]([OH:59])[CH2:55][CH2:54]5)[CH2:50]4)=[O:19])[N:14]3[CH3:17])=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1)[CH3:2]
Reactant: OC1CCN(C2CNC2)CC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)O)n(C)c2n1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)N3CC(N4CCC(O)CC4)C3)n(C)c2n1
Reaction time: 2 h
Yield: 26.3 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carboxylic acid (215 mg, 0.53 mmol), 2-chloro-1-methylpyridinium iodide (324 mg, 1.27 mmol) and DIPEA (460 μL, 2.64 mmol) in DMF (2 mL) was stirred for 5 min before the addition of 1-azetidin-3-ylpiperidin-4-ol (140 mg, 0.90 mmol) in DMF (2 mL). The resulting mixture was allowed to stir for 2 h then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 0-10%) affording 797 as a pale yellow solid (76 mg, 26%). LCMS (method G): RT 5.26 min, [M+H]+ 546.4. 1H NMR (CDCl3, 400 MHz): δ 8.06-8.06 (1 H, m), 7.76-7.75 (1 H, m), 7.31-7.24 (2 H, m), 4.72-4.71 (1 H, m), 4.50 (1 H, dd, J=10.65, 5.40 Hz), 4.30-4.20 (1 H, m), 4.14 (3 H, s), 4.14-4.07 (1 H, m), 3.88 (4 H, t, J=4.71 Hz), 3.81 (1 H, s), 3.37 (2 H, q, J=7.47 Hz), 3.28-3.27 (1 H, m), 2.72 (2 H, d, J=27.26 Hz), 2.25-2.10 (2 H, m), 2.01-1.91 (2 H, m), 1.68-1.60 (5 H, m), 1.46-1.43 (4 H, m)
Reaction SMILES: [Na].[C:2](=[N:15]O)([C:4]12[CH2:13][CH:9]([CH2:10][CH2:11][CH2:12]1)[CH:8]1[CH2:14][CH:5]2[CH2:6][CH2:7]1)[CH3:3].Cl>C(O)C.O>[NH2:15][CH:2]([C:4]12[CH2:13][CH:9]([CH2:10][CH2:11][CH2:12]1)[CH:8]1[CH2:14][CH:5]2[CH2:6][CH2:7]1)[CH3:3]
Reactant: CC(=NO)C12CCCC(C1)C1CCC2C1
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CC(N)C12CCCC(C1)C1CCC2C1
Reaction time: 0.25 h
Yield: 62.1 %

Procedure:
1.93 g (83.9 mmoles) of metallic sodium powder were added in small portions into a solution of 1.00 g (4.83 mmoles) of 1-acetyltricyclo[4,3,1,12,5 ]undecane oxime in anhydrous ethanol (16 ml) kept under reflux with stirring over a period of 15 minutes. Then, the reaction mixture was heated under reflux for an additional 15 minutes and the mixture was allowed to cool. The reaction mixture was diluted with water (5 ml), then neutralized with 5% hydrochloric acid and then concentrated. The residue was made alkaline with 5% aqueous sodium hydroxide solution and then extracted with diethyl ether. The ether solution was dried and concentrated to afford 0.58 g (yield 62%) of 1-(1-aminoethyl)-tricyclo[4,3,1,12,5 ]undecane.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][C@H:33]1[CH2:38][NH:37][C@@H:36]([CH3:39])[CH2:35][NH:34]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:34]5[CH2:35][CH:36]([CH3:39])[NH:37][CH2:38][CH:33]5[CH3:32])=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:29])[F:30])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: C[C@H]1CN[C@@H](C)CN1
Product: CC1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C(C)CN1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2,5-dimethyl-piperazin-1-yl)-thiazol-4-one one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-(S),5-(S)-Dimethyl-piperazine following General Procedure C.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9](OC)=[O:10])=[CH:7][N:6]=1>C(O)C>[CH3:3][O:4][C:5]1[N:6]=[CH:7][C:8]([CH2:9][OH:10])=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(OC)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Sodium borohydride (11.30 g, 299 mmol) was added to a solution of the methyl 6-methoxynicotinate (5.00 g, 29.9 mmol) in ethanol (100 mL) at 0° C. The reaction was allowed to warm to room temperature and stirred for 3 days. The reaction was cooled to 0° C. and quenched by slow addition of 1 N HCl until pH 4.0. The reaction mixture was concentrated to remove ethanol. The remaining aqueous solution was washed with ethyl acetate (2×), then neutralized with saturated aqueous sodium bicarbonate, then extracted with ethyl acetate (3×). The organic layers were combined, washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by silica chromatography (hexanes/ethyl acetate 1:1, 3:7) to give a clear oil. Mass/Yield—3.9 g/94% TLC (hexanes/ethyl acetate=1:1) Rf=0.22, UV active. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.91 (s, 3H) 4.61 (s, 2H) 6.68-6.77 (m, 1H) 7.49-7.68 (m, 1H) 8.09 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([O:14][CH2:15][CH3:16])[C@H:11]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C@@H:10]([OH:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:26]1[CH:27]=[C:28]([CH2:32][O:33][CH2:34][CH2:35][CH3:36])[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([O:14][CH2:15][CH3:16])[C@H:11]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:36][CH2:35][CH2:34][O:33][CH2:32][C:28]3[CH:29]=[CH:30][CH:31]=[CH:26][CH:27]=3)=[CH:19][CH:18]=2)[C@@H:10]([OH:24])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](O)[C@H]1c1ccc(O)cc1
Reactant: CCCOCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](O)[C@H]1c1ccc(OCCCOCc2ccccc2)cc1

Procedure:
treating the product of step e) with 3-bromo-propoxymethyl-benzene and potassium carbonate to yield (3R,4R,5S)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-ethoxy-3-hydroxy-piperidine-1-carboxylic acid tert-butylester;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[C:8]1=[O:27].[CH2:35]([O:37][CH2:38][CH2:39][N:40]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[C:41]1[NH:49][CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)[CH3:36]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:53]2[CH2:52][CH2:51][CH:50]([NH:49][C:41]3[N:40]([CH2:39][CH2:38][O:37][CH2:35][CH3:36])[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[N:42]=3)[CH2:55][CH2:54]2)([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[C:8]1=[O:27]
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Reactant: COc1cc(CN2CCC(CCOS(C)(=O)=O)(Cc3cccc(F)c3)C2=O)cc(OC)c1OC
Product: CCOCCn1c(NC2CCN(CCC3(Cc4cccc(F)c4)CCN(Cc4cc(OC)c(OC)c(OC)c4)C3=O)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(3,4,5-trimethoxybenzyl)-3-(3-fluorophenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][CH:14]=[C:10]3[CH2:9][N:8]([CH3:15])[C:7](=[O:16])[C:6]=2[CH:17]=1.[Cl:18]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:18][C:14]1[N:13]=[CH:12][N:11]2[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][C:6]=3[C:7](=[O:16])[N:8]([CH3:15])[CH2:9][C:10]=12
Reactant: CN1Cc2cncn2-c2ccc(F)cc2C1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2c(Cl)ncn2-c2ccc(F)cc2C1=O

Procedure:
2.31 g (10 mmol) of 8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one and 1.47 g (11 mmol) of N-chlorosuccinimide are heated to 100° for 30 minutes in dimethylformamide. Subsequently, the mixture is poured into water and extracted several times with chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulphate and evaporated. The residue is recrystallized from ethyl acetate and yields 3-chloro-8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 217°-218°.