Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH2:4].[C:5]([NH:8][C:9]1[C:10](=[O:23])[C:11]2[C:16]([C:17](=[O:22])[C:18]=1NCC)=[CH:15][CH:14]=[CH:13][CH:12]=2)(=O)[CH3:6]>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]1[C:18]2[C:17](=[O:22])[C:16]3[C:11]([C:10](=[O:23])[C:9]=2[N:8]=[C:5]1[CH3:6])=[CH:12][CH:13]=[CH:14][CH:15]=3
Reactant: CCNC1=C(NC(C)=O)C(=O)c2ccccc2C1=O
Reactant: NCCCl
Solvent: O=CO
Product: Cc1nc2c(n1CCCl)C(=O)c1ccccc1C2=O

Procedure:
A solution of 43 (5 g, 0.02 mol, prepared from 2a and 2-chloroethylamine in an analogous manner to that of 29 below) in formic acid (50 ml) was refluxed for 1 h, and then concentrated. Purification by column chromatography (CHCl3, silica gel), followed by recrystallization from benzene, afforded 21 as yellow crystals. Yield, mp, and spectral data are given in Table 3.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=1>>[CH3:31][S:28]([C:24]1[CH:23]=[C:22]([NH:20][C:18]2[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=4)[N:16]3[N:17]=2)[CH:27]=[CH:26][CH:25]=1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)c1ccc(-c2cccc3nc(N)nn23)cc1
Reactant: CS(=O)(=O)c1cccc(Br)c1
Product: CS(=O)(=O)c1ccc(-c2cccc3nc(Nc4cccc(S(C)(=O)=O)c4)nn23)cc1
Yield: 40.9 %

Procedure:
(3-Methanesulfonyl-phenyl)-[5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from 5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75 mg, 0.26 mmol) and 1-bromo-3-methanesulfonyl benzene (73 mg, 0.29 mmol) in a manner analogous to Example 77 to yield (3-methanesulfonyl-phenyl)-[5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine (47 mg, 39%) as a white powder following trituration with methanol. MP=279° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.18 (s, 1H), 8.49 (s, 1H), 8.37 (d, J=8.0 Hz, 2H), 8.15 (d, J=8.0 Hz, 2H), 7.70-7.81 (m, 3H), 7.55 (t, J=17.4 Hz, 8.0 Hz, 1H), 7.36-7.45 (m, 2H), 3.30 (s, 3H), 3.17 (s, 3H). MS=443 (MH)+.
Reaction SMILES: [CH2:1](CN)C=C.[NH2:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[CH2:13]C>>[CH3:13][N:9]([CH2:10][CH:11]=[CH2:12])[CH2:8][CH2:7][NH:6][CH3:1]
Reactant: CCN1CCC[C@H]1CN
Reactant: C=CCCN
Product: C=CCN(C)CCNC

Procedure:
By using N-allylmethylamine (821.5 mg) as a starting material, the title compound (246 mg) was obtained in the same manners as those of Reference Example 1, (1) and Reference Example 19, (3).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[CH3:9][O-:10].[Na+]>CO>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:10][CH3:9])=[N:3][CH:4]=1
Reactant: C[O-]
Reactant: Clc1ccc(Cl)nc1
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cl)cn1
Reaction time: 24 h

Procedure:
To a stirred suspension of 14.8 g of 2,5-dichloropyridine in 50 ml of methanol was added 30 ml of a 25% solution of sodium methoxide in methanol and the mixture was heated to reflux under nitrogen. After 24 hours, another 30 ml of the sodium methoxide solution was added and reflux was continued for a total of 68 hours. The sodium chloride which precipitated was removed by filtration and the filtrate was concentrated at atmospheric pressure to about 1/4 the original volume and partitioned between ether and water. The aqueous layer was extracted with ether and the combined ether layers were washed with saturated sodium chloride solution, dried over potassium carbonate and concentrated at atmospheric pressure to a pale brown oil. This residue was distilled to give 5-chloro-2-methoxypyridine as a colorless liquid boiling at about 82°-84° C. at 20 torr.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[C:8]2[N:15]=[CH:14][N:13]([CH3:16])[C:9]2=[N:10][C:11]=1[CH3:12])=[O:5])[CH3:2].[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:22][CH2:18][CH2:19][CH2:20][CH3:21])=[C:8]2[N:15]=[CH:14][N:13]([CH3:16])[C:9]2=[N:10][C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCCCN
Reactant: CCOC(=O)c1c(C)nc2c(ncn2C)c1Cl
Product: CCCCNc1c(C(=O)OCC)c(C)nc2c1ncn2C
Yield: 78 %

Procedure:
2.5 g. of 7-chloro-3,5-dimethyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid ethyl ester is refluxed for 10 minutes with 10 ml. of butylamine. The excess butylamine is removed and the residue dissolved in ether. The mixture is filtered and cooled. The 7-butylamino-3,5-dimethyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid ethyl ester precipitates and is recrystallized from petroleum ether, yield 78%, m.p. 62°-63°.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:36]([O:38]C)=[O:37])[CH2:11][C:12]1[N:16]=[CH:15][N:14]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=1)=[O:8].[OH-].[Na+]>C(O)C.O>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:36]([OH:38])=[O:37])[CH2:11][C:12]1[N:16]=[CH:15][N:14]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:13]=1)=[O:8]
Reactant: COC(=O)[C@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)[C@@H]1CCC(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C1CC[C@@H](C(=O)N[C@@H](Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C(=O)O)N1

Procedure:
According to the general procedure for saponification, 5.6 g crude Pyr-His(Trt)-OMe were treated with 3.6 g sodium hydroxide in ethanol/water yielding 5.6 g of crude material (yield based on HPLC: 99%)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[C:26](Cl)(=[O:28])[CH3:27]>>[C:26]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:28])[CH3:27]
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Reactant: CC(=O)Cl
Product: CC(=O)NCCc1ccc(-c2ccc(C(C)CNS(=O)(=O)C(C)C)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.6 g (1.8 mmol) of material from Example 50 and 8 μL (0.11 mmol) acetyl chloride. NMR was consistent with the proposed compound. Electrospray Mass Spectrum: M−1=401.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[C:22]1([CH2:28][CH2:29][CH2:30]O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH2:28][CH2:29][CH2:30][O:20][C:19](=[O:21])[CH2:18][NH:17][C:15](=[O:16])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NCC(=O)O
Reactant: OCCCc1ccccc1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NCC(=O)OCCCc1ccccc1

Procedure:
Following General Procedure X and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine (prepared from N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine benzyl ester (from Example 73 below) using General Procedure O) and and 3-phenyl-1-propanol (Aldrich), the tide compound was prepared as a solid (mp=137° C.). The reaction was monitored by tdc (Rf=0.15 in 50% EtOAc/hexanes) and the product was purified by flash chromatography using 50% EtOAc/hexanes as the eluent.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([O:12]C(=O)C)[C:2]=12.C([O-])([O-])=O.[K+].[K+].O>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([OH:12])[C:2]=12
Reactant: CC(=O)OC1CCCCc2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: OC1CCCCc2cccnc21
Yield: 98.6 %

Procedure:
To a solution of acetic acid 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl ester (53.26 g, 0.259 mol) in methanol (350 mL) was added K2CO3 (72.98 g, mol) and the resultant mixture was stirred at room temperature overnight. The mixture was poured into water (350 mL) and extracted with CHCl3(3×300 mL). The combined organic extracts were dried (Na2SO4), and concentrated to provide 41.70 g of 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([O:24]C)=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].O[Li].O>O.C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1ccnc(-n2nccc2OCc2cccc(C#N)c2)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cccc(COc2ccnn2-c2cc(C(=O)O)ccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 2-[5-[(3-cyanophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate (1.0 eq) and LiOH.H2O (3.0 eq) in a mixture of water (2 mL) and THF (2 mL) was stirred at room temperature for 30 min. Diluted with another 2 mL water, and the mixture was washed with ethyl acetate twice (6 mL×2). The water phase was acidified with 1N HCl (pH=3), filtered and dried the solid to give the title compound. 1H NMR (400 MHz, DMSO-d6): δ 5.36 (2H, s), 6.03 (1H, s), 7.61-7.64 (2H, m), 7.77-7.78 (1H, m), 7.82-7.84 (2H, m), 7.96 (1H, s), 8.09 (1H, s), 8.69 (1H, d, J=4.4 Hz), 13.92 (1H, s). LCMS (mobile phase: 10%-95% Acetonitrile-Water-0.02% NH4Ac): purity is >95%, Rt=2.106 min. [M+H] Calc'd for C17H12N4O3, 321; Found, 321.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:36][CH:37]([CH3:39])[CH3:38])=[C:32]([CH:35]=1)[C:33]#[N:34]>CN(C=O)C>[C:33]([C:32]1[CH:35]=[C:28]([CH:29]=[CH:30][C:31]=1[O:36][CH:37]([CH3:39])[CH3:38])[CH2:27][O:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1)#[N:34]
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Reactant: CC(C)Oc1ccc(CCl)cc1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(OC(C)C)c(C#N)c3)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
Ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (1.237 g, 4.77 mmol) was dissolved in DMF (12 mL) and cesium carbonate (1.554 g, 4.77 mmol) was added. The reaction mixture was stirred at room temperature for 10 min and 5-(chloromethyl)-2-isopropoxybenzonitrile (1.0 g, 4.77 mmol) was added. The reaction mixture was stirred at 40° C. for 2 h before it was cooled to room temperature. The heterogenous mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (1.32 g). LCMS m/z=433.5 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (t, J=7.2 Hz, 3H), 1.40 (d, J=6.1 Hz, 6H), 2.05-2.16 (m, 1H), 2.50 (dd, J=16.7, 11.1 Hz, 1H), 2.69-2.88 (m, 4H), 3.50-3.59 (m, 1H), 4.16-4.26 (m, 2H), 4.65 (septet, J=6.1 Hz, 1H), 5.00 (s, 2H), 6.80 (dd, J=8.7, 2.5 Hz, 1H), 6.94-6.97 (m, 2H), 7.20 (d, J=8.8 Hz, 1H), 7.58 (dd, J=8.7, 2.3 Hz, 1H), 7.64 (d, J=2.0 Hz, 1H), 8.45 (s, 1H).
Reaction SMILES: [CH:1]1([CH:4]([NH2:8])[CH:5]2[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[Cl:9][CH2:10][CH2:11][N:12]=[C:13]=[O:14]>O1CCCC1>[CH:1]1([CH:4]([CH:5]2[CH2:7][CH2:6]2)[NH:8][C:13]([NH:12][CH2:11][CH2:10][Cl:9])=[O:14])[CH2:3][CH2:2]1
Reactant: O=C=NCCCl
Reactant: NC(C1CC1)C1CC1
Solvent: C1CCOC1
Product: O=C(NCCCl)NC(C1CC1)C1CC1
Reaction time: 15 h

Procedure:
A solution made from 13.4 g of dicyclopropylmethylamine in 30 ml tetrahydrofuran is added dropwise to a solution of 13 g of β-chloroetyl isocyanate in 15 ml tetrahydrofuran while maintaining the inner temperature from 0° to +5° C. Then, the reaction mixture is kept at room temperature for 15 hours. Afterwards, the solution is evaporated to dryness and the dry residue, weighing 26.5 g, is used as such for the next step of the synthesis. For analytical purpose, a sample of the raw urea is recrystallised from acetonitrile. The N-(dicyclopropylmethyl) N-(β-chloroethyl) urea occurs as white crystals melting at 103°-104° C. with decomposition.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[C:16](=[O:17])[CH:10]([CH2:11][Se:12][CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl(O)(=O)(=O)=[O:19]>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:15][CH:14]2[C:16]([OH:19])([OH:17])[CH:10]([CH2:11][Se:12][CH2:13]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C2C[Se]CC1CN(Cc1ccccc1)C2
Reactant: [O-][Cl+3]([O-])([O-])O
Solvent: c1ccccc1
Product: OC1(O)C2C[Se]CC1CN(Cc1ccccc1)C2
Yield: 90.2 %

Procedure:
7-Benzyl-3-selena-7-azabicyclo[3.3.1]nonan-9-one (0.65 g, 2.2 mmol) was dissolved in dry benzene (250 mL). Perchloric acid (60%, 1.0 g, 6.0 mmol) was added dropwise very slowly with cooling and swirling. This precipitated an orange solid which adhered to the side of the flask. The benzene was decanted and the solid was recrystallized (95% ethanol) to give 7-benzyl-3-selena-7-azabicyclo[3.3.1]nonan-9,9-diol hydroperchlorate (0.62 g, 68.3%) as white needles: mp 214.0°-216.0° C. (dec); IR (KBr) cm-1 3430, 1080; 1H NMR (DMSO-d6) δ2.43 [br s, 2 H, H(2,4)ax ], 2.72 [br d, 2 H, H(2,4)eq ], 3.22-3.50 [m, 6 H, H(6,8)ax, H(1,5), OH], 3.50-3.64 [m, 2 H, H(6,8)eq ], 4.35 [d, 2 H, H(10-NCH2)], 7.40-7.70 [m, 5 H, ArH], 9.20 [br s, 1 H, H(7)]; 13C NMR (DMSO-d6) ppm 21.1 [C(2,4)], 34.7 [C(1,5)], 54.9 [C(6,8)], 60.1 [C(10)-NCH2)], 92.5 [C(9)], 129.2, 129.7, 130.0, 130.5 [ArC]; 15N NMR (DMSO-d6) ppm 51.88 [N(7)]; 77Se NMR (DMSO-d6) ppm 62.39 [Se(3)]. Analysis calculated for C14H20NClSeO6 : N, 3.39; Se, 19.13. Found: N, 3.20; Se, 19.51. ##STR29##
Reaction SMILES: C(OC([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH2:17][C:18]2[C:19]([CH3:24])=[N:20][NH:21][C:22]=2[CH3:23])=[CH:9]1)=O)(C)(C)C.[N:25]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[C:26]=[O:27].C(O)(=O)C>ClCCl>[CH3:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][NH:25][C:26]([N:21]2[C:22]([CH3:23])=[C:18]([CH2:17][C:10]3[C:11]4[C:12](=[N:13][CH:14]=[CH:15][CH:16]=4)[NH:8][CH:9]=3)[C:19]([CH3:24])=[N:20]2)=[O:27])=[CH:30][CH:31]=1
Reactant: Cc1n[nH]c(C)c1Cc1cn(C(=O)OC(C)(C)C)c2ncccc12
Reactant: COc1ccc(CN=C=O)cc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(CNC(=O)n2nc(C)c(Cc3c[nH]c4ncccc34)c2C)cc1
Reaction time: 0.5 h

Procedure:
3-(3,5-dimethyl-1H-pyrazol-4-ylmethyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (514, 10 mg, 0.03 mmol) was dissolved in dichloromethane (0.5 mL). 1,8-Diazabicylo[5.4.0]unde-7-ene (6 mg, 0.04 mmol) was added. 1-Isocyanatomethyl-4-methoxy-benzene (545, 6.5 mg, 0.04 mmol) was added. The reaction was allowed to proceed at room temperature for 30 minutes. Acetic acid (0.2 mL) was added to the reaction. The solvents were removed under reduced pressure. The residue was dissolved in dimethyl sulfoxide (0.2 mL) and purified by reverse phase HPLC on a Phenomenex column (50 mm×10 mm ID), eluting with water with 0.1% trifluoroacetic acid and 20-100% acetonitrile with 0.1% trifluoroacetic acid over 16 minutes at a flow rate of 6 mL/minute to provide the desired compound P-0135. MS (ESI) [M+H+]+=390.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([F:11])=[C:9]([F:12])[C:6]([CH2:7][OH:8])=[C:5]([F:13])[C:4]=1[F:14].[C:15]([C:17]([CH3:27])=[CH:18][C@@H:19]1[C@@H:21]([C:22](O)=[O:23])[C:20]1([CH3:26])[CH3:25])#[N:16]>CN(C)C1C=CN=CC=1.ClCCl>[C:15]([C:17]([CH3:27])=[CH:18][C@@H:19]1[C@@H:21]([C:22]([O:8][CH2:7][C:6]2[C:5]([F:13])=[C:4]([F:14])[C:3]([O:2][CH3:1])=[C:10]([F:11])[C:9]=2[F:12])=[O:23])[C:20]1([CH3:26])[CH3:25])#[N:16]
Reactant: CC(C#N)=C[C@@H]1[C@@H](C(=O)O)C1(C)C
Reactant: COc1c(F)c(F)c(CO)c(F)c1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1c(F)c(F)c(COC(=O)[C@@H]2[C@@H](C=C(C)C#N)C2(C)C)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
Under a nitrogen atmosphere, 0.49 g of N,N-dicyclohexylcarbodiimide was added to a mixture of 0.50 g of 4-methoxy-2,3,5,6-tetrafluorobenzyl alcohol, 0.43 g of (1R)-trans-3-(2-cyano-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid, 0.087 g of 4-dimethylaminopyridine and 7 ml of anhydrous dichloromethane, and the mixture was stirred at room temperature for 3 hours. Thereafter, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 0.62 g of 4-methoxy-2,3,5,6-tetrafluorobenzyl (1R) trans-3-(2-cyano-1-propenyl)-2,2-dimethylcyclopropanecarboxylate represented by the following formula:
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=2[O:22][CH3:23])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].Cl[C:25](Cl)([O:27][C:28](=O)[O:29]C(Cl)(Cl)Cl)Cl>C1COCC1>[CH:19]([C:16]1[CH:17]=[CH:18][C:13]([C:2]2([NH:1][C:28](=[O:29])[O:27][CH3:25])[C:10](=[O:11])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:12])=[C:14]([O:22][CH3:23])[CH:15]=1)([CH3:21])[CH3:20]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(C(C)C)ccc1C1(N)C(=O)c2ccccc2C1=O
Solvent: C1CCOC1
Product: COC(=O)NC1(c2ccc(C(C)C)cc2OC)C(=O)c2ccccc2C1=O
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (0.50 g, 1.62 mmol) in anhydrous THF (10 ml) was added triphosgene (0.21 g, 0.71 mmol) and stirred for 30 min. The reaction mixture was concentrated and was dissolved in methanol (6 mL) and was stirred for 2 hrs and was concentrated to afford the title compound (220 mg, 93%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>CO>[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:21][C:16]2[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]3[O:12][C:11]([CH3:24])([CH3:23])[CH:10]([C:7]4[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=4)[C:14]=3[C:15]=2[CH3:22])=[O:31])=[CH:28][CH:27]=1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc(F)cc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 91 %

Procedure:
By using (−)-3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 91%. Melting point: 253-254° C. [α]D=−77.4° (c=0.500, methanol).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33](O)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:13])[CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[C:22]([CH3:32])=[C:21]([C:33]([NH:36][C@H:37]4[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH2:39][CH2:38]4)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3cc(C(C)C)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Product: Cc1c(C(=O)N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c2ncnc(-c3cc(C(C)C)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(propan-2-yl)phenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c15) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]([S:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[C:5]3[CH:14]([CH2:15][C:16]([O:18]C)=[O:17])[CH2:13][CH2:12][N:6]3[C:7]=2[CH:8]=[C:9]([F:11])[CH:10]=1.[CH3:28][C:29]1[C:33](B(O)O)=[C:32]([CH3:37])[O:31][N:30]=1>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([S:20][C:4]2[C:3]3[C:2]([C:33]4[C:29]([CH3:28])=[N:30][O:31][C:32]=4[CH3:37])=[CH:10][C:9]([F:11])=[CH:8][C:7]=3[N:6]3[CH2:12][CH2:13][CH:14]([CH2:15][C:16]([OH:18])=[O:17])[C:5]=23)=[CH:26][CH:25]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: COC(=O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Product: Cc1noc(C)c1-c1cc(F)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)O

Procedure:
Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1.12-a]indol-1-yl]acetate (Example 7, Step 9) and 3,5-dimethylisoxazol-4-ylboronic acid, the title compound was synthesized following the procedures described Example 108.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]([CH2:14]Cl)=[C:5]2[O:16][CH3:17].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]([CH2:14][N:22]1[C:18](=[O:28])[C:19]3[C:20](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:21]1=[O:23])=[C:5]2[O:16][CH3:17]
Reactant: COc1c(CCl)n(C)c(=O)c2ccc(Cl)cc12
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(CN2C(=O)c3ccccc3C2=O)n(C)c(=O)c2ccc(Cl)cc12
Yield: 51.4 %

Procedure:
A solution of 6-chloro-3-chloromethyl-4-methoxy-2-methyl-1(2H)-isoquinolinone (0.81 g, 3 mmol) and potassium phthalimide (0.83 g, 4.5 mmol) in N,N-dimethylformamide (20 ml) was stirred at room temperature for 4 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-{(6-chloro-4methoxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione (0.59 g, 51.8%) as crystals.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:17])[CH2:4][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:9])[O:6]CC.[OH-].[Na+]>C(O)C.O>[NH2:1][CH2:2][CH:3]([OH:17])[CH2:4][P:5]([CH:10]([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16])(=[O:6])[OH:9]
Reactant: CCOC(OCC)P(=O)(CC(O)CN)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(OCC)P(=O)(O)CC(O)CN
Temperature: 25 °C

Procedure:
0.5 g of ethyl 3-amino-2-hydroxy-propyl(diethoxymethyl)phosphinate is dissolved in 5 ml of ethanol and this solution is added to a solution of 0.14 g of sodium hydroxide in 2 ml of water. This mixture is then heated to 60° for a period of 3 hours, cooled to room temperature and the solvent evaporated under reduced pressure. The oily residue is passed down an Ion Exchange Resin (DOWEX® 50W-X8 H+) using de-ionised water as eluant. Ninhydrin-positive fractions are combined and evaporated to give 3-amino-2-hydroxy-propyl(diethoxymethyl)phosphinic acid, m.p. 214°-215° (dec.), 31P-NMR: δ =+30.9 ppm (D2O).