Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:31])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:30])[CH2:9][CH2:10][C@@:11]3([C:27]([OH:29])=[O:28])[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]32)[C:3]1([CH3:33])[CH3:32].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OCC)(=O)C>CN(C=O)C>[CH3:30][C@:8]12[C@@:7]3([CH3:31])[C@@H:16]([C@:17]4([CH3:20])[C@@H:4]([CH2:5][CH2:6]3)[C:3]([CH3:32])([CH3:33])[C:2](=[O:1])[CH2:19][CH2:18]4)[CH2:15][CH2:14][C@@H:13]1[C@H:12]1[C@H:21]([C:24]([CH3:26])=[CH2:25])[CH2:22][CH2:23][C@:11]1([C:27]([OH:29])=[O:28])[CH2:10][CH2:9]2
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a chilled solution of (1R,3 aS,5aR,5bR,7aR,9S,11aR,11bR,13 aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (2.35 g, 5.15 mmol) in DMF (45 mL) at ˜4° C. under nitrogen was added pyridinium dichromate (PDC 3.87 g, 10.29 mmol) in a single portion. The suspension was rapidly stirred, forming an orange solution, but rapidly changed into dark brownish with all the PDC dissolved into the reaction mixture. The reaction was kept in an ice bath, and was allowed to warm to RT slowly over 8 hours. Stirring continued for 48 hrs at RT thereafter. The PDC reaction mixture acquired a dull dark brownish appearance but no PPT was observed. The crude DMF reaction solution was poured into vigorously stirred ethyl acetate (400 mL) causing a PPT of a light brownish solid. The suspension was filtered through a short bed (˜1″ thick) of silica gel type-H in a large diameter filter funnel. The clear filtrate was washed with 0.1 N HCl (200 mL), then with water (3×200 mL). All the volatile solvents were removed, giving 2.1 gm (88%) as a white solid. MS: m/e 477.21 (M+Na)+, 6.2 min (method 9). 1H NMR (400 MHz, CHLOROFORM-d) δ 4.76 (d, J=2.3 Hz, 1H), 4.63 (s, 1H), 3.06-2.98 (m, 1H), 2.55-2.37 (m, 2H), 2.28 (s, 2H), 1.99 (d, J=6.5 Hz, 2H), 1.95-1.87 (m, 1H), 1.71 (s, 3H), 1.64 (t, J=11.4 Hz, 2H), 1.59-1.20 (m, 16H), 1.08 (s, 3H), 1.03 (s, 3H), 1.00 (s, 3H), 0.99 (s, 3H), 0.94 (s, 3H).
Reaction SMILES: N(C(N(C)C)=O)=NC(N(C)C)=O.C(P(CCCC)CCCC)CCC.[O:26]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27]1.[C:32]([O:36][C:37]([NH:39][C:40]1[N:45]=[CH:44][C:43]([CH2:46][CH:47]([CH:55]([S:65][CH2:66][C:67]2[CH:72]=[CH:71][C:70]([O:73][CH3:74])=[CH:69][CH:68]=2)[CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60](O)[CH:59]=2)[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[CH:42][CH:41]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>C1(C)C=CC=CC=1>[C:32]([O:36][C:37]([NH:39][C:40]1[N:45]=[CH:44][C:43]([CH2:46][CH:47]([CH:55]([S:65][CH2:66][C:67]2[CH:72]=[CH:71][C:70]([O:73][CH3:74])=[CH:69][CH:68]=2)[CH2:56][CH2:57][C:58]2[CH:59]=[CH:60][CH:61]=[C:62]([O:31][CH:28]3[CH2:29][CH2:30][O:26][CH2:27]3)[CH:63]=2)[C:48]([O:50][C:51]([CH3:52])([CH3:53])[CH3:54])=[O:49])=[CH:42][CH:41]=1)=[O:38])([CH3:33])([CH3:34])[CH3:35]
Reactant: COc1ccc(CSC(CCc2cccc(O)c2)C(Cc2ccc(NC(=O)OC(C)(C)C)nc2)C(=O)OC(C)(C)C)cc1
Reactant: OC1CCOC1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: Cc1ccccc1
Product: COc1ccc(CSC(CCc2cccc(OC3CCOC3)c2)C(Cc2ccc(NC(=O)OC(C)(C)C)nc2)C(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 44.2 %

Procedure:
1,1′-azobis(N,N-dimethylformamide)(134 mg, 0.78 mmol) was added to a solution of tri-n-butylphosphine (221 μL, 0.89 mmol) in toluene (2 mL). Tetrahydrofuran-3-ol (36 μL, 44 mmol) and tert-butyl 2-({6-[(tert-butoxycarbonyl)amino]pyridin-3-yl}methyl)-5-(3-hydroxyphenyl)-3-[(4-methoxybenzyl)thio]pentanoate (154 mg, 0.25 mmol) was added sequentially. The reaction mixture was stirred for 12 h at 80° C. Toluene (100 mL) was added and the mixture was washed with brine, dried and concentrated. Flash chromatography (toluene/EtOAc, 100:0 to 70:30) gave tert-butyl 2-({6-[(tert-butoxycarbonyl)amino]pyridin-3-yl}methyl)-3-[(4-methoxybenzyl)thio]-5-[3-(tetrahydrofuran-3-yloxy)phenyl]pentanoate (75 mg, 35%).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[N:12]1([C:18]2[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]3[NH:26][N:27]=[CH:28][C:19]=23)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[C:29]([O:33][C:34]([N:36]([CH:49]([CH3:51])[CH3:50])[CH2:37][C@H:38]([C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)[C:39](O)=[O:40])=[O:35])([CH3:32])([CH3:31])[CH3:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:48][C:45]1[CH:46]=[CH:47][C:42]([C@H:38]([C:39]([N:15]2[CH2:16][CH2:17][N:12]([C:18]3[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]4[NH:26][N:27]=[CH:28][C:19]=34)[CH2:13][CH2:14]2)=[O:40])[CH2:37][N:36]([CH:49]([CH3:50])[CH3:51])[C:34](=[O:35])[O:33][C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:43][CH:44]=1
Reactant: N#Cc1cnc2[nH]ncc2c1N1CCNCC1
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(C#N)cnc3[nH]ncc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
DIEA (d 0.742; 0.102 mL, 0.585 mmol) was added to a solution of 4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile dihydrochloride (0.0661 g, 0.219 mmol), (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.050 g, 0.146 mmol, see Example B) and TBTU (0.0564 g, 0.176 mmol) in DCM (1 mL) and stirred at room temperature for 18 hours. The mixture was directly loaded onto a silica column and purified by chromatography (hexane:ethyl acetate, 1:1) to give (S)-tert-butyl 2-(4-chlorophenyl)-3-(4-(5-cyano-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate as a solid. The solid was dissolved in DCM (1 mL), and TFA (0.2 mL) was added. The mixture was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (S)-4-(4-(2-(4-chlorophenyl)-3-(isopropylamino)propanoyl)piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile dihydrochloride (0.043 g, 56%). MS APCI (+) m/z 452.1 detected.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[O:31][CH2:30]2)[CH2:26][CH2:25]1)=[O:23].[CH:38]1([S:41]([NH2:44])(=[O:43])=[O:42])[CH2:40][CH2:39]1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:44][S:41]([CH:38]3[CH2:40][CH2:39]3)(=[O:43])=[O:42])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][C:27]2([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[O:31][CH2:30]2)[CH2:28][CH2:29]1)=[O:23]
Reactant: Cc1ccc(C)c(Nc2c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc3c(C(=O)O)cnn23)c1
Reactant: NS(=O)(=O)C1CC1
Product: Cc1ccc(C)c(Nc2c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc3c(C(=O)NS(=O)(=O)C4CC4)cnn23)c1
Yield: 55.1 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2,5-dimethylphenylamino)-6-(2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.065 g, 0.13 mmol) obtained in Example 129, step 2 and cyclopropanesulfonamide (0.079 g, 0.65 mmol), the title compound (0.043 g, 55%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.[NH2:11]OS(O)(=O)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[C:7]#[N:11]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: NOS(=O)(=O)O
Solvent: O
Product: N#Cc1cc(Cl)ccc1O
Temperature: 60 °C
Reaction time: 7 h
Yield: 92.3 %

Procedure:
5-chloro-2-hydroxybenzaldehyde (300 g, 1.92 mol) and hydroxylamine-O-sulfonic acid (260 g, 2.30 mol) were suspended in water (4.5 L) at room temperature, which was then stirred at 60° C. for 7 hours. Water (3 L) was added to the reaction mixture, which was then cooled with ice, followed by filtering a crystal before further washing with water (1.5 L). The precipitated crystal was suspended in water (1.5 L), filtered, washed with water, and subjected to tray drying at 50° C. for 22 hours to obtain 272 g of the title compound (white crystal, yield: 93%).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[H-].[Na+].[C:9]([O:13][C:14](=[O:30])[NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[C:25]([C:26](F)=[O:27])=[CH:24][N:23]=[C:22]([Cl:29])[N:21]=1)([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C>[C:9]([O:13][C:14](=[O:30])[NH:15][CH2:16][CH2:17][CH2:18][N:19]1[C:20]2[N:21]=[C:22]([Cl:29])[N:23]=[CH:24][C:25]=2[C:26](=[O:27])[C:3]([C:4](=[O:5])[NH2:6])=[C:1]1[NH2:2])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCCCNc1nc(Cl)ncc1C(=O)F
Reactant: N#CCC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCn1c(N)c(C(N)=O)c(=O)c2cnc(Cl)nc21
Temperature: 3.5 °C
Reaction time: 0.25 h
Yield: 64 %

Procedure:
To a solution, cooled to 2-5°C. on an ice bath, of 1.21 g (14.39 mmol) of cyanoacetamide in 20 mL of anhydrous DMF are added portionwise 1.73 g (43.17 mmol) of 60% sodium hydride. The mixture is stirred for 15 minutes at 2-5°C., and this suspension is then added rapidly to the solution of 4.56 g (13.70 mmol) of the acid fluoride prepared in step 11.2 in 30 mL of anhydrous DMF, precooled to 2-5°C. on an ice bath. The mixture is stirred overnight at room temperature and then cooled to 2-5°C., and a further 0.22 g of 60% sodium hydride is added. The medium is stirred overnight at room temperature, and ice is then added slowly to destroy the excess hydride, and the reaction mixture is poured into an ice-water mixture. The resulting mixture is acidified by adding aqueous 1 N HCl solution. The precipitate formed is isolated by filtration, rinsed with water and then dried. The expected product is obtained in the form of an orange solid, which is used as obtained in the following step. Yield=64%.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[I:20])[C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:1]([O:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[I:20])[C:13]([O:15][CH3:16])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(I)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(I)c(OCc2ccccc2)c1
Temperature: 60 °C
Yield: 104.2 %

Procedure:
2.35 mL (19.78 mmol, 1.1 eq) of benzyl bromide are added to a solution of 5.0 g (17.98 mmol, 1 eq) of methyl 3-hydroxy-4-iodobenzoate in 30 ml of methyl ethyl ketone in the presence of 5.0 g (36.18 mmol, 2 eq) of potassium carbonate. The reaction mixture is heated at 60° C. for 5 hours and then hydrolyzed in water and extracted with ethyl acetate. 6.9 g of methyl 3-benzyloxy-4-iodobenzoate are obtained in oil form and are used in the following reaction without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:22])([C:14]2[C:19]([CH2:20]O)=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]2([C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:19]3[CH2:20][O:22]2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccnc1C1(O)CCN(Cc2ccccc2)CC1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: c1ccc(CN2CCC3(CC2)OCc2cccnc23)cc1
Yield: 63.2 %

Procedure:
To a solution of 1.1 g (3.5 mmol) 1′-benzyl-3-hydroxymethyl-2′,3′,5′,6′-tetrahydro-1′H-[2,4′]bipyridinyl-4′-ol and 1.0 ml (7.4 mmol) triethylamine in 35 ml dry tetrahydrofuran were added 0.26 ml (3.3 mmol) methane sulfonyl chloride at room temperature. The reaction mixture was heated at reflux for 1 h and then quenched with water. The aqueous layer was basified with aqueous 1 M sodium hydroxide and extracted with three portions of ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Flash-chromatography (aminopropyl-modified silica gel) gave the title compound (0.62 g, 62%) as a light yellow amorphous solid.
Reaction SMILES: [N:1]([C@@H:4]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C@H:5]([OH:24])[CH2:6][N:7]([CH2:19][C:20]([F:23])([CH3:22])[CH3:21])[S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:10])=[O:9])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O.C(OCC)(=O)C>[NH2:1][C@@H:4]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C@H:5]([OH:24])[CH2:6][N:7]([CH2:19][C:20]([F:23])([CH3:21])[CH3:22])[S:8]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)(=[O:9])=[O:10]
Reactant: COc1ccc(C[C@H](N=[N+]=[N-])[C@H](O)CN(CC(C)(C)F)S(=O)(=O)c2ccc(OC)cc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C[C@H](N)[C@H](O)CN(CC(C)(C)F)S(=O)(=O)c2ccc(OC)cc2)cc1
Reaction time: 24 h
Yield: 55 %

Procedure:
Azide 18f and triphenyl phosphine (1.2 eq) was dissolved in a solution of THF/H2O (4:1). The reaction mixture was allowed to run for 24 h. Upon completion the reaction was diluted with ethyl acetate and extracted 3 times. The organic layers were combined and dried over anhydrous sodium sulfate. The solvent was removed under vacuum and the residue was purified using flash chromatography 60% ethylacetate/hexanes followed by 3% MeOH/CH2Cl2. 55% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.74 (d, J=8.6 Hz, 2H), 7.09 (d, J=8.3 Hz, 2H), 6.98 (d, J=8.5 Hz, 2H), 6.82 (d, J=8.1 Hz, 2H), 3.93-3.90 (m, 1H), 3.85 (s, 3H), 3.77 (s, 3H), 3.51 (dd, J=27.4, 15.1 Hz, 1H), 3.41-3.20 (m, 3H), 3.04-3.01 (m, 1H), 2.88 (d, J=13.7 Hz, 1H), 2.33 (dd, J=13.4, 10.5 Hz, 1H), 1.46 (d, J=21.6 Hz, 3H), 1.37 (d, J=21.4 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][CH2:5][N:6]([CH2:29][CH2:30][CH2:31][CH2:32][N:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:23][C:24]2[NH:25][CH:26]=[CH:27][N:28]=2)[CH2:16][C:17]2[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=2)=[CH:10][CH:9]=1.Cl>CO>[CH2:37]([N:33]([CH2:34][CH2:35][CH3:36])[CH2:32][CH2:31][CH2:30][CH2:29][N:6]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:23][C:24]2[NH:25][CH:26]=[CH:27][N:28]=2)[CH2:16][C:17]2[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=2)=[CH:10][CH:9]=1)[CH2:5][CH2:4][C:3]([OH:40])=[O:2])[CH2:38][CH3:39]
Reactant: CCCN(CCC)CCCCN(CCC(=O)OC)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Agent: Cl
Solvent: CO
Product: CCCN(CCC)CCCCN(CCC(=O)O)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Yield: 56.8 %

Procedure:
The compound (129 mg) obtained in Example 34-3 was dissolved in anhydrous methanol (1.0 ml) and added with concentrated hydrochloric acid (10.0 ml) and the whole was refluxed under heating. After completion of the reaction, the solvent was distilled off, thereby obtaining a hydrochloride (71.4 mg) of the subject compound as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:5][C:3]=1[NH2:4].C([O-])([O-])=O.[K+].[K+].[CH3:24]/[C:25](=[CH:29]\[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)/[C:26](Cl)=[O:27]>CC(C)=O.O>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:5][C:3]=1[NH:4][C:26](=[O:27])/[C:25](/[CH3:24])=[CH:29]/[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C/C(=C\c1ccccc1)C(=O)Cl
Reactant: Nc1cc(OCCN2CCCCC2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C/C(=C\c1ccccc1)C(=O)Nc1cc(OCCN2CCCCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.1 %

Procedure:
2-chloro-5-(2-piperidinoethoxy)aniline (705 mg, 3.9 mmol, 1 eq.) was placed in a mixture of acetone (653 μL) and water (852 μL) in the presence of K2CO3 (1.1 g, 7.8 mmol, 2 eq.). (E)-2-methyl-3-phenylacryloyl chloride (705 mg, 3.9 mmol, 1 eq.) was then added at 0° C. The reaction mixture was allowed to warm-up to room temperature, stirred for 2 hours and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford (E)-N-(2-chloro-5-(2-(piperidin-1-yl)ethoxy)phenyl)-2-methyl-3-phenylacrylamide (500 mg, 66%).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)[C:10]([N:12]1[CH2:17][CH2:16][C:15]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:11])=O)(C)(C)C.ClCCl.FC(F)(F)C(O)=O.[OH-].[Na+]>>[NH2:8][C@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)[C:10]([N:12]1[CH2:13][CH2:14][C:15]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:17]1)=[O:11]
Reactant: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@@H](Cc2ccc(Cl)c(Cl)c2)NC(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@H](N)Cc2ccc(Cl)c(Cl)c2)CC1
Reaction time: 2 h
Yield: 85.4 %

Procedure:
300 mg (0.54 mmol) of ethyl 1-[(R)-2-tert-butoxycarbonylamino-3-(3,4-dichloro-phenyl)propionyl]-4-cyclohexylpiperidine-4-carboxylate are diluted in 5 ml of a 4/1 dichloromethane/trifluoroacetic acid solution. After stirring for 2 hours, the mixture is poured into aqueous 1N sodium hydroxide solution and then extracted with dichloromethane. The organic phase is dried over sodium sulfate, filtered and concentrated. 210 mg of ethyl 1-[(R)-2-amino-3-(3,4-dichlorophenyl)propionyl]-4-cyclohexylpiperidine-4-carboxylate in the form of a white powder are obtained in a yield of 86%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][N:17]=1)[C:11]([O:13][CH3:14])=[O:12].[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1B(O)O.CO>O.C(Cl)Cl.Cl[Pd]Cl>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][N:17]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccnc(-c2ccc(Cl)cc2Cl)c1
Temperature: 100 °C
Yield: 46.6 %

Procedure:
Potassium carbonate (1.812 g, 13.11 mmol), methyl 2-chloroisonicotinate (3 g, 17.48 mmol), 2,4-dichlorophenylboronic acid (5.00 g, 26.23 mmol), PdCl2 (dppf) (0.380 g, 0.52 mmol), and MeOH (30.6 mL) were split in two 20 mL microwave vials and heated to 100° C. for 35 min in a single node microwave reactor. The reaction mixture was diluted with water and DCM, extracted with DCM and evaporated. Purified by automated flash chromatography using 5% EtOAc in heptane ->30% EtOAc over 15 CV at 280 nm. Methyl 2-(2,4-dichlorophenyl)isonicotinate (2.3 g, 47%) was isolated as a white solid. 1H NMR (400 MHz, cdcl3) δ 3.98 (s, 3H), 7.37 (dd, 1H), 7.53 (d, 1H), 7.57 (d, 1H), 7.86 (dd, 1H), 8.20 (s, 1H), 8.87 (d, 1H). MS m/z 282 (M+H)+
Reaction SMILES: [C:1]12([OH:13])[CH2:10][C:5]3([OH:11])[CH2:6][CH:7]([CH2:9][C:3]([OH:12])([CH2:4]3)[CH2:2]1)[CH2:8]2.[C]=O.O=O.[C:18]([OH:21])(=[O:20])[CH3:19]>>[C:5]12([OH:11])[CH2:10][C:1]3([OH:13])[CH2:8][CH:7]([CH2:9][C:3]([OH:12])([CH2:2]3)[CH2:4]1)[CH2:6]2.[C:18]([C:19]12[CH2:9][C:3]3([OH:12])[CH2:2][C:1]([OH:13])([CH2:10][C:5]([OH:11])([CH2:4]3)[CH2:6]1)[CH2:8]2)([OH:21])=[O:20]
Reactant: CC(=O)O
Agent: O=O
Agent: OC12CC3CC(O)(C1)CC(O)(C3)C2
Agent: [C]=O
Product: O=C(O)C12CC3(O)CC(O)(CC(O)(C3)C1)C2
Temperature: 60 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
10 mmol of 1,3,5-adamantanetriol, 1 mmol of NHPI, 0.005 mmol of Co(AA)2 were added to 25 ml of acetic acid, and the mixture was stirred at 60° C. for 6 hours in a reactor with a gas pack inflated with a mixed gas (mixed gas: 2 L of carbon monoxide adn 0.5 L of oxygen; pressure: 5 kg/cm2) connected thereto. As a result, with a conversion of 1,3,5-adamantanetriol of 99%, there was obtained 1-carboxy-3,5,7-adamantanetriol (yield: 80%).
Reaction SMILES: Cl.[N:2]1([CH2:8][CH:9]2[C:14](=[O:15])[N:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]3=[N:11][C:10]2=[O:20])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.CC(C)([O-])C.[K+].Cl[CH2:28][N:29]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][C:35]([O:44][CH3:45])=[CH:36][C:37]=2[CH:41]([CH3:43])[CH3:42])[S:30]1(=[O:32])=[O:31]>CN(C)C=O.O>[N:2]1([CH2:8][C:9]2[C:14](=[O:15])[N:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]3=[N:11][C:10]=2[O:20][CH2:28][N:29]2[C:39](=[O:40])[C:38]3[C:33](=[CH:34][C:35]([O:44][CH3:45])=[CH:36][C:37]=3[CH:41]([CH3:43])[CH3:42])[S:30]2(=[O:31])=[O:32])[CH2:3][CH2:4][O:5][CH2:6][CH2:7]1
Reactant: O=C1N=C2C=CC=CN2C(=O)C1CN1CCOCC1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1nc3ccccn3c(=O)c1CN1CCOCC1)C2=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.1 %

Procedure:
A mixture of 3-(4-morpholinylmethyl)pyrido[1,2-a]pyrimidine-2,4-dione hydrochloride (0.6 g) and potassium t-butoxide (0.49 g) in dimethylformamide (20 mL) was stirred at room temperature for five minutes. 2-Chloromethyl-4-isopropyl-6-methoxysaccharin (0.61 g) was added and stirring was continued at room temperature for one hour. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (3×200 mL). The dichloromethane extract was dried over sodium sulfate and stripped of volatiles, finally under high vacuum. The crude product (780 mg) was combined with that (0.65 g) from another run at the same scale using sodium hydride (60% dispersion in mineral oil, 0.19 g) instead of potassium t-butoxide and purified by column chromatography on silica gel with dichloromethane-methanol (95:5) as eluant affording 2-[3-(4-morpholinylmethyl)-4-oxo-4-H-pyrido[1,2-a]pyrimidin-2yl]oxymethyl-4-isopropyl-6-methoxysaccharin (500 mg, 23% yield), part of which was recrystallized from ethanol (m.r. 177°-180° C.).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]([NH2:14])[CH:11]([CH3:13])[CH3:12].[BH4-].[Na+].CO>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:14][CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)CN
Reactant: O=Cc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)CNCc1ccc(F)cc1
Reaction time: 18 h
Yield: 75.7 %

Procedure:
A mixture of 4-fluorobenzaldehyde (6.0 mL, 55.93 mmol), and isobutylamine (3.72 g, 50.85 mmol) in toluene (30 mL) was heated at reflux using Dean-Stark apparatus of 5 hours. The mixture was stood at ambient temperature for 18 hours then cooled in an ice-bath. Sodium borohydride (2.89 g, 76.28 mmol) was added followed by MeOH (5 mL). After 1 hour at 0° C. the reaction was quenched with 1M HCl, basified with a saturated solution of NaHCO3 and extracted into EtOAc (3×). The combined extracts were washed with brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-10% MeOH in DCM) afforded the title compound (6.98 g, 76%) as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 7.28 (m, 2H), 7.00 (m, 2H), 3.74 (s, 2H), 2.42 (d, J=6.8 Hz, 2H), 1.76 (m, 1H), 0.91 (d, J=6.6 Hz, 6H).