Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:34])([F:33])[C:8]1[N:12]2[N:13]=[C:14]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:32]=[CH:31][C:26]([O:27][CH2:28][CH2:29][OH:30])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:30][CH2:29][CH2:28][O:27][C:26]1[CH:31]=[CH:32][C:23]([CH:20]2[CH2:21][CH2:22][N:17]([C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([C:7]([F:6])([F:33])[F:34])=[N:9][N:10]=4)[N:13]=3)[CH2:18][CH2:19]2)=[CH:24][CH:25]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
A solution of methanesulfonyl chloride (20.37 mL, 262.16 mmol) in DCM (300 mL) was is added to 2-(4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethanol (89 g, 218.46 mmol) and triethylamine (60.9 mL, 436.93 mmol) in DCM (900 mL) at 0° C. over a period of 30 minutes under nitrogen. The resulting solution was stirred at 0° C. for 1 hour. The reaction mixture was diluted with DCM (1 L), and washed with water (2 L). The organic layer was dried over MgSO4, filtered and evaporated to afford 2-(4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl methanesulfonate (104 g, 98%) as a solid.
Reaction SMILES: [C:1]([C:3]1[C:8]([NH:9][C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=2)=[CH:7][C:6]([NH:21][C@@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]2[NH:28]C(=O)OC(C)(C)C)=[C:5]([F:36])[CH:4]=1)#[N:2]>C(O)(C(F)(F)F)=O>[NH2:28][C@H:23]1[CH2:24][CH2:25][CH2:26][CH2:27][C@H:22]1[NH:21][C:6]1[C:5]([F:36])=[CH:4][C:3]([C:1]#[N:2])=[C:8]([NH:9][C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Nc2cc(-c3ccccc3)no2)c(C#N)cc1F
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(F)c(N[C@@H]2CCCC[C@@H]2N)cc1Nc1cc(-c2ccccc2)no1
Reaction time: 0.33 h
Yield: 160.8 %

Procedure:
The compound tert-butyl (1S,2R)-2-(4-cyano-2-fluoro-5-(3-phenylisoxazol-5-ylamino)phenylamino)cyclohexylcarbamate (40 mg, 0.081 mmol) was dissolved in TFA (1.0 mL). After 20 min, TFA was removed in vacuo to give 4-((1R,2S)-2-aminocyclohexylamino)-5-fluoro-2-(3-phenylisoxazol-5-ylamino)benzonitrile (51 mg).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][C:12]([OH:14])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.Cl.[NH2:29][CH:30]1[CH:35]2[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]2)[CH2:31]1.C(N(CC)CC)C>C1COCC1.[Cl-].[Na+].O>[N:32]12[CH2:37][CH2:36][CH:35]([CH2:34][CH2:33]1)[CH:30]([NH:29][C:12](=[O:14])[CH2:11][C:3]1[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:31]2
Reactant: Cn1c(CC(=O)O)cc2ccccc21
Reactant: NC1CN2CCC1CC2
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1c(CC(=O)NC2CN3CCC2CC3)cc2ccccc21
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of 1-methyl-1H-indole-2-acetic acid (830 mg) in THF (20 ml) was added 1,1'-carbonyldiimidazole (782 mg), and the mixture was stirred for 1 h. 3-Aminoquinuclidine dihydrochloride (960 mg) was then added, followed by triethylamine (2.34 g), and the mixture was stirred overnight at room temperature. The mixture was then poured into brine (200 ml) and extracted with ethyl acetate (2x200 ml). The combined, dried organic extracts were evaporated in vacuo to give a solid which was purified by FCC eluting with System A (50:8:1) to give the title compound (1.30 g), m.p. 185-187°.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH2:31])[CH3:27].Cl>C1COCC1>[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH:31][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:27]
Reactant: O=C(O)CCCCc1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)CCCCc1ccccc1

Procedure:
5-Phenylvaleric acid (2.67 g, 15 mmol) in distilled THF was reacted with CDI (15 mmol) followed by glycine ethyl ester.HCl (15 mmol) and C2H5)3N (15 mmol) as described in Example 56 Part A. The crude material (3.25 g, 82%) was used without purification.
Reaction SMILES: [C:1]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][C:10]([OH:12])=O)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(OCCCC)(=O)C.C(OC(=O)C)(=O)C.C([O-])(=O)C.[Mg+2].C([O-])(=O)C>C(O)(=O)C>[C:1]([NH:7][C@@H:8]1[C:13](=[O:14])[O:15][C:10](=[O:12])[CH2:9]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(=O)CC(=O)N[C@@H](CC(=O)O)C(=O)O
Agent: CC(=O)[O-]
Agent: [Mg+2]
Solvent: CC(=O)OC(C)=O
Solvent: CCCCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)CC(=O)N[C@H]1CC(=O)OC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-acetoacetyl-L-aspartic acid, 21.7 parts, was mixed with 30 parts by volume of n-butyl acetate and 10.7 parts acetic anhydride. A solution of 0.20 parts anhydrous magnesium acetate in 2.0 parts by volume of glacial acetic acid was added and the slurry was stirred for 30 minutes at 25° C. The mixture was stirred for 2.5 hours at 40°-50° C. and then was cooled to 25° C. The solid was collected on a filter under nitrogen, it was rinsed with n-butyl acetate, and then was dried at 0.1 mm to afford 19.3 parts N-acetoacetyl-L-aspartic anhydride.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]2[N:28]=[C:27]3[C:23]([N:24]=[CH:25][N:26]3[C@@H:29]3[CH2:33][C@H:32]([NH:34][C:35](=[O:38])[CH2:36][CH3:37])[C@@H:31]([OH:39])[C@H:30]3[OH:40])=[C:22]([NH:41][CH2:42][CH:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:21]=2)[CH2:16]1)(C)(C)C.CO>Cl>[NH2:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]2[N:28]=[C:27]3[C:23]([N:24]=[CH:25][N:26]3[C@@H:29]3[CH2:33][C@H:32]([NH:34][C:35](=[O:38])[CH2:36][CH3:37])[C@@H:31]([OH:39])[C@H:30]3[OH:40])=[C:22]([NH:41][CH2:42][CH:43]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[N:21]=2)[CH2:16]1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)OC(C)(C)C)C4)nc32)[C@H](O)[C@@H]1O
Agent: Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{(R)-1-[9-((1R,2S,3R,4S)-2,3-Dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester trifluoroacetate (3.22 g, 4.80 mmol) is dissolved in 1.25 M HCl in MeOH (60 ml, 75 mmol) and left to stir at room temperature overnight. The solvent is removed in vacuo and the crude product is dissolved in a minimal volume of EtOH/saturated sodium carbonate solution and purified by reverse phase column chromatography (Isolute™ C18, 0-100% MeOH in water) to yield the title product.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:27]=[C:28]([NH2:32])[CH:29]=[C:30]([CH3:31])[C:6]=2[N:5]=1)[CH2:2][CH3:3]>C(O)(C)C>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:27]=[C:28]([NH:32][C:6](=[N:5][C:4]#[N:8])[CH:30]([CH3:31])[CH3:29])[CH:29]=[C:30]([CH3:31])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(N)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Solvent: CC(C)O
Product: CCCc1nc2c(C)cc(NC(=NC#N)C(C)C)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 1c from 4'-[(2-n-propyl-4-methyl-6-amino-1H-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol -5-yl)-biphenyl and (1-methyl-ethyl)-(methylmercapto)-methylene-imino-nitrile in isopropanol.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([NH:17][C:18]([C:20]1[N:24]2[CH:25]=[CH:26][CH:27]=[C:28]([OH:29])[C:23]2=[N:22][C:21]=1[CH3:30])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:31]1([CH2:36]O)[CH2:35][CH2:34][CH2:33][CH2:32]1.C(P(=CC#N)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Si:1]([O:8][CH2:9][C@H:10]([NH:17][C:18]([C:20]1[N:24]2[CH:25]=[CH:26][CH:27]=[C:28]([O:29][CH2:36][CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[C:23]2=[N:22][C:21]=1[CH3:30])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1nc2c(O)cccn2c1C(=O)N[C@@H](CO[Si](C)(C)C(C)(C)C)c1ccccc1
Reactant: OCC1CCCC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cc1nc2c(OCC3CCCC3)cccn2c1C(=O)N[C@@H](CO[Si](C)(C)C(C)(C)C)c1ccccc1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
A mixture of 120 mg of N-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-phenylethyl]-8-hydroxy-2-methylimidazo[1,2-a]pyridine-3-carboxamide, 60 μl of cyclopentylmethanol, 156 μl of (tributylphosphoranylidene)acetonitrile, and 2.4 ml of toluene was stirred at 110° C. for 16 hours, followed by purification using silica gel chromatography, to obtain 100 mg of N-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-phenylethyl]-8-(cyclopentylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[O:6][C:7]([F:10])([F:9])[O:8][C:4]=2[CH:3]=1.C(O[B:17]1[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]1)(C)C>O1CCCC1>[F:9][C:7]1([F:10])[O:6][C:5]2[CH:11]=[CH:12][C:2]([B:17]3[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]3)=[CH:3][C:4]=2[O:8]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: FC1(F)Oc2ccc(Br)cc2O1
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc3c(c2)OC(F)(F)O3)OC1(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To an oven-dried three-necked round bottom flask under nitrogen was added 5-bromo-2,2-difluorobenzo[d][1,3]dioxole (2.516 g, 10.6 mmol) and anhydrous tetrahydrofuran (26 mL). The solution was cooled to 0° C. Isopropylmagnesium chloride-lithium chloride complex (1.3 M; 10 mL, 13.0 mmol) was added slowly and stirred for 1 h. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.2 mL, 10.62 mmol) was added, and the reaction mixture was stirred for 1 h. The reaction was quenched with saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. The solution was filtered and concentrated to provide 2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a yellow oil (2.54 g, 84%): 1H NMR (400 MHz, CDCl3) δ 7.56 (dd, J=8.0, 1.0 Hz, 1H), 7.47 (d, J=0.6 Hz, 1H), 7.06 (dd, J=7.9, 0.4 Hz, 1H), 1.34 (s, 12H); 19F NMR (376 MHz, CDCl3) δ −50.18; EIMS m/z 284.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1([CH3:24])[C:8]([CH3:10])([CH3:9])[O:7][B:6]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[O:5]1>CO>[CH3:9][C:8]1([CH3:10])[C:4]([CH3:3])([CH3:24])[O:5][B:6]([C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[CH:15][CH:16]=2)[O:7]1
Reactant: CC1(C)OB(c2ccc(N3CCC(=O)CC3)cc2)OC1(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)OB(c2ccc(N3CCC(O)CC3)cc2)OC1(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium tetrahydroborate (0.012 g, 0.33 mmol) was added to a mixture of 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidin-4-one (0.050 g, 0.17 mmol, from Combi-Blocks) in methanol (1.0 mL) at 0° C. and then the reaction was stirred at 0° C. for 1 hour. The solvent was removed and the residue was treated with water and then filtered. The residue was dried to provide the desired product as a white solid. LCMS calculated for C17H27BNO3 (M+H)+: m/z=304.2. Found 304.1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[O:9][C:10]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][C:12](=[O:14])[CH:13]=1.[C:21]([O:25][C:26]([N:28]1[C:41]2[CH:40]=[CH:39][CH:38]=[C:37](B3OC(C)(C)C(C)(C)O3)[C:36]=2[S:35][C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:27])([CH3:24])([CH3:23])[CH3:22]>O1CCOCC1>[C:21]([O:25][C:26]([N:28]1[C:29]2[CH:30]=[CH:31][CH:32]=[C:33]([C:8]3[O:9][C:10]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:11][C:12](=[O:14])[CH:13]=3)[C:34]=2[S:35][C:36]2[C:41]1=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1c2ccccc2Sc2c(B3OC(C)(C)C(C)(C)O3)cccc21
Reactant: O=c1cc(Cl)oc(N2CCOCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1c2ccccc2Sc2c(-c3cc(=O)cc(N4CCOCC4)o3)cccc21
Temperature: 100 °C
Yield: 100.1 %

Procedure:
Powdered potassium carbonate (2.03 g, 14.68 mmol) and 2-chloro-6-morpholin-4-yl-pyran-4-one (3) (1.44 g, 6.70 mmol) were added to a stirred solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenothiazine-10-carboxylic acid tert-butyl ester (2.85 g, 6.70 mmol) in anhydrous dioxane (20 ml) and the mixture degassed (sonication for 20 minutes then saturated with N2) thoroughly. Tetrakis (triphenylphosphine) palladium was then added in a single portion and the mixture degassed (sonication for 20 minutes then saturated with N2) once again before a reflux condenser was attached and the mixture heated to 100° C. under a nitrogen atmosphere for 20 hours. Water (30 ml) was added and the mixture extracted with EtOAc (3×30 ml). The organic extracts were then dried using MgSO4, filtered and concentrated in vacuo to yield a dark brown, crystalline solid (3.21 g, 100%) that was taken forward with no further purification. m/z (LC-MS, ESP): 479 [M+H]+, RT=4.55 mins.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([C:20]#[N:21])=[CH:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCO.[H][H]>[Pd].C(O)(=O)C>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([C:20]#[N:21])[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC1=CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: N#CC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Yield: 90.1 %

Procedure:
6-Benzenesulfonyl-3,4-dihydro-naphthalene-1-carbonitrile (5.1 g, 17.2 mmol), 70 mL EtOH, and 50 mL acetic acid were placed in a Parr vessel, and 1.0 g of 10% Palladium on carbon (Fluka Chemica Co.) was added. The reaction mixture was shaken for 15 hours under 55 psi hydrogen. The Parr vessel was purged with nitrogen and the reaction mixture was filtered. The filtrate was added to 500 mL water, and the aqueous mixture was extracted twice with 200 mL of EtOAc. The combined organic layers were dried (MgSO4) and evaporated to yield 4.6 g (15.5 mmol, 90%) of 6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalene-1-carbonitrile as an oil. MS: 298 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].O.[NH4+].[N+]([O-])([O-])=O.[Ce+3:14].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>>[OH2:3].[C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[Ce:14]
Reactant: [Ce+3]
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)CC(C)=O
Product: [Ce]

Procedure:
In an Erlenmeyer flask of 1 liter capacity, 6.51 grams of cerium nitrate and 4.5 grams of acetylacetone are dissolved in 300 ml. of distilled water. A 2% ammonium solution is added in drops, shaking vigorously, until a pH value of exactly 8.0 is achieved. This results in a light yellow precipitate of cerium acetylacetone-monohydrate, identified by the formula Ce(CH3COCHCOCH3)3. H2 0 which is suctioned off by a Buechner funnel and rinsed with 300 ml. of distilled water. The precipitate is dried under high vacuum without heating until a dust-like or pulverulent product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].C(Cl)(=O)C([Cl:24])=O>ClCCl.CN(C)C=O>[Cl:24][C:16]([C:15]1[CH:19]=[CH:20][C:12]([O:11][C@@H:8]2[CH2:9][CH2:10][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7]2)=[CH:13][CH:14]=1)=[O:17]
Reactant: COC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)O)cc2)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)Cl)cc2)CC1
Temperature: 25 °C

Procedure:
0.4 g of cis-4-(4-methoxycarbonylcyclohexyloxy)benzoic acid is placed in 10 mL of dichloromethane with stirring, at room temperature, under a nitrogen atmosphere. 0.18 mL of oxalyl chloride (2.16 mmol, 1.5 eq.) and 2 drops of dimethylformamide are successively added. The reaction medium is stirred for 2 hours and concentrated under vacuum. The methyl cis-4-(4-chlorocarbonylphenoxy)cyclohexanecarboxylate formed is dissolved in 15 mL of acetonitrile and placed under nitrogen. The mixture is cooled in an ice bath and 0.210 g of potassium thiocyanate (2.16 mmol, 1.5 eq.) is added. The reaction mixture is stirred at room temperature for 1 hour 30 minutes. 0.455 g of cyclopentyloxyacetic acid hydrazide (2.87 mmol, 2 eq.) dissolved in 5 mL of acetonitrile is then added to the methyl cis-4-(4-isothiocyanatocarbonylphenoxy)cyclohexanecarboxylate obtained and the mixture is refluxed for 2 hours 30 minutes and then left to stand at room temperature for 36 hours. The precipitate formed is filtered off and washed with acetonitrile. 0.450 g of methyl cis-4-[4-(5-cyclopentyloxymethyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenoxy]cyclohexanecarboxylate is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29].[NH2:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:30][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29]
Reactant: Nc1ccncc1
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1ccccc1)C(=O)N(c1c(Cl)cccc1Cl)C2
Solvent: ClCCl
Product: O=C1N(c2c(Cl)cccc2Cl)Cc2cnc(Nc3ccncc3)nc2N1c1ccccc1
Yield: 15.7 %

Procedure:
A solution of 100 mg (0.22 mmol) of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-1-phenyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 200 mg (2.12 mmol) of 4-aminopyridine in 2 ml of dichloromethane was stirred at room temperature overnight. The mixture was evaporated and the residue was purified by flash column chromatography on silica gel using 10% methanol/dichloromethane for the elution. Product containing fractions were combined and evaporated to give 16 mg (15%) of 3-(2,6-dichlorophenyl)-3,4-dihydro-1-phenyl-7-[(4-pyridyl)amino]pyrimido[4,5-d]pyrimidin-2(1H)-one as an off-white solid which decomposed at 289° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]=[N+]=[N-])=[C:6]([O:14][CH3:15])[CH:5]=1>[Pd].C(O)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[C:6]([O:14][CH3:15])[CH:5]=1
Reactant: COC(=O)c1ccc(CN=[N+]=[N-])c(OC)c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(CN)c(OC)c1
Yield: 80.5 %

Procedure:
Hydrogenate a mixture of 4-azidomethyl-3-methoxy-benzoic acid methyl ester (4.1 g, 18.5 mmol) and palladium on carbon (4.9 g, 4.63 mmol) in ethanol (200 mL) under a hydrogen atmosphere at 345 KPa for 24 hrs at room temperature. Filter the reaction mixture through diatomaceous earth and concentrate the filtrate to provide the crude title compound (2.9 g, 14.9 mmol). MS (m/z): 196 (M+1). Use it as is in next step.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9](=O)[C@@H:10]([C:22]2([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)[CH2:3]1.B.C1COCC1.Cl>C1COCC1>[CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C@@H:10]([C:22]2([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)[CH2:3]1
Reactant: CC1CN(C(=O)[C@H](c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)CC(C)N1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: C[C@@H]1CN(C[C@H](c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)C[C@H](C)N1
Temperature: 25 °C
Yield: 61.2 %

Procedure:
To solution of 1-(3,5-Dimethyl-piperazin-1-yl)-2-(R)-(1-hydroxy-cyclohexyl)-2-(3-trifluoromethoxy-phenyl)-ethanone (24.7 g, 59.6 mmol) in THF (140 mL) was added BH3.THF (300 mL, 1M, 300 mmol). The resultant mixture was heated to reflux for 22 h. On a smaller scale this reaction only takes about 2 h. After cooling down, 2N aqueous HCl (500 mL) was added to the mixture. After heating to reflux for 1 h, the mixture was allowed to cool down to RT and extracted with ethyl acetate (300 mL). The aqueous phase was basified with 50% NaOH to PH=12 and extracted with ethyl acetate (400 mL×4). The organic extracts were dried over Na2SO4 and concentrated in vacuo to provide crude 1-{(1S)-2-[cis-3,5-dimethylpiperazine-1-yl]-1-[3-(trifluoromethoxy)phenyl]ethyl}-cyclohexanol (14.6 g, 61%).
Reaction SMILES: [Mg].[CH2:2](Br)[C:3]#[CH:4].[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C@@H:15]([O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH:16]=[O:17])=[O:12])([CH3:9])([CH3:8])[CH3:7].[NH4+].[Cl-]>CCOCC.C(Br)C#C.C1(C)C=CC=CC=1.Cl[Hg]Cl>[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:29][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1)[C@@H:15]([O:18][Si:19]([CH:20]([CH3:21])[CH3:22])([CH:23]([CH3:24])[CH3:25])[CH:26]([CH3:27])[CH3:28])[CH:16]([OH:17])[CH2:4][C:3]#[CH:2])=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: C#CCBr
Reactant: CC(C)[Si](O[C@@H](C=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Agent: Cl[Hg]Cl
Agent: [Cl-]
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C#CCC(O)[C@H](O[Si](C(C)C)(C(C)C)C(C)C)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 10 °C
Reaction time: 0.75 h
Yield: 66.5 %

Procedure:
To a solution of magnesium metal (16.4 mmol) and HgCl2 (0.03 g) in Et2O (4 mL) in a flask at room temperature was added several drops of 80% propargyl bromide (16.4 mmol) solution in toluene (1.82 mL) contained in an addition funnel. The mixture turned cloudy. Ether (10 mL) was then added to both the flask and to the propargyl bromide solution in the addition funnel. The funnel solution was added dropwise to the reaction mixture which was cooled to 10° C. The white opaque mixture was stirred for 45 minutes at room temperature after the addition was completed. A solution of the title aldehyde of Step 4 (4.64 mmol) in Et2O (10 mL) was added dropwise to the flask at room temperature. After 2 h at room temperature, the mixture was cooled down to 0° C. and a saturated NH4Cl solution (25 mL) was added. The Et2O layer was collected and the aqueous layer was extracted with Et2O (10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL) and then dried over MgSO4. After evaporation, the residue (a clear, yellow liquid) was purified by medium column chromatography (10% EtOAc in hexane) to give the title alkyne (1.49 g, 66.5% yield). The 1H, 13C and APT NMR spectral data were consistent for the proposed structure.