Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH:7]1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH:7]1[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:2]
Reactant: CCOC(=O)C=C1CCN(C(=O)OCC)CC1Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCN(C(=O)OCC)CC1Cc1ccccc1

Procedure:
A solution of 114 g of 1-ethoxycarbonyl-3-benzyl-4-piperidylidene-acetic acid ethyl ester in 120 cc of ethyl acetate is hydrogenated in the presence of 15 g of 10% palladium on charcoal at 11 atmospheres and at a temperature of 50° for 18 hours. After removing the catalyst, the solvent is evaporated at reduced pressure. The 1-ethoxycarbonyl-3-benzyl-4-piperidine-acetic acid ethyl ester (mixture of isomers) obtained as residue, is used for the next reaction step without purification.
Reaction SMILES: [CH2:1]([C:3]([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]2([OH:35])[CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:24]([CH3:36])[CH:23]=1)([C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[C:8]([CH3:21])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[CH3:37][O:38][C:39](=[O:48])[CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[C:45](Br)[CH:46]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[CH3:37][O:38][C:39](=[O:48])[CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[C:45]([C:9]2[CH:10]=[CH:11][C:6]([C:3]([CH2:4][CH3:5])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]4([OH:35])[CH2:31][CH2:32][CH2:33][CH2:34]4)=[C:24]([CH3:36])[CH:23]=3)[CH2:1][CH3:2])=[CH:7][C:8]=2[CH3:21])[CH:46]=1
Reactant: CCC(CC)(c1ccc(/C=C/C2(O)CCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)Cc1cncc(Br)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(/C=C/C2(O)CCCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Temperature: 140 °C
Yield: 80.1 %

Procedure:
A solution of 1-[(E)-2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-vinyl]-cyclopentanol (Example 33-(3); 0.05 g, 0.10 mmol), (5-bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 35.3 mg, 0.15 mmol), tetrakistriphenylphosphine palladium (16.5 mg, 0.0143 mmol) and potassium phosphate (32.6 mg, 0.15 mmol) in N,N-dimethylformamide (0.3 mL) was stirred with microwave heating at 140° C. for 10 minutes. The reaction mixture was filtered through cotton plug, and the mixture was purified by silica gel chromatography (40% ethyl acetate/hexane) to give the title compound (41.0 mg, 78%).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:11]([O:13][C:14](=[O:25])[CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH3:12].Br[CH2:27][C:28]1[C:29]([F:40])=[CH:30][N:31]=[C:32]2[C:37]=1[N:36]=[C:35]([O:38][CH3:39])[CH:34]=[CH:33]2.O>C1COCC1.CC(=O)OCC>[CH2:11]([O:13][C:14](=[O:25])[CH:15]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([O:38][CH3:39])[N:36]=2)[N:31]=[CH:30][C:29]=1[F:40])[CH3:12]
Reactant: CCOC(=O)CCNC(=O)OC(C)(C)C
Reactant: COc1ccc2ncc(F)c(CBr)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CNC(=O)OC(C)(C)C)Cc1c(F)cnc2ccc(OC)nc12
Reaction time: 1.5 h
Yield: 74.7 %

Procedure:
To a solution of LiHMDS (1M, 17 mL, 2.2 eq.), cooled to −78° C., was added dropwise a solution of 3-tert-butoxycarbonylamino-propionic acid ethyl ester (1.70 g, 7.82 mmol, prepared according to Tetrahedron Lett. (2003), 44, 2807-2811) in THF (20 mL). The solution was stirred at the same temperature for 90 min. A solution of 8-bromomethyl-7-fluoro-2-methoxy-[1,5]naphthyridine (2.12 g, 1 eq., prepared according to WO 2008/078305) in THF (10 mL) was quickly added and the reaction proceeded 2 h, keeping the internal temperature below −50° C. Water (100 mL) and EA (200 mL) were added. The two layers were decanted and the aq. layer was extracted with EA. The combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was chromatographed (Hept-EA 2-1) to afford the title intermediate as a yellow oil (2.38 g, 75% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]=1.[O:12]1CCOCC1>>[N:3]1[C:4]2[C:9](=[N:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[CH:1]=[O:12]
Reactant: Cc1ccc2ncccc2n1
Reactant: C1COCCO1
Product: O=Cc1ccc2ncccc2n1
Temperature: 25 °C

Procedure:
A mixture of 2-methyl-1,5-naphthyridine (8-2) (2.9 g, 20.1 mmol) and SeO2 (2.2 g, 20.1 mmol) in 40 mL of dioxane was refluxed for 3 h. After cooled to room temperature, the reaction mixture was concentrated. The residue was treated with brine and extracted with DCM/i-PrOH=4/1. The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by chromatography on silica gel to afford the title compound (1.81 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:17]([O:21][C:22](=[O:27])[NH:23][CH2:24][CH2:25]Br)([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+]>CN(C=O)C.C(O)(=O)C>[C:17]([O:21][C:22]([NH:23][CH2:24][CH2:25][O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:12])([F:13])([F:14])[F:15])[CH:10]=1)[C:5]([OH:7])=[O:6])=[O:27])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: O=C(O)c1cc(O)cc(S(F)(F)(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCOc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg (0.57 mmol) of the compound of Example 24A, 140 mg (0.63 mmol) of tert-butyl-(2-bromoethyl)carbamate and 388 mg (1.2 mmol) of caesium carbonate were initially charged in 1.5 ml of DMF and stirred at RT overnight. 1.7 ml of 1 M aqueous sodium hydroxide solution were then added, and the mixture was stirred at RT for another 1 h. The reaction mixture was then acidified slightly with concentrated acetic acid and purified directly by preparative HPLC (Method 18). This gave 63 mg (26% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:13])=[C:9](\[CH3:12])/[CH2:10][OH:11])=[CH:4][CH:3]=1.[CH2:14]([O:16][C@@H](CC1C=CC(O)=CC=1)C(OCC)=O)[CH3:15]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[CH3:13])=[C:9](/[CH3:12])\[C:10]([O:16][CH2:14][CH3:15])=[O:11])=[CH:6][CH:7]=1
Reactant: C/C(CO)=C(/C)c1ccc(Br)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)/C(C)=C(/C)c1ccc(Br)cc1
Yield: 141.6 %

Procedure:
The title compound (0.83 g, 87% yield) was prepared from (E)-3-(4-bromophenyl)-2-methyl -but-2-en-1-ol (0.50 g, 2.07 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.519 g, 2.18 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][N:11]=[C:10]([NH:13][C:14](=[O:39])[N:15]([CH2:24][CH2:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:46](OC(=O)C)(=[O:48])[CH3:47]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:27]1([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:25][CH2:24][N:15]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:14]([NH:13][C:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:46](=[O:48])[CH3:47])=[CH:7][CH:6]=3)[S:12][N:11]=2)=[O:39])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(-c2nc(NC(=O)N(CCc3ccccn3)CCC(c3ccccc3)c3ccccc3)ns2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(-c2nc(NC(=O)N(CCc3ccccn3)CCC(c3ccccc3)c3ccccc3)ns2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(5-(4-aminophenyl)-1,2,4-thiadiazol-3-yl)-1-(3,3-diphenylpropyl)-1-(2-(pyridin-2-yl)ethyl)urea (0.042 g, 0.079 mmol), prepared in the previous step, in DCM (1.5 mL) at 0° C. was added pyridine (50 μL, 49 mg, 0.62 mmol) and acetic anhydride (9.0 μL, 9.0 mg, 0.088 mmol). The reaction mixture was warmed to room temperature. After 1 h, additional acetic anhydride (10 μL) and a small amount of DMAP were added. Stirring was continued at room temperature. After 3 h, the reaction mixture was diluted with EtOAc, washed with saturated NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated. The crude reaction mixture was dissolved in DCM (˜2 mL) and diluted with ˜5 mL of hexanes. The precipitate was collected by filtration and dried under high vacuum to give N-(4-(3-(((3,3-diphenylpropyl)(2-(2-pyridinyl)ethyl)carbamoyl)amino)-1,2,4-thiadiazol-5-yl)phenyl)acetamide 158. Mass spectrum, calculated for C33H32N6O2S 576.2; found 577.2 (M++1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][C:20]=4Cl)[C:11]3=[O:22])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:23][N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]1.[OH-].[K+].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][C:20]=4[O:31][CH2:30][CH:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)[C:11]3=[O:22])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CN1CCC(CO)CC1
Reactant: O=C1N(c2ccc3ncsc3c2)CCN1c1cnccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN1CCC(COc2ccncc2N2CCN(c3ccc4ncsc4c3)C2=O)CC1
Yield: 5.2 %

Procedure:
1-Benzothiazol-6-yl-3-(4-chloro-pyridin-3-yl)-imidazolidin-2-one (I-180a: 150 mg, 0.4534 mmol) was reacted with (1-methyl-piperidin-4-yl)-methanol (88 mg, 0.6801 mmol), KOH (101 mg, 1.8138 mmol), K2CO3 (63 mg, 0.4534 mmol) and toluene (6 mL) to afford crude product. Purification by column chromatography on silica gel (10% MeOH in CHCl3), followed by preparative HPLC afforded 10 mg of the product (5% yield).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:3]=1[NH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7].[H][H]>CCOC(C)=O>[NH2:15][C:12]1[CH:13]=[CH:14][C:2]([F:1])=[C:3]([CH:11]=1)[NH:4][C:5](=[O:10])[C:6]([F:7])([F:8])[F:9]
Reactant: O=C(Nc1cc([N+](=O)[O-])ccc1F)C(F)(F)F
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: Nc1ccc(F)c(NC(=O)C(F)(F)F)c1
Reaction time: 4 h

Procedure:
A Schlenk-flask (250 mL) was evacuated and flushed with argon two times. Then 10% Pd/C (0.74 g, VWR International, oxidized form) and EtOAc (30 mL) were placed into it, and the flask was closed with a septum. The mixture was flushed with hydrogen and stirred vigorously to activate the catalyst. Then 32-NO2—H (5.14 g, 20.4 mmol) in 20 mL of EtOAc was added by syringe through a septum. (Addition was accompanied by the exothermic reaction). The solution was hydrogenated for 4 h at 20° C. Then hydrogen was replaced by argon and the mixture was filtered through Celite®. The filter-cake was washed with EtOAc (2×50 mL) and the solvent was evaporated in vacuo to yield the title compound as a brownish solid with m.p. 116-118° C.; yield—4.35 g (96%). 1H NMR (CDCl3, 300 MHz, ppm): δ=3.30 (br. s, 3H, NH2), 6.44 (ddd, 3JHH=8.8, 4JHF=4.1, 3JHH=2.8, 1H, H-4), 6.92 (dd, 3JHH=8.9, 3JHF=10.4, 1H, H-3), 7.63 (dd, 4JHH=2.8, 4JHF=6.4, 1H, H-6), 8.01 (s, 1H, NH); 13C NMR (75 MHz, CDCl3): δ=107.8 (s, C-4/6), 112.2 (d, 3JCF=7.1, C-6/4), 115.4 (q, 1JCF=289, CF3), 115.5 (d, 2JCF=28, C-3), 124.0 (d, 2JCF=11.2, C-1), 143.3 (s, C-5), 144.6 (d, 1JCF=236, C-2), 154.5 (q, 2JCF=37.5, CO); ESI-MS, negative mode: m/z (rel. int., %)=221 (100) [M−H]−; elemental analysis (%): C, 43.16; H, 2.85; N, 12.86 (found); C, 43.25; H, 2.72; N, 12.61 (calc.)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:28])[C@H:16]([CH:25]([CH3:27])[CH3:26])[NH:17]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:30]>O1CCOCC1>[ClH:30].[CH2:1]([O:8][C:9](=[O:29])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:28])[C@H:16]([CH:25]([CH3:27])[CH3:26])[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(tert-Butoxycarbonyl)-L-valyl-L-proline benzyl ester (20.0 g) was dissolved in 4N hydrogen chloride in dioxane (30 ml) under ice bath cooling. After being stirred at room temperature for one hour, the reaction mixture was evaporated under reduced pressure. The residue was pulverized with ether to give L-valyl-L-proline benzyl ester hydrochloride (14.56 g).
Reaction SMILES: [CH3:1][C@@H:2]([NH:13][CH2:14][C@@H:15]([C:17]1[CH:18]=[CH:19][C:20]2[N:21](N=N[N:25]=2)[CH:22]=1)[OH:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.O.O.Cl[Sn]Cl.[C:31]([OH:43])(=[O:42])[CH2:32][C:33]([CH2:38][C:39]([OH:41])=[O:40])([C:35]([OH:37])=[O:36])[OH:34]>CO.C(O)C>[C:31]([OH:43])(=[O:42])[CH2:32][C:33]([CH2:38][C:39]([OH:41])=[O:40])([C:35]([OH:37])=[O:36])[OH:34].[NH2:25][C:20]1[N:21]=[CH:22][C:17]([C@H:15]([CH2:14][NH:13][C@H:2]([CH3:1])[CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)[OH:16])=[CH:18][CH:19]=1
Reactant: C[C@H](Cc1c[nH]c2ccccc12)NC[C@H](O)c1ccc2nnnn2c1
Agent: Cl[Sn]Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCO
Solvent: O
Solvent: CO
Product: C[C@H](Cc1c[nH]c2ccccc12)NC[C@H](O)c1ccc(N)nc1
Reaction time: 1 h

Procedure:
A solution of 0.5 g of this tetrazole in 15 ml of methanol is treated with 0.6 g of SnCl2.2H2O for 5 hours at reflux under nitrogen. The reaction mixture is partially concentrated and then poured into a mixture of 25 ml of CH2Cl2 and 15 ml of 1N NaOH solution. The layers are separated and the aqueous layer further extracted with CH2Cl2. The combined organic phases are backwashed with saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Concentration of this solution and chromatography on silica gel affords the product which is dissolved in ethanol and treated with one equivalent of an ethanolic solution of citric acid. The mixture is aged for approximately one hour and the citrate salt is collected by filtration.
Reaction SMILES: C([O:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])=[CH:9][C:8]=1[N+:19]([O-:21])=[O:20])(C)(C)C.[ClH:23]>O1CCOCC1>[ClH:23].[CH3:17][N:16]([CH3:18])[CH2:15][CH2:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([OH:22])=[O:5])=[C:8]([N+:19]([O-:21])=[O:20])[CH:9]=1
Reactant: CN(C)CCOc1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)CCOc1ccc(C(=O)O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 4-(2-dimethylamino-ethoxy)-2-nitro-benzoic acid tert-butyl ester (4.53 g, 14.61 mmol) in dioxane (100 mL) was added 37% HCl (25 mL). The mixture was stirred at room temperature for 15 hours, then the suspension was evaporated and the solid dried under vacuum at 50° C. to give the title compound as yellowish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH:13]=2)=[C:4]([C@@H:21]([N:23]=[N+]=[N-])[CH3:22])[CH:3]=1>C(O)C.[Pt](=O)=O>[NH2:23][C@H:21]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH2:9]1)[CH3:22]
Reactant: C[C@H](N=[N+]=[N-])c1cc(Cl)ccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: O=[Pt]=O
Solvent: CCO
Product: C[C@H](N)c1cc(Cl)ccc1C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 15 h

Procedure:
A mixture of tert-butyl 4-{4-chloro-2-[(1S)-1-(azido)ethyl]phenyl}-3,6dihydropyridine-1-carboxylate (22.9 g, 63.1 mmol) and platinum (IV) oxide (1.08 g, 4.73 mmol) in ethanol/glacial acetic acid (1:1, 200 mL) was hydrogenated at atmospheric pressure for approximately 15 h. The resulting mixture was degassed via three vacuum/hydrogen ingress cycles to remove the liberated nitrogen and the hydrogenation was then continued for a further 24 h. The reaction mixture was filtered through a short column of celite®, the filtrate evaporated and the residue partitioned between methylene chloride and 1N sodium hydroxide. The organic phase was separated and the aqueous phase was re-extracted twice with methylene chloride. The combined organic extracts were washed with water, brine, dried (Na2SO4), and concentrated in vacuo to give crude (˜70% pure) title compound as a colorless foam.
Reaction SMILES: [CH3:1][Si:2]([CH3:38])([CH3:37])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]=O)[CH:9]=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.CC(O)=O.[BH3-]C#N.[Na+]>CCO>[O:42]1[CH2:43][CH2:44][N:39]([CH2:27][C:10]2[CH:9]=[C:8]([N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:37])[CH3:38])[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:35])([CH3:34])[CH3:36])[N:13]3[N:14]=[CH:15][C:16]([C:17]4[CH:18]=[N:19][C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[C:12]3[N:11]=2)[CH2:40][CH2:41]1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C=O)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(CN2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 107.4 %

Procedure:
To 7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidine-5-carbaldehyde (0.15 g, 0.3 mmol) in EtOH (10 mL) was added morpholine (0.12 mL, 1.4 mmol) and AcOH (0.2 mL), and the resulting mixture was stirred at room temperature for 15 minutes. NaBH3CN (0.12 g, 2.0 mmol) in EtOH (1.5 mL total) was then added and the reaction mixture was stirred at room temperature for 16 hours, at which time LC/MS analysis confirmed full consumption of starting material. Saturated NaHCO3 solution (˜20 mL) was added and the mixture was stirred for 30 minutes. The mixture was transferred to a separatory funnel with CH2Cl2 (30 mL) and H2O (10 mL) and brine (20 mL) was then added. Organics were extracted with CH2Cl2 (4×30 mL), dried (Na2SO4) and concentrated in vacuo to give crude 5-(morpholinomethyl)-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine as a brown oil (0.2 g). LCMS: 2.01 mins, m/z=621.3 (MH+).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[Cl:9][C:10]1[CH:11]=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:14][C:15]=1Cl>>[Cl:9][C:10]1[CH:11]=[C:12]([C:17]([F:18])([F:19])[F:20])[CH:13]=[CH:14][C:15]=1[O:7][C:6]1[CH:1]=[C:2]([CH3:8])[CH:3]=[CH:4][CH:5]=1
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Reactant: Cc1cccc(O)c1
Product: Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1

Procedure:
reacting the salt of m-cresol with 3,4-dichlorobenzotrifluoride to form a 3-(2-chloro-4-trifluoromethylphenoxy)toluene;
Reaction SMILES: C([Li])CCC.CN(C)CCNC.[CH3:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][CH:16]=1.[I:23]I.[Cl-].[Na+]>C1COCC1>[I:23][C:17]1[CH:16]=[C:15]([O:14][CH3:13])[N:20]=[CH:19][C:18]=1[CH:21]=[O:22]
Reactant: COc1ccc(C=O)cn1
Reactant: II
Agent: CNCCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(I)c(C=O)cn1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
At −78° C., 25.1 ml (40.1 mmol, 1.1 eq.) of n-butyllithium were added to a solution of 5.7 ml (43.8 mmol, 1.2 eq.) of N,N,N′-trimethylethylenediamine in 135 ml of THF, the mixture was stirred for 45 min and 5.0 g (36.5 mmol) of 6-methoxypyridine-3-carbaldehyde were added. After 45 min at −78° C., a further 45.6 ml (72.9 mmol, 2.0 eq.) of n-butyllithium were added, the reaction mixture was stirred for 1 h, allowing the temperature to rise to −40° C., the mixture was stirred at −40° C. for a further 1 h and then cooled back to −78° C., and a solution of 18.5 g (72.9 mmol) of iodine in 90 ml of THF was added over a period of 50 min. The temperature was maintained at −78° C. for a further 4 h and then slowly allowed to rise to RT overnight. The reaction mixture was poured into 300 ml of saturated aqueous sodium chloride solution and, after phase separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried (sodium sulphate), filtered and concentrated under reduced pressure. The residue was stirred with acetonitrile and filtered off, and the precipitate was dried under HV. Yield: 647 mg (purity 91%, 6% of theory)
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([CH2:13][OH:14])[CH2:11][S:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.FC(F)(F)C(O)=O.C1(N=C=NC2CCCCC2)CCCCC1>CS(C)=O.C(OCC)(=O)C>[O:15]=[C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:12]([CH:13]=[O:14])[CH2:11][S:10]1
Reactant: O=C1SC[C@@H](CO)N1Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: O=C[C@@H]1CSC(=O)N1Cc1ccccc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
In 45 ml of dimethylsulfoxide was dissolved 20 g of (4R)-3-benzyl-4-hydroxymethylthiazolidin-2-one under room temperature, 1.45 ml of pyridine, 1.38 ml of trifluoroacetic acid, and 30 ml of ethyl acetate were added to the solution in this order. At 25° C., 22.2 g of dicyclohexylcarbodiimide and 15 ml of ethyl acetate were added to the above mixture, and the resulting mixture was stirred at 50° C. for 3 hours. To the reaction mixture was added 100 ml of ethyl acetate, the mixture was stirred at 10° C. or lower for 30 minutes, and precipitated product was filtered off. The filtrate was washed with brine (saturated brine:water=1:1), and the aqueous layer was further extracted with ethyl acetate. The organic layers were combined, washed with brine (saturated brine:water=1:1), dried, and concentrated to obtain (4R)-2-oxo-3-benzylthiazolidin-4-carbaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH:13]=O)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:15][O:16][CH:17]([O:21][CH3:22])[CH2:18][NH:19][CH3:20].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][N:19]([CH3:20])[CH2:18][CH:17]([O:21][CH3:22])[O:16][CH3:15])=[CH:11][NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1c[nH]nc1-c1ccc(F)cc1
Reactant: CNCC(OC)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(CN(C)Cc1c[nH]nc1-c1ccc(F)cc1)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
A solution of 3-(4-fluorophenyl)-1H-pyrazole-4-carbaldehyde (3 g, 15.78 mmol, 1.00 equiv) and (2,2-dimethoxyethyl)(methyl)amine (2.3 g, 19.30 mmol, 1.22 equiv) in acetic acid (1.89 g, 31.47 mmol, 2.00 equiv) and 1,2-dichloroethane (30 mL) was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (10 g) was then added and the resulting solution was stirred at room temperature for 3 h. The resulting mixture was washed with 2×20 mL of 5% potassium carbonate solution and 2×20 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 3.29 g (71%) of N-((3-(4-fluorophenyl)-1H-pyrazol-4-yl)methyl)-2,2-dimethoxy-N-methylethanamine as a yellow oil. LCMS (method C, ESI): RT=0.63 min, m/z=294.0 [M+H]+.