Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14](=[O:36])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[Cl:35])[CH2:16][CH:17]=O)C1C=CC=CC=1.[NH2:37][CH:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:47]([O:46][C:44]([N:41]1[CH2:42][CH2:43][CH:38]([N:37]2[CH2:17][CH2:16][C@@H:15]([CH2:19][C:20]3[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:22][C:21]=3[Cl:35])[C:14]2=[O:36])[CH2:39][CH2:40]1)=[O:45])([CH3:50])([CH3:48])[CH3:49]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=CC[C@@H](Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1
Yield: 58 %

Procedure:
Treat a solution of (R)-4-((R)-benzyl-2-oxo-oxazolidin-3-yl)-3-(4-benzyloxy-2,6-dichloro-benzyl)-4-oxo-butyraldehyde (Preparation 10) (4.0 g, 7.6 mmol) and 4-Amino-1N-Boc-piperidine (1.5 g, 7.6 mmol) in CH2Cl2 (100 mL) with acetic acid (0.4 mL, 7.6 mmol) and stir the reaction 1 hr at room temperature. Treat the reaction with sodium triacetoxyborohydride (3.2 g, 15 mmol) and stir overnight at room temperature. Quench the reaction with water and separate the organic layer. Wash the organic with brine, dry over MgSO4, filter, and remove the solvent. Purify the crude by silica gel column chromatography using Hexanes:EtOAc to elute the pure product. Remove the solvent to afford 2.35 g (58%) of desired product. MS (m/e): 555 (M+Na+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@@H:10]([NH:21][C@H:22]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])[C:11]([NH:13][C:14]3C=CC=CC=3O)=[O:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[C:31](N1C=CN=C1)(N1C=CN=C1)=S.[NH2+]1C2C=CC=CC=2N=N1.CNC>ClCCl.O1CCCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([NH:21][C@H:22]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH:24]([CH3:25])[CH3:26])[C:11]([N:13]([CH3:14])[CH3:31])=[O:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)[C@H](CC(C)C)N[C@@H](C(=O)Nc1ccccc1O)c1ccc2occc2c1
Agent: CNC
Agent: c1ccc2c(c1)N=N[NH2+]2
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)NC(C(=O)N(C)C)c1ccc2occc2c1
Reaction time: 18 h
Yield: 40.5 %

Procedure:
A solution of methyl N-{(1R)-1-(benzofuran-5-yl)-2-[(2-hydroxyphenyl)amino]-2-oxoethyl}-L-leucinate (410 mg) and 1,1′-thiocarbonyldiimidazole (196 mg) in dichloromethane (5 ml) was left to stand for 18 hours. Water (20 □l) was added to the reaction mixture and this was then stirred rapidly for 30 minutes. After this, 1H-Benzotriazolium, 1-[bis(dimethylamino)methylene]-, tetrafluoroborate(1-), 3-oxide (TBTU, 710 mg) and a solution of dimethylamine in tetrahydrofuran (3 ml of 2M solution) were added. The reaction mixture was stirred for a further 18 hours and was then passed down an SPE (5 g, silica) eluting with a gradient (3:1 to 1:2 cyclohexane:ethyl acetate). The required fractions were combined and evaporated to furnish methyl N-[1-(benzofuran-5-yl)-2-(dimethylamino)-2-oxoethyl]-L-leucinate (140 mg).
Reaction SMILES: CC1(C)N([O])C(C)(C)CCC1.[F:12][C:13]1[C:18]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:17][C:16]([CH2:23][OH:24])=[CH:15][C:14]=1[O:25][CH:26]([CH3:28])[CH3:27].Cl([O-])=[O:30].[Na+].Cl[O-].[Na+].[OH-].[Na+].S([O-])([O-])=O.[Na+].[Na+]>CC#N.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].O>[F:12][C:13]1[C:18]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:17][C:16]([C:23]([OH:30])=[O:24])=[CH:15][C:14]=1[O:25][CH:26]([CH3:28])[CH3:27]
Reactant: [O-][Cl+][O-]
Reactant: CC(C)Oc1cc(CO)cc(OC(C)C)c1F
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=P([O-])([O-])[O-]
Agent: O=S([O-])[O-]
Solvent: CC#N
Solvent: O
Product: CC(C)Oc1cc(C(=O)O)cc(OC(C)C)c1F
Yield: 12.3 %

Procedure:
TEMPO (12 mg, 79 μmol) was added to (4-fluoro-3,5-diisopropoxyphenyl)methanol (7) (382 mg, 1.58 mmol) in a mixture of MeCN (10 mL) and sodium phosphate buffer at 35° C. Sodium chlorite (285 mg, 3.15 mmol) in water (5 mL) and sodium hypochlorite (97 μl, 1.6 mmol) were added cautiously (portionwise, 20% of one then the other every 10 min until the addition was complete). Once the reaction was complete the mixture was basified to pH 9 by the addition of NaOH (15 mL). Sodium sulfite (aq., 20 mL) was added and the aqueous mixture was washed with diethyl ether (50 mL). The aqueous layer was acidified by the addition of 4M HCl and the product was extracted into EtOAc (50 mL). The organic solution was dried over MgSO4, filtered and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (12 g, 0-40% EtOAc in isohexane) to afford 4-fluoro-3,5-diisopropoxybenzoic acid (8) (50 mg, 12%) as a white solid: m/z 255 [M−H]− (ES−).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10]C)=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnc(Cl)cn1
Temperature: 25 °C
Yield: 72.6 %

Procedure:
A solution of methyl 5-chloro-2-pyrazinecarboxylate (Bio-Farma; 1.50 g, 8.69 mmol) in a mixture of methanol (16 ml) and water (8 ml) was stirred at room temperature and treated with potassium carbonate (1.201 g, 8.69 mmol). The resulting solution was stirred for 2 hrs and the methanol removed under reduced pressure. The residue was partitioned between ethyl acetate and water (20 ml) and the aqueous layer acidified by addition of 5M hydrochloric acid. Extraction (×2) with ethyl acetate and drying over MgSO4 followed by removal of the solvent under reduced pressure, gave the title compound (1.00 g) as a white solid;
Reaction SMILES: CO[C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:18]([C:19]([NH2:21])=[O:20])=[CH:17][N:16]=3)[CH2:10][CH2:9]2)=[CH:5][C:4]=1[O:30][CH2:31][CH2:32]C.Cl.Cl.COC(=O)C1C(C(F)(F)F)=CC(NC2CCNCC2)=NC=1.[Cl:57]C1C=CC(C=O)=CC=1OCC>>[Cl:57][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:18]([C:19]([NH2:21])=[O:20])=[CH:17][N:16]=3)[CH2:10][CH2:9]2)=[CH:5][C:4]=1[O:30][CH2:31][CH3:32]
Reactant: CCOc1cc(C=O)ccc1Cl
Reactant: CCCOc1cc(CN2CCC(Nc3cc(C(F)(F)F)c(C(N)=O)cn3)CC2)ccc1OC
Agent: COC(=O)c1cnc(NC2CCNCC2)cc1C(F)(F)F
Agent: Cl
Product: CCOc1cc(CN2CCC(Nc3cc(C(F)(F)F)c(C(N)=O)cn3)CC2)ccc1Cl

Procedure:
The title compound was prepared in analogy to the synthesis of 6-[1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinamide (example 197) from 6-(piperidin-4-ylamino)-4-trifluoromethyl-nicotinic acid methyl ester dihydrochloride (intermediate B7) and 4-chloro-3-ethoxy-benzaldehyde (intermediate E2) in a yield of 13.1 mg (19%). MS (ISP): 458.3 [M+H]+.
Reaction SMILES: Cl.C(N(CC)CC)C.[N-:9]=[N+:10]=[N-:11].[Na+].[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[CH:18][CH:17]=1)([O-:15])=[O:14].Cl>CN1CCCC1=O>[NH:9]1[C:23]([CH2:22][C:19]2[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=2)=[N:24][N:11]=[N:10]1
Reactant: N#CCc1ccc([N+](=O)[O-])cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cc2nnn[nH]2)cc1
Temperature: 150 °C

Procedure:
Triethylamine hydrochloride (41.25 g, 0.3 mol) and sodium azide (39 g, 0.6 mol) were added to a solution of 4-nitrophenylacetonitrile (32.4 g, 0.2 mmol) in anhydrous N-methylpyrrolidin-2-one (500 ml) and the mixture heated at 150° C. for 4h. The solution was cooled to room temperature and poured into 2N HCl (2 l) whereupon a solid crystallised out. The product was filtered, washed with water (500 ml) and hexane and dried in vacuo (37.4 g); δ (250 MHz, CDCl3) 4.34 (2H, s, CH2), 7.42 (2H, d, J=8.7 Hz, Ar--H), 8.12 (2H, d, J=8.7 Hz, Ar--H).
Reaction SMILES: C([C@H]1NC(C)(C)N(C)C1=O)C1C=CC=CC=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:27])(=O)=O)=CC=1.CC(C)=O.[Br:41][C:42]1[CH:43]=[C:44]([CH2:48][CH:49]=[O:50])[CH:45]=[CH:46][CH:47]=1>CCOCC.C(O)(C)C>[F:27][C@H:48]([C:44]1[CH:45]=[CH:46][CH:47]=[C:42]([Br:41])[CH:43]=1)[CH:49]=[O:50]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: O=CCc1cccc(Br)c1
Agent: CN1C(=O)[C@@H](Cc2ccccc2)NC1(C)C
Solvent: CC(C)O
Solvent: CCOCC
Solvent: CC(C)=O
Product: O=C[C@H](F)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A homogeneous mixture of (5R)-5-benzyl-2,2,3-trimethyl imidazolidin-4-one dichloroaccetic acid salt (97 mg, 0.4 mmol) and N-fluorobenzenesulfonimide (3.15 g, 10 mmol) in a 9:1 mixture of acetone and isopropanol at room temperature is treated with (3-bromophenyl)acetaldehyde (280 mg, 1.4 mmol), stirred for 1 h at room temperature, cooled to −78° C., diluted with ether, and filtered through a pad of celite. The filtercake is washed with additional ether. The combined filtrates are treated with methylsulfide (5 mL), washed with saturated NaHCO3 and brine, dried over MgSO4 and concentrated under reduced pressure to give (R)-2-fluro-2-(3-bromophenyl)acetaldehyde.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]#[N:7])[CH:3]=[C:2]1[C:8]#[N:9].[H-].[Na+].[NH2:12]OP(=O)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C=O)C>[NH2:12][N:1]1[CH:5]=[C:4]([C:6]#[N:7])[CH:3]=[C:2]1[C:8]#[N:9]
Reactant: N#Cc1c[nH]c(C#N)c1
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C#N)n(N)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.7 %

Procedure:
To a solution of DMF (100 mL) was added 1H-pyrrole-2,4-dicarbonitrile (1.00 g, 8.54 mmol) followed by NaH, 60% dispersion in mineral oil (0.51 g, 12.8 mmol). The solution was stirred at rt for 15 min and then (aminooxy)(diphenyl)phosphine oxide (2.99 g, 12.8 mmol) was added, and the solution was heated to 80° C. for 2 h. Upon cooling to rt the solution was filtered washing with CH2Cl2. The solution was partially concentrated and a white precipitate formed which was filtered. The mother liquor was then evaporated under vacuum and subsequently purified by MPLC (Isco) 100% CH2Cl2 ramping to 9:1 v/v CH2Cl2-EtOAc. The resulting purified fractions were combined and concentrated in vacuo yielding 0.92 g of a white solid (6.98 mmol, yield 82%). 1H-NMR (DMSO-d6) 7.92 (d, J=1.8 Hz, 1H), 7.39 (d, J=1.9 Hz, 1H), 6.66 (s, 2H); MS [M+H]+=133.0; LCMS RT=0.96 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:20]2[C:19]3[CH2:18][CH2:17][C@@:15]4([CH3:16])[C:11](=[CH:12][CH2:13][C@@H:14]4[O:21][C:22](=[O:24])[CH3:23])[C:10]=3[CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]([O:25][CH3:26])[CH:4]=1>[Pd].C([O-])([O-])=O.[Ca+2].C1COCC1>[CH3:1][O:2][C:3]1[C:20]2[C:19]3[CH2:18][CH2:17][C@@:15]4([CH3:16])[C@@H:11]([CH2:12][CH2:13][C@@H:14]4[O:21][C:22](=[O:24])[CH3:23])[C:10]=3[CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]([O:25][CH3:26])[CH:4]=1
Reactant: COc1cc2c(c(OC)c1)C1=C(CC2)C2=CC[C@H](OC(C)=O)[C@@]2(C)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Product: COc1cc2c(c(OC)c1)C1=C(CC2)[C@@H]2CC[C@H](OC(C)=O)[C@@]2(C)CC1

Procedure:
700 mg. pf rac.-1,3-dimethoxy-17β-acetoxy-1,3,5(10),8,14-estrapentaene in 10 ml. of distilled THF is hydrogenated over 200 mg. Pd/CaCO3 (5%) at room temperature and under normal pressure until 46.6 ml. of H2 has been absorbed. After the mixture has been filtered off from the catalyst, dried, and evaporated, 447 mg. of rac.-1,3-dimethoxy-17β-acetoxy-1,3,5(10),8-esratetraene is obtained from methanol, m.p. 111/112°-113° C.
Reaction SMILES: [BH4-].[Na+].C[O:4][C:5]([C:7]1[S:8][C:9]2[CH2:10][N:11]([C:16](=[O:24])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[CH2:12][CH2:13][C:14]=2[N:15]=1)=O>CO.O>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([N:11]1[CH2:12][CH2:13][C:14]2[N:15]=[C:7]([CH2:5][OH:4])[S:8][C:9]=2[CH2:10]1)=[O:24]
Reactant: COC(=O)c1nc2c(s1)CN(C(=O)c1ccccc1F)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(c1ccccc1F)N1CCc2nc(CO)sc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.9 %

Procedure:
Sodium borohydride (0.035 g, 0.94 mmol) was added to a stirred suspension of 5-(2-fluorobenzoyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-carboxylic acid methyl ester (0.25 g, 0.78 mmol) in MeOH (5 mL). The mixture was stirred at room temperature for 3 hours, diluted with H2O and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The crude product was purified by preparative TLC (AcOEt in petroleum ether 50/50) to yield 5-(2-fluorobenzoyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-methanol (0.18 g, 79% yield).
Reaction SMILES: BrC1C=C(C(Cl)=O)C=CC=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1)[NH2:15].[Br:34][C:35]1[CH:36]=[C:37]([C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:38]=[CH:39][CH:40]=1>C1(C)C=CC=CC=1.C(O)C>[Br:34][C:35]1[CH:36]=[C:37]([C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:38]=[CH:39][CH:40]=1.[Br:34][C:35]1[CH:36]=[C:37]([CH:38]=[CH:39][CH:40]=1)[C:41]([NH:43][C:44]([NH:15][C:14]1[CH:16]=[CH:17][C:18]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[C:12]([Cl:11])[CH:13]=1)=[S:45])=[O:42]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)c1cccc(Br)c1
Agent: O=C(N=C=S)c1cccc(Br)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(Br)c4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
3-Bromo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-bromo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-bromo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (81 mg, yield 93%).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH3:13])[C:7](=[O:12])[NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>CN(C=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH3:13])[C:7](=[O:12])[N:8]([CH2:24][C:23]3[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)[S:9](=[O:10])(=[O:11])[C:4]=2[CH:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CN1C(=O)NS(=O)(=O)c2cc(Br)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)N(C)c3ccc(Br)cc3S2(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 7-bromo-4-methyl-2H-benzo[e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide (510 mg, 1.7 mmol) in DMF (10 mL), 60% NaH (69 mg, 1.7 mmol) was added in portions at 0° C. The resulting mixture was stirred at rt for 10 min and p-methoxybenzyl chloride (0.25 mL, 1.7 mmol) was added. The resulting mixture was stirred at 70° C. for 5 h, cooled to rt and poured over ice. The resulting compound was extracted with EtOAc (3×20 mL). The combined EtOAc layers were dried over Na2SO4, filtered, and concentrated. The residue obtained was purified by flash column chromatography on silica gel (0-100% EtOAc/heptanes) to obtain compound 40a. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.01 (d, J=2.0 Hz, 1H), 7.74 (dd, J=8.8, 2.3 Hz, 1H), 7.40 (d, J=8.6 Hz, 2H), 7.10 (d, J=8.6 Hz, 1H), 6.83 (d, J=8.6 Hz, 2H), 4.99 (s, 2H), 3.77 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:4]=[C:5]2[CH:10]=[N:9][CH:8]=[CH:7][N:6]2[CH:11]=1>CO.[H][H].[Pd]>[F:12][C:2]([F:1])([F:13])[C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1
Reactant: [H][H]
Reactant: FC(F)(F)c1cn2ccncc2n1
Agent: [Pd]
Solvent: CO
Product: FC(F)(F)c1cn2c(n1)CNCC2
Yield: 93.7 %

Procedure:
2-(Trifluoromethyl)imidazo[1,2-a]pyrazine (1.63 g, 8.71 mmol) was dissolved in methanol (70 mL) and hydrogenated at RT under 1 atm hydrogen over 10% palladium on carbon paste (0.464 g, 0.436 mmol) for 16 h. The catalyst was filtered and the filtrate concentrated to an oil that solidified upon standing to a waxy solid 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (1.56 g, 8.16 mmol, 94% yield).
Reaction SMILES: [O:1]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C@H:2]1[O:10][C@H:9]([C:11]([O-:13])=[O:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[Na+]>O>[O:1]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C@H:2]1[O:10][C@H:9]([C:11]([OH:13])=[O:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: CCCCCCO[C@H]1O[C@H](C(=O)[O-])[C@H](O)[C@H](O)[C@H]1O
Agent: [Na+]
Solvent: O
Product: CCCCCCO[C@H]1O[C@H](C(=O)O)[C@H](O)[C@H](O)[C@H]1O
Yield: 95 %

Procedure:
100 g (0.33 mole) of sodium hexyl α-D-galactopyranoside uronate prepared according to Example 11 are solubilized in water (15% solution). After acidification to pH=2, concentrating under vacuum and selectively precipitating the salts in acetone, hexyl α-D-galactopyranoside uronic acid, whose physicochemical characteristics are indicated below, is recovered with a 95% yield:
Reaction SMILES: [F:1][C:2]1[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])=[CH:28][CH:27]=[C:26]([F:37])[C:3]=1[C:4]([NH:6]C1C=C2C(I)=NN(CC3C=CC(OC)=CC=3)C2=NC=1)=[O:5].C(N(CC)CC#C)C.C(N(CC)CC)C.C1COCC1>[Cl-].[Na+].O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:32])=[O:33])=[CH:28][CH:27]=[C:26]([F:37])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)c(I)nn3Cc2ccc(OC)cc2)c1F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C#CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(N)=O)c1F
Temperature: 50 °C
Yield: 264.9 %

Procedure:
2,6-Difluoro-N-(3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (100 mg, 0.156 mmol), N,N-diethylprop-2-yn-1-amine (19.1 mg, 0.172 mmol), triethylamine (212.6 μL 1.56 mmol), copper(I) iodide (1.19 mg, 0.00624 mmol) and THF (10 mL) were added to a 100 mL round-bottomed flask. Next, Pd(PPh3)4 (7.21 mg, 0.00624 mmol) was added under nitrogen. The mixture was heated to 50° C. for 24 hours. The mixture was cooled to room temperature and diluted with brine (50 mL). The mixture was extracted with EtOAc (50 mL), dried with sodium sulfate, filtered and concentrated to get N-(3-(3-(diethylamino)prop-1-ynyl)-1-(4-methoxybenzyl)-1H-pyrazolo[3, 4-1)]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (115 mg, 88%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][N:51]([C:54]([C:56]2[CH:61]=[CH:60][C:59](Br)=[CH:58][N:57]=2)=[O:55])[CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42].COC(=O)C1C=CC(Br)=CC=1>>[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][N:51]([C:54]([C:56]2[CH:61]=[CH:60][C:59]([N:27]3[C:17]4[N:18]=[C:19]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[N:20]=[C:15]([C:12]5[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]6[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=6)[CH2:30][C:31]6[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=6)=[N:14][CH:13]=5)[C:16]=4[CH2:29][CH2:28]3)=[CH:58][N:57]=2)=[O:55])[CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:42])[CH3:43]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Br)cn2)CC1
Agent: COC(=O)c1ccc(Br)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)nc3)cn2)cc1

Procedure:
From bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and 4-(5-bromo-pyridine-2-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (prepared in the same manner as Step A in Example 1-D-79, 76 mg), instead of 4-bromobenzoic acid methyl ester in Example 1-D-08, in the same manner as Example 1-D-08, a crude product of 4-[5-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridine-2-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester was obtained, and then the PMB groups and BOC group were removed according to the above Deprotection method 1, to obtain the desired compound (D-128) as a yellow solid (47 mg, 39%).
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:16][N:17]([CH:19](OC)OC)[CH3:18]>>[CH3:16][N:17]([CH3:19])[CH:18]=[CH:1][C:2]1[N:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cnc1C
Product: CCOC(=O)c1cc([N+](=O)[O-])cnc1C=CN(C)C

Procedure:
A solution containing 20.88 g of ethyl 2-methyl-5-nitronicotinate in 100 mL 1,1-dimethoxytrimethylamine is heated at reflux for three hours and 15 minutes. The mixture is cooled and the solid collected by filtration, washed with methanol and air dried to give 26 g of the desired enamine as a dark red solid mp 176°-179° C.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([NH:6][C:7]2[CH:19]=[C:18]([CH:20]=[CH2:21])[CH:17]=[CH:16][C:8]=2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.I[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32].C(N(CCCC)CCCC)CCC.F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.CN(C)C(=O)C>[F:1][C:2]1[CH:23]=[CH:22][C:5]([NH:6][C:7]2[CH:19]=[C:18](/[CH:20]=[CH:21]/[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])[CH:17]=[CH:16][C:8]=2[C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])=[CH:4][CH:3]=1
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(Nc2ccc(F)cc2)c1
Reactant: COc1ccccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CC(=O)N(C)C
Solvent: CCCCN(CCCC)CCCC
Solvent: CCOC(C)=O
Product: COc1ccccc1/C=C/c1ccc(C(=O)OC(C)(C)C)c(Nc2ccc(F)cc2)c1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
To N,N-dimethylacetamide 2.0 mL solution of tert-butyl 2-(4-fluoroanilino)-4-vinylbenzoate 0.10 g were added 2-iodoanisole 0.046 mL, tributylamine 0.15 mL, palladium acetate 4.0 mg and tri-tert-butylphosphine tetrafluoroborate 3.0 mg at room temperature, and it was stirred under nitrogen atmosphere at 110° C. for 1 hour and 30 minutes. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 10% citric acid aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=20:1] to give tert-butyl 2-(4-fluoroanilino)-4-((E)-2-(2-methoxyphenyl)vinyl)benzoate.