Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.[N:15]1([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:28]=[C:29]([O:36][C@@H:37]([C@H:39]4[CH2:43][NH:42][C:41](=[O:44])[CH2:40]4)[CH3:38])[C:30]4[N:31]([N:33]=[CH:34][CH:35]=4)[CH:32]=3)=[CH:23][CH:22]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)CC)C>ClCCl>[C:1]([N:18]1[CH2:17][CH2:16][N:15]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[N:28]=[C:29]([O:36][C@@H:37]([C@H:39]4[CH2:43][NH:42][C:41](=[O:44])[CH2:40]4)[CH3:38])[C:30]4[N:31]([N:33]=[CH:34][CH:35]=4)[CH:32]=3)=[CH:25][CH:26]=2)[CH2:20][CH2:19]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)cc2)cn2nccc12)[C@H]1CNC(=O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCN(c2ccc(-c3cn4nccc4c(O[C@H](C)[C@H]4CNC(=O)C4)n3)cc2)CC1
Reaction time: 1.5 h
Yield: 95.3 %

Procedure:
Acetic anhydride (5 μl, 0.05 mmol) was added to a solution of (R)-4-((R)-1-(6-(4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrazin-4-yloxy)ethyl)pyrrolidin-2-one 2,2,2-trifluoroacetate 5.44 (22.38 mg, 0.04 mmol) and triethylamine (0.05 mL, 0.33 mmol) in dichloromethane (1.8 mL) at room temperature. After 90 min, reaction mixture was loaded directly onto silica gel and purified (0-8% methanol/dichloromethane) to yield (R)-4-((R)-1-((6-(4-(4-acetylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)ethyl)pyrrolidin-2-one 5.45 (17.1 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]1.[NH2:22][C:23]1[C:24]([C:30](O)=[O:31])=[N:25][C:26]([Br:29])=[CH:27][N:28]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[NH2:22][C:23]1[C:24]([C:30]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:9]2)=[O:31])=[N:25][C:26]([Br:29])=[CH:27][N:28]=1
Reactant: Nc1ncc(Br)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2ccncc2N)C1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCCN(c2ccncc2NC(=O)c2nc(Br)cnc2N)C1
Reaction time: 60 h

Procedure:
A solution containing 1 eq each of tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate, 3-amino-6-bromopyrazine-2-carboxylic acid, HOAT and EDC in DMF, at a concentration of 0.5 M, was stirred for 60 hours. The solution was diluted with EtOAc and was washed with H2O (4×), NaCl(sat.), was dried over MgSO4, was filtered and the volatiles were removed in vacuo. After purification by silica gel chromatography (EtOAc eluant), tert-butyl 1-(3-(3-amino-6-bromopyrazine-2-carboxamido)pyridin-4-yl)piperidin-3-ylcarbamate was obtained (78%). LCMS (m/z): 492.2 (MH+); LC Rt=2.68 min.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH2:17])[C:15](=[O:18])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].[CH:19](O)=[O:20].C(OCC)(=O)C>C(OC(=O)C)(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][CH:19]=[O:20])[C:15](=[O:18])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: O=CO
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC=O)[C@H]2SC1

Procedure:
3-Acetoxymethyl-7β-aminoceph-3-em-4-carboxylic acid (50.0 g) was dissolved in acetic anhydride (75 ml.) and formic acid (400 ml.) with stirring at 20° C. When complete solution was obtained (~ 5 min.) the solvents were evaporated (rotary evaporator, oil-pump), leaving a gum which was shaken with ethyl acetate (250 ml.). The insoluble material was removed by filtration and the filtrate was evaporated to dryness leaving a gum which was triturated under ether and petroleum-ether (b.p. 40°-60°), giving 3-acetoxymethyl-7β-formamidoceph-3-em-4-carboxylic acid as a pale yellow powder (43.6 g.), TLC RF 0.19, [α]D20 + 113.5° (c 1.00, dioxan), λ max (pH6 buffer) 259 nm. (ε 8,400), νmax (Nujol) 1772 (β-lactam) 1748 (acetate), 1708 (carboxylic acid), 1654, 1548 cm.-1 (amide), τ (D2O with NaHCO3)1.67 (0.9-proton singlet: CHO), 1.75 (0.1-proton singlet: CHO), 4.20 (1-proton doublet, J 4.5 Hz.: C-7 H), 4.80 (1-proton doublet, J4.5 Hz.: C-6 H), 5.00, 5.26 [two 1-proton doublets (branches of a quartet), J 13 Hz: C-3 CH2 ], 6.24 6.64 [two 1-proton doublets (branches of a quartet), J 18 Hz.: C-2 H2 ] 7.86 (3-proton singlet: CH3CO) (there is evidence for "cis" and "trans" forms in the secondary amide part).
Reaction SMILES: C1(C(=[N:14][C:15]([CH3:21])([CH2:18][CH2:19][F:20])[C:16]#[N:17])C2C=CC=CC=2)C=CC=CC=1.[ClH:22]>O1CCCC1.O>[ClH:22].[NH2:14][C:15]([CH3:21])([CH2:18][CH2:19][F:20])[C:16]#[N:17]
Reactant: CC(C#N)(CCF)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(N)(C#N)CCF
Temperature: 25 °C
Reaction time: 8 h

Procedure:
17.45 g (50.45 mmol; 81% purity) of rac-2-[(diphenylmethylene)amino]-4-fluoro-2-methylbutanonitrile from Example 69A were dissolved in 235.6 ml of tetrahydrofuran and 9.1 ml of water, 111 ml (55.46 mmol) of hydrogen chloride solution (0.5 N in diethyl ether) were added and the mixture was stirred at room temperature overnight. The slightly turbid reaction solution was admixed with 25.21 ml (50.42 mmol) of hydrogen chloride solution (2 N in diethyl ether) and concentrated by rotary evaporation. The isolated crude product was reacted further directly without further purification.
Reaction SMILES: [NH2:1][C@@H:2]([CH:6]1[CH2:10][CH2:9]CC1)[C:3]([OH:5])=[O:4].[OH-].[Na+].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BH4-].[Na+]>O>[CH2:13]([NH:1][C@@H:2]([CH:6]1[CH2:10][CH2:9]1)[C:3]([OH:5])=[O:4])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@H](C(=O)O)C1CCCC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)[C@@H](NCc1ccccc1)C1CC1
Yield: 69.9 %

Procedure:
(S)-2-amino-2-cyclopentylacetic acid (1) (66.0, 0.46 mol, 1.0 eq) was added in portions into 2N NaOH (230 mL, 0.46 mol, 1.0 eq) with stirring. After complete dissolution of the amino acid, benzaldehyde (49.0 g, 0.46 mol, 1.0 eq) was added all at once. The reaction mixture was allowed to stir at room temperature for 1 h. Sodium borohydride (17.5 g, 0.46 mol, 1.0 eq) was added slowly in portions at 0° C., and the reaction mixture was stirred at room temperature for 4 h. Then the reaction mixture was diluted with water (250 mL) and extracted twice with diethyl ether (250 mL). The clear aqueous layer was neutralized with 4N HCl (aq) to pH=7 and the white suspension were stirred at rt for 0.5 h. After filtration, the solid was washed with water (250 mL), the filter cake was dried to yield the product 2 (66 g, 59%) as a white solid.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([O-])(C)C.[K+].[CH3:27][O:28][C:29]([C@@H:31]1[CH2:35][C@H:34](OS(C)(=O)=O)[CH2:33][N:32]1[S:41]([C:44]1[CH:53]=[CH:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=1)(=[O:43])=[O:42])=[O:30]>CN(C=O)C>[CH3:27][O:28][C:29]([C@@H:31]1[CH2:35][C@@H:34]([S:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:33][N:32]1[S:41]([C:44]1[CH:53]=[CH:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=1)(=[O:43])=[O:42])=[O:30]
Reactant: COC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)CN1S(=O)(=O)c1ccc2ccccc2c1
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
64.2 g (167 mmol) of triphenylmethanthiol was slowly added at room temperature to a solution of 17.9 g (160 mmol) of potassium tert-butylate in 300 ml DMF and stirred mechanically for 30 min. Then 63 g (152 mmol) of (4S,2S)-4-methanesulfonyloxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid methylester in 300 ml DMF were added at 20° C. by cooling at the end with an ice bath. The reaction was heated for 1.3 h at 100° C., cooled, evaporated to 400 ml and extracted with 250 ml aqueous saturated NH4Cl/EtOAc (3×300). The organic phases were washed with aq. 10% NaCl, dried (Na2SO4) and evaporated. Flash chromatography (CH2Cl2/MeOH 99:1) gave 58.6 g (65%, (2S,4R)/(2R,4R)-isomer ca 4:1, 1H-NMR) and 9.2 g (10%, (2S,4R)/(2R,4R)-isomer ca 1:1, 1H-NMR) of (2S,4R)-1-(naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid methyl ester, MS: 594 (MH+).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([O:17][CH3:18])=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CC(C)([O-:22])C.[K+].O=O.Cl>O1CCCC1>[OH:22][C:13]1([C:15]([O:17][CH3:18])=[O:16])[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)C1c2ccccc2Oc2ccccc21
Agent: Cl
Agent: O=O
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C1(O)c2ccccc2Oc2ccccc21

Procedure:
48.05 g (0.2 mol) methyl xanthene-9-carboxylate are dissolved in 1200 mL of tetrahydrofuran and at 0° C. combined with 23.63 g (0.2 mol) of potassium tert-butoxide. Oxygen is the piped in for 2 hours at −10° C. to −5° C., then the mixture is acidified with 2 N aqueous hydrochloric acid and the majority of the solvent is distilled off. The residue remaining is extracted with ethyl acetate and water, the organic phase is extracted with aqueous Na2S2O5 solution, washed with water, and dried, and the solvent is distilled off. The product is purified by crystallization from diisopropylether and cyclohexane. Yield: 11.10 g white crystals (22% of theoretical yield)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=1.[C:21]([C:23]1[CH:24]=[CH:25][C:26]([F:31])=[C:27]([CH:30]=1)[CH:28]=[O:29])#[N:22].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Cl:13][C:14]1[CH:19]=[C:18]([CH:28]([OH:29])[C:27]2[CH:30]=[C:23]([CH:24]=[CH:25][C:26]=2[F:31])[C:21]#[N:22])[C:17]([Cl:20])=[CH:16][N:15]=1
Reactant: N#Cc1ccc(F)c(C=O)c1
Reactant: Clc1ccc(Cl)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#Cc1ccc(F)c(C(O)c2cc(Cl)ncc2Cl)c1
Reaction time: 0.5 h
Yield: 74 %

Procedure:
Diisopropylamine (0.52 ml, 3.70 mmol) was dissolved in tetrahydrofuran (5 ml). At −78° C., a hexane solution (1.54M, 2.20 ml, 3.39 mmol) of n-butyl lithium was added dropwise to the resulting solution. The reaction mixture was stirred at the same temperature for 30 minutes. A tetrahydrofuran solution (20 ml) of 2,5-dichloropyridine (0.46 g, 3.08 mmol) was added dropwise to the reaction mixture. After stirring further at the same temperature for 1 hour, a tetrahydrofuran solution (5 ml) of 5-cyano-2-fluorobenzaldehyde (0.46 g, 3.08 mmol) was added dropwise to the reaction mixture. The resulting mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added a saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to silica gel chromatography. The fraction obtained from the n-hexane:ethyl acetate=10:2 eluate was concentrated under reduced pressure to give the title compound (0.68 g, 2.28 mmol, 74%) as a pale yellowish brown oil.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[BH4-].[Na+].CO.[H][H]>C(O)(C)(C)C.C1(C)C=CC=CC=1>[OH:2][CH2:3][C@H:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:10])[CH2:8][CH2:9]1
Reactant: COC(=O)[C@@H]1CCC(=O)N1Cc1ccccc1
Reactant: [H][H]
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CC(C)(C)O
Product: O=C1CC[C@@H](CO)N1Cc1ccccc1
Reaction time: 8 h
Yield: 78.4 %

Procedure:
A solution of (S)-5-oxo-1-(phenylmethyl)-2-pyrrolidinecarboxylic acid methyl ester (132 g, 0.556 mol) in 600 mL of t-butanol was cooled to ca. 18° C. Sodium borohydride (41 g, 1.12 mol) was added in one portion. To the suspension was added over 45 min 425 mL of methanol. The reaction was kept at 15° C. during the addition, during which time hydrogen gas was evolved. After the addition, the mixture was kept at 20° C. until hydrogen evolution had subsided, and was allowed to stand at room temperature overnight. The solvents were removed on a rotary evaporator, and the residue was dissolved in 1 L of water and acidified to pH 7.5 with 2N HCl. The mixture was extracted with methylene chloride and the combined extracts were washed with 2N HCl and brine, and dried over Na2SO4. Evaporation of the solvent afforded 96.3 g of crude product, which was recrystallized once from toluene to give 89.5 g (77% yield) of (S)-5-(hydroxymethyl)-1-(phenylmethyl)-2-pyrrolidinone as a white solid, mp 82°-4° C. (toluene). 1H NMR (CDCl3) δ 1.92 and 1.94 (dd, J=6.5 Hz, 1 H, OH), 1.96-2.11 (m, 2 H, CH2), 2.36-2.61 (m, 2 H, COCH2), 3.48-3.78. (m, 3 H, CH2O and CH), 4.29 and 4.81 (AB, Jgem =15 Hz, 2 H, CH2Ph), 7.26-7.35 (m, 5 H, phenyl). [α]25D =+116° (c 1.07, methanol). Anal. Calcd for C12H15NO2 : C, 70.22; H, 7.37; N, 6.75. Found: C, 70.06; H, 7.41; N 6.75.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[C@H:15]([OH:16])[CH:14]=[CH:13][CH2:12][O:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:25])C=1.CSC>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH:10]1[CH:15]([OH:16])[CH:14]2[CH:13]([O:25]2)[CH2:12][O:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1OCC=C[C@H]1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CSC
Product: CC(C)(C)[Si](C)(C)OCC1OCC2OC2C1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0° C., stirred solution of trans-2-(tert-butyldimethylsilanyloxymethyl)-3,6-dihydro-2H-pyran-3-ol (0.110 g, 0.45 mmol) in CH2Cl2 (10 ml) was added m-CPBA (75%, 0.108 g, 1.08 mmol) and the mixture was stirred for 1 h at 0° C. Dimethyl sulfide (0.01 ml) was added and stirring was continued for 10 min. The solvent was removed in vacuo and the crude product was diluted with EtOAc (30 ml). The resulting solution was washed successively with saturated aqueous Na2CO3 (10 ml), water (10 ml×2) and brine (10 ml). The organic phase was dried over anhydrous Na2SO4. The solvent was removed in vacuo and the crude product was purified by flash chromatography (2540% EtOAc in hexane).
Reaction SMILES: Br[C:2]1[C:7]([O:8][C:9]([F:12])([F:11])[CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:13]1(B(O)O)[CH2:15][CH2:14]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[CH:13]1([C:2]2[C:7]([O:8][C:9]([F:12])([F:11])[CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:15][CH2:14]1
Reactant: CC(F)(F)Oc1cccnc1Br
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(F)(F)Oc1cccnc1C1CC1
Temperature: 80 °C
Yield: 43 %

Procedure:
2-Bromo-3-(1,1-difluoroethoxy)pyridine (Preparation 266, 700 mg, 2.948 mmol), cycloproyl boronic acid (252 mg, 2.94 mmol), and potassium phosphate tribasic (1.56 g, 7.35 mmol) were suspended in a mixture of toluene (100 mL) and water (20 mL), with rapid stirring. The suspension was heated to 80° C., and the solvent de-gassed by direct bubbling of N2 gas through the suspension for 30 minutes. The reaction was then heated to 95° C., and tricyclohexyl phosphine (82 mg, 0.29 mmol), rapidly followed by palladium acetate (33 mg, 0.15 mmol), were added. The reaction was left to stir and heat at 95° C. for 18 hours. The reaction was cooled to room temperature, and filtered through a plug of arbocel, eluting with ethyl acetate. The solvent was removed to leave a dark yellow oil. Ethyl acetate was added (100 mL), and the organic phase extracted with 2M HCl solution (3×100 mL). The organic phase was discarded. Ethyl acetate (150 mL) was added to the combined aqueous layers, and solid sodium bicarbonate was added until the aqueous layer reached pH 7. The mixture was transferred to a separating funnel, the organic layer was removed and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic phases were dried over magnesium sulfate, filtered and the solvent removed to leave a yellow oil. The material was purified by silica gel column chromatography eluting with 1:1 heptane:ethyl acetate to afford the title compound as a colourless oil (252 mg, 43%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[C:10]([O:13][C@@H:14]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@@H:15]1Br)(=[O:12])[CH3:11]>C(Cl)Cl.[N-]1C=CN=C1.[Ag+].[Cl-].[Zn+2].[Cl-]>[C:10]([O:13][C@@H:14]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:15]1[O:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Reactant: N#Cc1cccc(O)c1
Agent: [Ag+]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(C#N)c1
Yield: 33.3 %

Procedure:
If the procedure described in Preparation LXXXIII is followed starting from 2 g (16.8.10-3 mol) of 3-hydroxybenzonitrile, 2.9 mg (16.5.10-3 mol) of silver imidazolate, 6.5 g (18.3.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 4.6 g (33.6.10-3 mol) of zinc chloride in 80 ml of methylene chloride, 2.2 g (yield: 33%) of the expected product are obtained after purification by chromatography on silica gel using a hexane/ethyl acetate mixture (3/1 v/v) as the eluent, and precipitation in ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[CH:13][N:14]=[N:15][C:16]([C:17]([OH:19])=O)=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[CH3:27][S:28]([C:31]1[CH:36]=[C:35]([CH2:37][NH2:38])[CH:34]=[CH:33][N:32]=1)(=[O:30])=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.[Cl-].[NH4+]>[CH3:27][S:28]([C:31]1[CH:36]=[C:35]([CH2:37][NH:38][C:17]([C:16]2[N:15]=[N:14][CH:13]=[C:12]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=[CH:10][C:11]=23)=[O:19])[CH:34]=[CH:33][N:32]=1)(=[O:30])=[O:29]
Reactant: O=C(O)c1nncc2c1cnn2-c1ccc(F)cc1
Reactant: CS(=O)(=O)c1cc(CN)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1cc(CNC(=O)c2nncc3c2cnn3-c2ccc(F)cc2)ccn1
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyridazine-4-carboxylic acid (55.0 mg, 0.213 mmol), C-(2-methanesulfonyl-pyridin-4-yl)-methylamine trifluoroacetic acid salt (80.0 mg, 0.266 mmol) and DIPEA (112 μL, 0.644 mmol) in DMF (3.0 mL) is added TBTU (93.0 mg, 0.290 mmol). After 30 minutes, the mixture is diluted with saturated aqueous ammonium chloride (20 mL) and extracted with EtOAc (3×15 mL). The combined organic layers are washed with brine (4×5 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with a gradient of 25-100% EtOAc in hexanes. The resulting solid is triturated with ethyl ether to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH:27]1([CH2:30][N:31]2[CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[CH:33]=[N:32]2)[CH2:29][CH2:28]1.C(=O)(O)[O-].[Na+].O1CCOCC1>CO.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.O>[CH:27]1([CH2:30][N:31]2[CH:35]=[C:34]([C:2]3[CH:11]=[C:10]4[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]5[CH:17]=[C:16]([N:18]6[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]6)[N:15]=[C:14]([NH2:25])[N:13]=5)[CH2:9]4)=[CH:4][CH:3]=3)[CH:33]=[N:32]2)[CH2:29][CH2:28]1
Reactant: CC1(C)OB(c2cnn(CC3CC3)c2)OC1(C)C
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CC1Cc2ccc(-c3cnn(CC4CC4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2 (1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 1-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.1 mg, 0.029 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. After cooling it was diluted with methanol. After filtration the filtrate was purified with RP-HPLC (pH=10) to afford the desired product (5.3 mg). LCMS (M+H)+: m/z=459.3.
Reaction SMILES: C1C2NC3C(=CC=CC=3)SC=2C=CC=1C(O)=[O:16].[C:18]([N:21]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH2:25][CH2:24][C:23]2[CH:32]=[CH:33][C:34]([C:36](=[O:38])C)=[CH:35][C:22]1=2)(=[O:20])[CH3:19]>>[C:18]([N:21]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH2:25][CH2:24][C:23]2[CH:32]=[CH:33][C:34]([C:36]([OH:16])=[O:38])=[CH:35][C:22]1=2)(=[O:20])[CH3:19]
Reactant: CC(=O)c1ccc2c(c1)N(C(C)=O)c1ccccc1CC2
Reactant: O=C(O)c1ccc2c(c1)Nc1ccccc1S2
Product: CC(=O)N1c2ccccc2CCc2ccc(C(=O)O)cc21
Yield: 62 %

Procedure:
The experimental protocol used is the same as that described for the synthesis of intermediate 1.10, using 1-(5-acetyl-10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)ethanone (J. Chem. Soc. 1973, 859-863) as starting product. A pale yellow solid is obtained with a yield of 62%. Melting point: 189-189.5° C.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH3:5][CH:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][CH2:8][CH:7]1N.C([O-])(=O)C>O1CCOCC1>[CH3:5][CH:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][CH2:8][CH:7]1[NH:1][C:2](=[O:3])[NH2:4]
Reactant: CC1CCC(N)C(C)C1
Reactant: NC(N)=O
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CC1CCC(NC(N)=O)C(C)C1

Procedure:
8.2 g of N-[4-(β-<2-methoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl]-urea.(melting point 171°-173°C) are suspended in 150 ml of dioxane and heated under reflux for 1 hour after addition of 3.75 g of 2.4-dimethyl-cyclohexyl-amine-acetate. Then the solvent is distilled off in vacuo and water is added to the residue. The crystals obtained of N-[4-(β-<2-methoxy5-chlorobenzamido>-ethyl)-benzenesulfonyl]-N'-(2.4-dimethylcyclohexyl)-urea are recrystallized from methanol/dimethyl formamide and melt at 200°-201°C.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[F:16][C:17]([F:30])([F:29])[C:18]1[N:23]=[CH:22][C:21]([C:24](=[CH2:28])[C:25]([OH:27])=[O:26])=[CH:20][CH:19]=1.[OH-].[K+]>CN1C(=O)CCC1>[F:29][C:17]([F:16])([F:30])[C:18]1[N:23]=[CH:22][C:21]([CH:24]([CH2:28][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[C:25]([OH:27])=[O:26])=[CH:20][CH:19]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=C(C(=O)O)c1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CC(C(=O)O)c2ccc(C(F)(F)F)nc2)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 2-(6-(trifluoromethyl)pyridin-3-yl)acrylic acid and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.