Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:11][C:12]1[N:20]2[C:15]([C:16](N3C=NC=N3)=[N:17][CH:18]=[N:19]2)=[C:14]([C:26]2[CH:27]=[N:28][N:29]([CH3:38])[C:30]=2[C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[N:13]=1>CN(C)C=O.C(OCC)(=O)C>[N:1]1([C:16]2[C:15]3=[C:14]([C:26]4[CH:27]=[N:28][N:29]([CH3:38])[C:30]=4[C:31]4[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=4)[N:13]=[C:12]([CH3:11])[N:20]3[N:19]=[CH:18][N:17]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(-c2c(-c3nc(C)n4ncnc(-n5cncn5)c34)cnn2C)cc1
Reactant: C1CNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(-c3nc(C)n4ncnc(N5CCC5)c34)cnn2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Azetidine (27.0 μL, 0.400 mmol) and cesium carbonate (97%, 202 mg, 0.601 mmol) were added to a solution of 7-methyl-5-[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]-4-(1H-1,2,4-triazol-1-yl)imidazo[5,1-f][1,2,4]triazine (material from the previous reaction, ≦0.16 mmol) in N,N-dimethylformamide (3.0 mL), and the reaction mixture was stirred for 1 hour at room temperature. The reaction was diluted with ethyl acetate, washed with water, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification using silica gel chromatography (Gradient: 0% to 5% methanol in dichloromethane), followed by azeotroping with heptane, provided the product as a white solid. Yield: 35 mg, 0.097 mmol, 61% over 2 steps. LCMS m/z 360.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.20-2.28 (m, 2H), 2.35 (s, 3H), 2.64 (s, 3H), 3.5-3.9 (v br m, 2H), 3.90 (s, 3H), 3.9-4.3 (v br m, 2H), 7.21 (AB quartet, JAB=8.1 Hz, ΔvAB=32.1 Hz, 4H), 7.64 (s, 1H), 7.78 (s, 1H).
Reaction SMILES: [CH2:1]([N:5]([CH3:14])[C:6](=[O:13])[CH2:7][O:8][CH2:9][CH2:10][CH2:11]O)[CH2:2][CH2:3][CH3:4].[Br:15]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Br:15][CH2:11][CH2:10][CH2:9][O:8][CH2:7][C:6]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH3:14])=[O:13]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCN(C)C(=O)COCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCN(C)C(=O)COCCCBr
Yield: 66.4 %

Procedure:
Using the procedure of Step C of the Preparation of Example 83, 1.56 g of the product of Step A, 3.18 g of tetrabromo methane and 2.51 g of triphenyl phosphine were reacted to obtain after chromatography, 1.356 g of the expected product.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)(=[O:5])=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].S(O[CH2:30][CH2:31][CH2:32][Cl:33])(C1C=CC(C)=CC=1)(=O)=O>CN(C=O)C.O>[CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:30][CH2:31][CH2:32][Cl:33])[CH:7]=1)(=[O:4])=[O:5]
Reactant: Cc1ccc(S(=O)(=O)OCCCCl)cc1
Reactant: CNS(=O)(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CNS(=O)(=O)c1cccc(OCCCCl)c1
Reaction time: 0.75 h

Procedure:
N-Methyl-3-hydroxybenzene sulfonamide (175 mg, 0.94 mmole) in 15 mL of DMF was treated with Cs2CO3 (305 mg, 0.94 mmole), and stirred for 45 minutes. A solution of 3-Chloro-1-propanol tosylate (223 mg, 0.90 mmole) in 3 mL of DMF was added. The reaction was heated at 55° for 3 hours, and stirred at 23° for 16 hours. The reaction was diluted with H2O and extracted with Et2O. The extracts were washed with H2O, dried and the solvent removed. The residue was chromatographed on a silica gel column, and elution with 30% EtOAc in hexane gave the titled product, 75 mg (30%). MS (ESI) 264 (MH+).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1>CO.[OH-].[Pd+2].[OH-]>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: Oc1cccnc1C1=CCC2(CC1)OCCO2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Oc1cccnc1C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2-(1,4-dioxa-spiro[4.5]dec-7-en-8-yl)-pyridin-3-ol (1.3 g, 5.573 mmol) in methanol (60 mL) added to palladium (II) hydroxide (330 mg, 0.62 mmol) in a Parr bottle under argon. The reaction mixture was degassed with argon, evacuated and backfilled with hydrogen then shaken under 50 psi the gas at ambient temperature for 24 hours. After depressurizing and bubbling with argon, the reaction mixture was filtered through Celite 521, washing the filter with MeOH, and filtrate evaporated in vacuo giving a white solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:7]=[C:8]([CH2:13][C:14]#[N:15])[CH:9]=[CH:10][C:11]=1[F:12].C(=O)([O-])O.[Na+]>>[N+:1]([C:9]1[CH:10]=[C:11]([F:12])[C:6]([F:5])=[CH:7][C:8]=1[CH2:13][C:14]#[N:15])([O-:4])=[O:2]
Reactant: N#CCc1ccc(F)c(F)c1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Product: N#CCc1cc(F)c(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Fuming nitric acid (25 ml) was stirred with cooling (ice/water bath) and 3,4-difluorophenylacetonitrile (5 g, 32.7 mmol) was added dropwise. The mixture was left to stir for 15 h and was then poured onto ice. The mixture was neutralised with sodium hydrogen carbonate and extracted with dichloromethane. The combined organic phases were dried (MgSO4), filtered and concentrated under reduced pressure to give 2(2'-nitro-4',5'-difluorophenyl)-acetonitrile as a yellow oil which was immediately in ethanol/acetic acid (19:1) and hydrogenated over 10% palladium on charcoal at 65 p.s.i. The reaction mixture was filtered and concentrated under reduced pressure. The oily residue was taken up in ethyl acetate and washed with aqueous sodium hydrogen carbonate solution. The combined organic phases were dried (MgSO4), filtered and concentrated under reduced pressure to give 5,6-Difluoroindole as a yellow solid. Mass spectroscopy showed 154.1 (MH+).
Reaction SMILES: [F:1][CH:2]([F:38])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH3:37])=[CH:10][C:11]=2[CH:13]([O:15][CH2:16][C:17]2([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:22][CH2:21][N:20]([C:23](OC(C)(C)C)=O)[CH2:19][CH2:18]2)[CH3:14])[CH:6]=[N:5]1.C([BH3-])#N.[Na+].C=O>FC(F)(F)C(O)=O.C(O)(=O)C>[F:38][CH:2]([F:1])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH3:37])=[CH:10][C:11]=2[CH:13]([O:15][CH2:16][C:17]2([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]2)[CH3:14])[CH:6]=[N:5]1
Reactant: Cc1cc(C(C)OCC2(c3ccc(F)cc3)CCN(C(=O)OC(C)(C)C)CC2)c2c(cnn2CC(F)F)c1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(C)OCC2(c3ccc(F)cc3)CCN(C)CC2)c2c(cnn2CC(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(±)-tert-Butyl 4-((1-(1-(2,2-difluoroethyl)-5-methyl-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (10 mg, 0.02 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 1 mL) and stirred at room temperature for 1 h. The reaction was concentrated, loaded onto a strong cation exchange cartridge in methanol, and flushed with several volumes of methanol which were discarded. The crude secondary amine was eluted in 2 M ammonia in methanol and concentrated. The resulting residue was dissolved in acetonitrile (1 mL), cooled to 0° C., and treated with sodium cyanoborohydride (5.9 mg, 0.01 mmol) and formalin (0.52 mL). After 5 min, the reaction was treated with a few drops of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was concentrated and purified by column chromatography (10% methanolic ammonia/methylene chloride) to afford 4 mg (47%) as a clear oil. LC/MS (HPLC method 1): tR=2.35 min, 446.56(MH)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9](O)=[O:10])[C:7]([NH2:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]>C1COCC1>[OH:10][CH2:9][C:8]1[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[NH2:13]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)O
Solvent: C1CCOC1
Product: Nc1ccc([N+](=O)[O-])cc1CO
Yield: 234 %

Procedure:
5-Nitroanthranilic acid (5.0 g, 27.45 mmol) is dissolved in THF (100 mL) and 1 M borane/THF complex (55 mL, 54.9 mmol) is added. The mixture is heated to reflux for 1 h. Analysis by TLC indicates complete consumption of starting material. The volatiles are removed in vacuo and the residue is dissolved in ethyl acetate (150 mL). The organic phase is washed with 1 N HCl, saturated NaHCO3, and saturated NaCl. Evaporation provides 10.8 g (98%) of a dark brown oil product which is used directly in the next reaction; 1H-NMR (500 MHz, CDCl3); δ 4.61 (s, 2 H), 6.62 (s, 1 H), 8.01 (m, 2 H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]([NH2:24])=[O:23])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14]CC3C=CC=CC=3)[CH:9]=2)=[CH:6][N:7]=1>[Pd].C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:22]([NH2:24])=[O:23])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=2)=[CH:6][N:7]=1
Reactant: NC(=O)c1nc(-c2cccc(OCc3ccccc3)c2)cnc1N
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NC(=O)c1nc(-c2cccc(O)c2)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a 25 mL recovery flask was added 3-amino-6-{3-[(phenylmethyl)oxy]phenyl}pyrazine-2-carboxamide (33 mg, 0.103 mmol) and ethyl acetate (10 mL). A catalytic amount of 10% Pd/C was added. The flask was sealed with a septum and fitted with an H2 balloon. The reaction mixture was stirred overnight at room temperature. The reaction mixture was passed through a Celite pad. The filtrate was concentrated to give 3-amino-6-(3-hydroxyphenyl)pyrazine-2-carboxamide (23 mg, 96% yield) as a yeloow powder. 1H NMR (400 MHz, d6-DMSO): δ 9.47 (s, 1H), 8.74 (s, 1H), 7.55-7.53 (m, 1H), 7.46 (m, 1H), 7.25-7.22 (t, 1H), 6.78-6.76 (m, 1H); MS (EI) for C11H10N4O2: 231 (MH+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:38]=[CH:37][C:15]([CH2:16][N:17]2[C:22](=[O:23])[C:21]3[C:24]([O:33][CH3:34])=[C:25]4[C:30](=[O:31])[N:29]([CH3:32])[CH2:28][CH2:27][N:26]4[C:20]=3[C:19]([CH2:35][OH:36])=[N:18]2)=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.O>[F:11][C:12]1[CH:38]=[CH:37][C:15]([CH2:16][N:17]2[C:22](=[O:23])[C:21]3[C:24]([O:33][CH3:34])=[C:25]4[C:30](=[O:31])[N:29]([CH3:32])[CH2:28][CH2:27][N:26]4[C:20]=3[C:19]([CH:35]=[O:36])=[N:18]2)=[CH:14][CH:13]=1
Reactant: COc1c2n(c3c(CO)nn(Cc4ccc(F)cc4)c(=O)c13)CCN(C)C2=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1c2n(c3c(C=O)nn(Cc4ccc(F)cc4)c(=O)c13)CCN(C)C2=O
Temperature: -35 °C
Reaction time: 2 h

Procedure:
To a cold (−78° C.) solution of oxalyl chloride (0.25 mL, 2.8 mmol) in anhydrous dichloromethane (15 mL) under an atmosphere of nitrogen, a solution of anhydrous DMSO (0.21 mL, 2.93 mmol) in anhydrous dichloromethane (5 mL) was added. The resultant mixture was stirred at the same temperature for 10 minutes. A solution of 2-(4-fluorobenzyl)-4-(hydroxymethyl)-10-methoxy-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.47 g, 1.22 mmol) in a mixture of anhydrous dichloromethane (3 mL) and DMSO (5 mL) was added. After stirring at the same temperature for 2 hours, the reaction mixture was allowed to warm to −35° C., and treated with triethylamine (8 mL). The reaction mixture was allowed to warm to room temperature and pour into water (40 mL). The product mixture was diluted with dichloromethane. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residual oil was treated with hexane and cooled to 0° C. The solid precipitated was filtered and vacuum dried to provide the title compound.
Reaction SMILES: [C:1]([NH:10][C@@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:19](Br)[CH:20]=[CH2:21].[H-].[Na+].Cl>C1(C)C=CC=CC=1>[CH2:21]([N:10]([C@@H:11]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:12])[C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:20]=[CH2:19]
Reactant: CCCCCCCC(=O)N[C@H](C)c1ccccc1
Reactant: C=CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CCN(C(=O)CCCCCCC)[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.8 %

Procedure:
A solution of 10.0 g (40.0 mmol) of (R)-N-octanoyl-1-phenylethylamine in 20 ml of toluene, and 9.90 g (80.0 mmol) of allyl bromide were added to a suspension of 3.20 g (80.0 mmol) of sodium hydride (60%) in 74 ml of toluene, and the reaction was allowed to proceed at 100° C. for 6 hours. The reaction mixture was cooled to room temperature and added dropwise to 80 ml of ice-cooled 1 N hydrochloric acid to thereby terminate the reaction. The resulting mixture was extracted with three 30-ml portions of hexane. The organic phase was washed with 50 ml of water and then dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was quantitated by HPLC. Thus was obtained 9.87 g (86%) of the title compound.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][C:4]1=[O:9].Br[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([B:18]2[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]2)=[CH:14][CH:13]=1>C(Cl)Cl>[CH3:23][C:21]1([CH3:24])[C:20]([CH3:25])([CH3:26])[O:19][B:18]([C:15]2[CH:14]=[CH:13][C:12]([CH2:11][N:3]3[CH2:8][CH2:7][O:6][CH2:5][C:4]3=[O:9])=[CH:17][CH:16]=2)[O:22]1
Reactant: O=C1COCCN1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(CN3CCOCC3=O)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
NaH (81 mg, 3 eq.) was added to a solution of morpholin-3-one in DCM. 2-(4-bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane was added to the resulting solution and the reaction was stirred at room temperature for 16 hrs. DCM was evaporated, followed by addition of water. The solution was extracted with EtOAc. The organic layers were dried over MgSO4 and evaporated in vacuo to afford the title product used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[CH2:14][C@@H:13]3[CH2:15][C@H:10]2[CH2:11][O:12]3)=[CH:6][CH:5]=1)([O-])=O>CCOC(C)=O.[Pd]>[C@H:13]12[CH2:15][C@H:10]([N:9]([CH2:8][C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:17][CH:16]=3)[CH2:14]1)[CH2:11][O:12]2
Reactant: O=[N+]([O-])c1ccc(CN2C[C@@H]3C[C@H]2CO3)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(CN2C[C@@H]3C[C@H]2CO3)cc1
Yield: 9.7 %

Procedure:
A solution of (1S,4S)-5-(4-nitrobenzyl)-2-oxa-5-azabicyclo[2.2.1]heptane (943 mg; 4.03 mmol; 1.0 eq.) in EtOAc (10 mL) was hydrogenated under 10 bars H2 in presence of Pd/C (moistened, 10%, 43 mg, 0.40 mmol; 0.1 eq.) O/N. The crude was filtered through a celite pad, concentrated under reduced pressure and purified by flash chromatography on silica (DCM:MeOH:NH4OH, 96:3:1) to give the title compound as an yellow oil (80 mg, 10%). 1H NMR (300 MHz, DMSO-d6) δ 6.95 (d, J=8.4 Hz, 2H), 6.54-6.44 (m, 2H), 4.91 (s, 2H), 4.31 (s, 1H), 3.87 (d, J=7.4 Hz, 1H), 3.58-3.41 (m, 3H), 3.35 (d, J=8.1 Hz, 1H), 2.66 (dd, J=9.9, 1.7 Hz, 1H), 2.34 (d, J=10.0 Hz, 1H), 1.74 (dd, J=9.5, 2.1 Hz, 1H), 1.54 (d, J=9.5 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:41])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([CH2:31][CH2:32][O:33][Si](C(C)(C)C)(C)C)[CH2:20][CH2:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)=[CH:14][CH:13]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CO>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:41])[CH:10]=[CH:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]([CH2:31][CH2:32][OH:33])[CH2:20][CH2:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)OCCN(CCc1c[nH]c2ccccc12)Cc1ccc(C=CC(=O)Nc2ccccc2N)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccccc1NC(=O)C=Cc1ccc(CN(CCO)CCc2c[nH]c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 80.2 %

Procedure:
To a stirred solution at −20° C. of 5 (1.49 g, 2.62 mmol) in anhydrous THF (30 mL) under nitrogen was slowly added a solution of TBAF (2.88 mL, 2.88 mmol, 1.0M in THF). The reaction mixture was allowed to warm-up to the room temperature over 1 h and was stirred for additional 22 hours. MeOH was added and the reaction mixture was concentrated, diluted with AcOEt, and successively washed with saturated aqueous solution of NaHCO3, H2O, a saturated aqueous solution of NH4Cl and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (MeOH/CH2Cl2, 5/95→10/90 plus several drops of NH4OH) and triturated with a mixture of AcOEt/CH2Cl2/hexane to afford the title compound 6 (956 mg, 2.10 mmol, 80% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ(ppm): 10.76 (s, 1H), 9.39 (s, 1H), AB system (δA=7.58, δB=7.44, JAB=8.0 Hz, 4H), 7.56 (d, J=15.7 Hz, 1H), 7.42-7.34 (m, 2H), 7.33 (d, J=8.0 Hz, 1H), 7.12 (d, J=2.3 Hz, 1H), 7.05 (td, J=7.2, 1.2 Hz, 1H), 6.98-6.90 (m, 2H), 6.90 (d, J=15.8 Hz, 1H), 6.77 (dd, J=8.0, 1.4 Hz, 1H), 6.60 (ddd, J=7.5, 7.5, 1.4 Hz, 1H), 4.98 (bs, 2H), 4.43 (t, J=5.4 Hz, 1H), 3.78 (s, 2H), 3.56 (td, J=6.3, 5.6 Hz, 2H), 2.94-2.84 (m, 2H), 2.82-2.74 (m, 2H), 2.68 (t, J=6.5 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][CH:12]=[C:13]2[C:17]([CH3:18])=[C:16]([CH3:19])[NH:15][C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]#[CH:23]>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][CH:12]=[C:13]2[C:17]([CH3:18])=[C:16]([CH3:19])[N:15]([CH2:23][C:22]#[CH:21])[C:14]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1[nH]c2c(OCc3ccccc3)nncc2c1C
Reactant: C#CCBr
Product: C#CCn1c(C)c(C)c2cnnc(OCc3ccccc3)c21
Yield: 27.4 %

Procedure:
The title compound was prepared as a pale yellow powder in 27.40% yield in a similar procedure to that described in Example 41 by using 7-benzyloxy-2,3-dimethylpyrrolo[2,3-d]pyridazine and 3-bromo-1-propyne.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[C:5]([OH:10])[N:4]=1.S(OC)(O[CH3:15])(=O)=O>[OH-].[Na+]>[CH3:1][S:2][C:3]1[N:8]=[C:7]([O:9][CH3:15])[CH:6]=[C:5]([OH:10])[N:4]=1
Reactant: COS(=O)(=O)OC
Reactant: CSc1nc(O)cc(O)n1
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(O)nc(SC)n1
Temperature: 25 °C

Procedure:
15.8 g (0.2 mol) of 2-methylthio-4,6-dihydroxypyrimidine are added while stirring well, to 100 cc of sodium hydroxide solution 2N and the mixture is stirred at 50° for half an hour. The mixture is subsequently cooled to room temperature and 13.9 g (0.11 mol) of dimethyl sulphate are added dropwise, while stirring; by the addition of sodium hydroxide solution 2N the pH value is kept at between 8 and 8.2. After the dropwise addition a precipitate is obtained. The mixture is stirred at 50° for a further 21/2 hours, whereby the pH value is kept at between 8 and 8.3, then cooled to 0° and filtered. The obtained white powder has a M.P. of 193°-195°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10](OC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.CO>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:10]=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](C=O)Cc1ccccc1
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a stirred solution of compound 31c (25.0 g, 90 mmol) in toluene-DCM (4:1, 1000 mL) was added dropwise a solution of DIBAL-H in toluene (1.0 M, 179 mL, 179 mmol) at −78° C. under argon and the mixture was stirred for 1 h at this temperature. Methanol (200 mL) was added immediately to quench the reaction. The reaction mixture was poured into a solution of 200 mL of 20% sodium potassium tartrate (Rochelle salt) and stirred at rt until the two layers separated. The organic layer was concentrated in vacuo and the residue was purified by CC (hexane/EA=2:1) to give compound 31d as a white solid (19.9 g, 89% yield).
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.C([Mg:14][Cl:15])(C)C.[Li+].[Cl-]>C1COCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([Mg:14][Cl:15])=[CH:3][C:4]=1[F:10])#[N:7]
Reactant: N#Cc1ccc(I)cc1F
Reactant: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc([Mg]Cl)cc1F
Reaction time: 0.08 h

Procedure:
To a stirred solution of 4-iodo-2-fluorobenzonitrile (2.5 g, 10.12 mmol) in 10.12 ml THF under argon, a solution of isopropylmagnesium chloride. LiCl in THF (10.12 ml, 13.16 mmol) was added at 0° C. The reaction mixture was stirred at this temperature for 5 min to afford the title compound, which was used immediately in the next step as a stock solution (˜0.5M in THF).
Reaction SMILES: [I:1][C:2]1[N:7]2[N:8]=[C:9]([S:19][CH3:20])[C:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:24][CH:25]1[CH2:27][CH2:26]1.C(OCC)(=O)C>CN(C)C=O>[CH:25]1([CH2:24][N:11]([C:10]2[C:9]([S:19][CH3:20])=[N:8][N:7]3[C:2]([I:1])=[CH:3][CH:4]=[CH:5][C:6]=23)[C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:17])[CH3:15])[CH2:27][CH2:26]1
Reactant: CSc1nn2c(I)cccc2c1NC(=O)OC(C)(C)C
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1nn2c(I)cccc2c1N(CC1CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl N-[7-iodo-2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate (600 mg) in N,N-dimethylformamide (6 mL) was added sodium hydride (60% in oil; 80 mg) with ice bath, and the reaction mixture was stirred for 30 minutes at room temperature. (Bromomethyl)cyclopropane (0.22 mL) was added to the reaction mixture at the same temperature, and stirring was continued for 1 hour at 40° C. After completion of the reaction, the reaction mixture was gradually added to ice, extraction was performed with ethyl acetate, and the organic extract was washed with water and brine. The organic extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to afford a crude product of tert-butyl N-cyclopropylmethyl-N-[7-iodo-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:12][C:13]([C@H:15]1[CH2:17][C@@H:16]1[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10]C)=[CH:6][CH:5]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+].Cl>C(Cl)Cl>[OH:1][CH2:2][C@H:3]([NH:12][C:13]([C@H:15]1[CH2:17][C@@H:16]1[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: COc1ccc([C@H](CO)NC(=O)[C@H]2C[C@@H]2c2cccs2)cc1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: O=C(N[C@@H](CO)c1ccc(O)cc1)[C@H]1C[C@@H]1c1cccs1
Temperature: -7.5 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
To a suspension of (1S,2S)-2-thiophen-2-yl-cyclopropanecarboxylic acid [(R)-2-hydroxy-1-(4-methoxy-phenyl)-ethyl]-amide (105 mg, 0.331 mmol) in DCM (3 mL) at −10° C. was added BBr3 (1M, 0.994 mL, 0.994 mmol). The mixture was stirred between −10 to −5° C. for 1 h. Work up with NaHCO3/HCl to give the crude product which was further purified by flash column (5% MeOH in DCM) of give the titled product (70 mg, 70%).
Reaction SMILES: [CH:1]1[C:10]([OH:11])=[C:6]([CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][C:2]=1[CH3:3].C[C@H]1C[C@H](O)[C@H](C(C)C)CC1.C[C@@H]1C[C@H](O)[C@@H](C(C)C)CC1>>[CH3:3][C@H:2]1[CH2:1][C@@H:10]([OH:11])[C@H:6]([CH:7]([CH3:9])[CH3:8])[CH2:5][CH2:4]1
Reactant: Cc1ccc(C(C)C)c(O)c1
Agent: CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O
Agent: CC(C)[C@H]1CC[C@H](C)C[C@@H]1O
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O

Procedure:
Mixtures of 50 to 70 % by weight of thymol with 50 to 30 % by weight of d-neomenthol or d-menthol were used as starting material in accordance with the general conditions described above. In Table I below, column 1 gives the composition of the starting material, column 2 the balance yield of d,l-menthol in percent of the theoretical, whilst the other columns give the contents in the reaction product of d,l-neomenthol, d,l-isomenthol, menthone and other ketones, also hydrocarbons, the OH-number, the optical rotation and the thymol content, calculated from the UV-absorption.