Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.Cl[C:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[CH:27][N:26]=1.C(N(CC)CC)C.O1CCOCC1>C(OCC)(=O)C>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:25]4[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[CH:27][N:26]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(N)cc23)CC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(Nc4ncccc4[N+](=O)[O-])cc23)CC1
Temperature: 101 °C
Yield: 70 %

Procedure:
5-Amino-3-(N-t-butoxycarbonylpiperid-4-yl)-1H-indole and 2-chloro-3-nitropyridine were used. Triethylamine was the base, dioxane was the reaction solvent, the reaction was heated at reflux (101° C.) for 5 hours, and the chromatographic solvent system was ethyl acetate [30-40%] in hexanes to afford the title compound (70%) as a dark red foam: 1H NMR (CDCl3) δ155.8, 155.0, 151.6, 135.5, 134.6, 129.4, 126.9, 121.3, 120.8, 119.8, 114.8, 113.1, 111.5, 79.4, 44.5, 33.6, 32.8, 28.5. Anal. calcd. for C23H27N5O4.1/4 C4H8O2 [ethyl acetate]: C, 62.73; H, 6.36; N, 15.24. Found: C, 62.51; H, 6.08; N, 15.21.
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@:5]([CH3:38])([C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[C:21]([C:34]([F:37])([F:36])[F:35])[CH:20]=3)=[N:17][N:18]=2)[CH2:4][O:3]1.[C:40](#N)[CH3:41].O>>[CH3:39][C:2]1([CH3:1])[N:6]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@@:5]([CH3:38])([C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]4[CH:41]=[CH:40][CH:33]=[CH:32][CH:31]=4)=[C:21]([C:34]([F:37])([F:36])[F:35])[CH:20]=3)=[N:17][N:18]=2)[CH2:4][O:3]1
Reactant: CC#N
Reactant: CCCCCCCCOc1ccc(-c2nnc([C@@]3(C)COC(C)(C)N3C(=O)OC(C)(C)C)s2)cc1C(F)(F)F
Solvent: O
Product: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)c1nnc(-c2ccc(OCCCCc3ccccc3)c(C(F)(F)F)c2)s1
Yield: 75 %

Procedure:
The title compound was prepared analogously to (R)-tert-butyl 2,2,4-trimethyl-4-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)oxazolidine-3-carboxylate (14a) in 75% yield. MS (ESI): 592.14 (MH+), HPLC retention time on a C8(2) column (30×3.00 mm, 3μ) is 3.55 min with gradient 50-98% acetonitrile-H2O (0.1% TFA) in 3.5 min as mobile phase
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[F:18])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.Cl[CH2:20][C:21]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:22]=1[O:23][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:20][C:21]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:22]=3[O:23][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:13][C:12]=2[F:18])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: COC(=O)C(C)Oc1cc(Cl)ccc1CCl
Reactant: Oc1ccc(-n2nc3c(c2Cl)CCCC3)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(Cl)ccc1COc1ccc(-n2nc3c(c2Cl)CCCC3)c(F)c1
Yield: 81.1 %

Procedure:
By the method of Example 1, Step K, 0.49 g (0.0016 mole) of 3-chloro-2-(2-fluoro-4-hydroxyphenyl)-4,5,6,7-tetrahydroindazole and 0.52 g (0.002 mole) of methyl 2-(2-chloromethyl-5-chlorophenoxy)propionate (Example 2, Step F) were reacted in the presence of 0.41 g (0.003 mole) of anhydrous potassium carbonate in 30 mL of N,N-dimethylformamide, yielding 0.64 g of methyl 2-[2-[4-(3-chloro-4,5,6,7-tetrahydroindazol-2-yl)-3-fluorophenoxymethyl]-5-chlorophenoxy]propionate as a syrup. The NMR and IR spectra were consistent with the proposed structure. NMR: 1.64 (d, 3H, JHH =8.0 Hz); 1.82 (m, 4H); 2.50 (t, 2H, JHH =4.0 Hz); 2.68 (t, 2H, JHH =4.0 Hz); 3.76 (s, 3H); 4.82 (q, 1H, JHH =8 Hz); 5.18 (s, 2H,); 6.78-7.40 (m, 6H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[O:24]1[CH2:27][CH:26]([O:28][NH2:29])[CH2:25]1>>[O:24]1[CH2:27][CH:26]([O:28]/[N:29]=[C:21](/[C:18]2[N:17]=[C:16]3[N:12]([CH2:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[N:13]=[N:14][C:15]3=[N:20][CH:19]=2)\[CH3:22])[CH2:25]1
Reactant: NOC1COC1
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Product: C/C(=N\OC1COC1)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 23 %

Procedure:
The title compound was prepared from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (22.4) and O-(oxetan-3-yl)hydroxylamine (intermediate U) in 23% yield using the same procedure as described in the synthesis of example 22. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.27 (s, 1H), 8.89 (m, 1H), 8.35 (d, 1H), 8.01 (m, 2H), 7.82 (m, 1H), 7.52 (dd, 1H), 6.22 (s, 2H), 5.45 (t, 1H), 4.86 (t, 2H), 4.66 (m, 2H), 2.40 (s, 3H). LCMS (method B): [MH]+=376, tR=2.26 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([C:15]([O:17]CC)=O)[C:10]([O:12]CC)=O.Cl.[NH2:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1.[CH2:27]1[CH2:35][N:34]2[C:29](=[N:30][CH2:31][CH2:32][CH2:33]2)[CH2:28]1>CN(C)C=O>[OH:17][C:15]1[N:23]2[CH:24]=[CH:25][N:26]=[C:22]2[N:21]=[C:10]([OH:12])[C:9]=1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1].[CH2:27]1[CH2:35][N:34]2[C:29](=[N:30][CH2:31][CH2:32][CH2:33]2)[CH2:28]1
Reactant: Nc1ncc[nH]1
Reactant: CCOC(=O)C(C(=O)OCC)c1c(F)cccc1Cl
Agent: C1CN=C2CCCN2C1
Agent: Cl
Solvent: CN(C)C=O
Product: Oc1nc2nccn2c(O)c1-c1c(F)cccc1Cl
Temperature: 100 °C
Yield: 44.5 %

Procedure:
A mixture of 2.89 g of diethyl (2-chloro-6-fluorophenyl)malonate, 1.20 g of aminoimidazole hydrochloride, 2.48 g of 1,5-diazabicyclo[4.3.0]-5-nonene (DBN) and 10 ml of N,N-dimethylformamide (DMF) was heated at 100° C. for 4 hours. The reaction mixture was allowed to cool, filtered the precipitate and dried to give 1.80 g of 5,7-dihydroxy-6-(2-chloro-6-fluorophenyl)imidazo[1,2-a]pyrimidine DBN salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:21])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](/[CH:12]=[N:13]/[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH:8]=[CH:7]2.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[N:14]1[N:13]=[C:12]([C:9]2[CH:8]=[CH:7][C:6]3[C:11](=[C:2]([Br:1])[CH:3]=[C:4]([F:21])[CH:5]=3)[N:10]=2)[N:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=12
Reactant: Fc1cc(Br)c2nc(/C=N/Nc3ccccn3)ccc2c1
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Solvent: ClCCl
Product: Fc1cc(Br)c2nc(-c3nnc4ccccn34)ccc2c1
Temperature: 23 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
(E)-1-((8-Bromo-6-fluoroquinolin-2-yl)methylene)-2-(pyridin-2-yl)hydrazine (100 mg, 0.290 mmol) was weighed into a 25 mL 1 neck round bottom flask and suspended in 6.0 mL of DCM, followed by addition of iodobenzene diacetate (103 mg, 0.32 mmol). The reaction was stirred at 23° C. overnight, after which all starting materials had been consumed. The reaction was transferred to a reparatory funnel and partitioned between 30 mL DCM and 30 mL Na2SO3, and the aqueous layer was washed with DCM. The combined organics were dried over magnesium sulfate and concentrated in vacuo to afford a white/yellow powder. The powder was triturated with 10 mL of anhydrous Et2O, affording the desired product as a white solid (74 mg, 74.4% yield). MS APCI (+) m/z 343 (M+1) detected.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:7]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC.[OH-].[Na+]>C1COCC1>[Cl:19][C:17]1[CH:16]=[CH:15][C:14]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)=[C:13]([CH:18]=1)[CH2:12][N:8]1[C:9]([CH3:11])=[CH:10][C:6]([CH2:4][OH:3])=[N:7]1
Reactant: CCOC(=O)c1cc(C)n(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(CO)nn1Cc1cc(Cl)ccc1OCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ester 3 (0.3 g, 0.72 mmol) in THF (6 mL) under N2 atmosphere was added 1 M LiAlH4 in Et2O (2.2 mL, 2.20 mmol). The resulting mixture was stirred at RT for 2 h. 2 M NaOH (2 mL) was added dropwise and the precipitate was removed by filtration. The volatiles were removed in vacuo. The residue was dissolved in EtOAc (20 mL), washed with water (2×15 mL), brine (15 mL), dried (Na2SO4) and evaporated to dryness to give alcohol 4 as a white solid, 0.16 g (60%).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14](Br)[CH:15]=1.C(N(CC)CC)C>C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:15]=1
Reactant: Brc1cncc(Br)c1
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Brc1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.8 %

Procedure:
Add phenylacetylene (1.11 mL, 10.10 mmol) dropwise to a mixture of 3,5-dibromopyridine (2.05 g, 8.65 mmol), bis(triphenylphosphine)palladium (II) dichloride (300 mg, 0.427 mmol), and copper (I) iodide (160 mg, 0.840 mmol) in triethylamine (8.50 mL, 60.98 mmol) and stir for 3 h at room temperature. Dilute the reaction mixture with ethyl acetate and wash with a saturated aqueous solution of sodium chloride. Dry (sodium sulfate), filter and concentrate. Purify the residue by silica gel chromatography, eluting with a gradient of 100:0 to 90:10 hexanes:ethyl acetate, to give the title compound (710 mg, 32%).
Reaction SMILES: [S:1]1([CH2:7][CH:6]=[CH:5][CH2:4]1)(=[O:3])=[O:2].[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=O.[OH-].[Na+]>C(O)C>[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=[C:4]1[CH:5]=[CH:6][C:7](=[CH:13][C:9]2[S:8][CH:12]=[CH:11][CH:10]=2)[S:1]1(=[O:3])=[O:2]
Reactant: O=Cc1cccs1
Reactant: O=S1(=O)CC=CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=S1(=O)C(=Cc2cccs2)C=CC1=Cc1cccs1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
About 80 mmol (9.4 g) of 3-sulfolene (MW=118) and 170 mmol (19.04 g) (15.9 ml) of thiophene-2-aldehyde (MW=112, d=1.2 g/cm3) were added to an alkaline solution of 1 g of NaOH in 200 ml of ethanol. The mixture was stirred at room temperature for 3 days. A yellow precipitate formed which was filtered off with suction and washed thoroughly with ethanol and water.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]2[N:8]=[C:9]([CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH:10]=[C:3]12.Br[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1.FC1C=C(F)C=CC=1N1CCN2N=C(COC3C=CC=CC=3)C=C2C1=O>>[F:23][C:20]1[CH:21]=[CH:22][C:17]([N:7]2[CH2:6][CH2:5][N:4]3[N:8]=[C:9]([CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH:10]=[C:3]3[C:2]2=[O:1])=[N:18][CH:19]=1
Reactant: CC(=O)OCc1cc2n(n1)CCNC2=O
Reactant: Fc1ccc(Br)nc1
Agent: O=C1c2cc(COc3ccccc3)nn2CCN1c1ccc(F)cc1F
Product: CC(=O)OCc1cc2n(n1)CCN(c1ccc(F)cn1)C2=O

Procedure:
The compound was prepared from acetic acid 4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylmethyl ester and 2-bromo-5-fluoropyridine using the method described in the preceding example 43 (5-(2,4-difluoro-phenyl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O.C(OCC)C>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][CH2:28][C:27]1[CH:30]=[CH:31][C:24]([O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:25][CH:26]=1)[CH3:3]
Reactant: CCOC(=O)CN
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)CNCc1ccc(OCc2ccccc2)cc1
Reaction time: 16 h
Yield: 50.5 %

Procedure:
To a suspension of 11.0 g of glycine ethyl ester hydrochloride in 100 mL of dimethylformamide at 25° was added 22.0 mL of triethylamine. To the resulting milky suspension was added 9.08 g of 4-benzyloxybenzyl chloride in 50 mL of DMF dropwise over 0.5 hour. The mixture was stirred for 16 hours at 25°. The reaction mixture was diluted with diethyl ether and then filtered to remove the precipitated triethylamine hydrochloride. The resulting solution was concentrated in vacuo, and the residue was dissolved in ethyl acetate. The solution was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Kugelrohr distillation provided 5.90 g of N-(4-benzyloxybenzyl)glycine ethyl ester [bp 160°-180° (0.015 torr.)]; NMR (200 MHz, CDCl3): δ7.43-7.27 (m, 5H); 7.06 (A2B2, 4H); 5.01 (s, 2H); 4.14 (quart., 2H); 3.71 (s, 2H); 3.36 (s, 3H); 2.01 (bs, 1h); 1.24 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[Br:17][C:18]1[CH:19]=[CH:20][C:21]([C:24](O)=O)=[N:22][CH:23]=1>>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)=[N:22][CH:23]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(Br)cn2)o1
Yield: 39 %

Procedure:
As described for example 137a, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (4.14 g, 19.0 mmol) using 5-bromo-2-carboxy pyridine instead of 6-chloronicotinic acid was converted to the title compound (2.83 g, 39%) which was obtained as a brown solid. MS: m/e=385.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:21])[NH:5][N:6]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:2].[OH-].[K+].C1(=O)O[CH2:27][CH2:26][O:25]1.C(=O)=O>CN(C)C=O>[OH:25][CH2:26][CH2:27][N:5]1[C:4](=[O:21])[C:3]([C:1]#[N:2])=[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:6]1
Reactant: O=C1OCCO1
Reactant: N#Cc1c(-c2ccccc2)c(-c2ccccc2)n[nH]c1=O
Agent: O=C=O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1c(-c2ccccc2)c(-c2ccccc2)nn(CCO)c1=O
Temperature: 100 °C

Procedure:
17.7 grams (0.065 mole) of the product of Example 1 was dissolved in 60 mls of dry dimethylformamide along with 0.25 grams of potassium hydroxide and 7.5 grams (0.085 mole) of ethylene carbonate. The mixture was heated to 100° C. and maintained for 2 hours until no carbon dioxide was liberated. The solution was then heated at 110° C. for 30 minutes. The solution was filtered and the dimethylformamide was distilled under reduced pressure with a mechanical pump. The solid was dried in a drying pistol using xylene as the solvent. The residual solid was recrystallized from ethyl alcohol to give 10.4 grams (50%) yield of a solid melting at 197°-198° C. Calculated for C19H15N3O2, C, 71.9; H, 4.8; N, 13.2. Found: C, 71.7; H, 4.71; N, 13.5. The infrared spectra showed the OH group at 2.9μ, the nitrile band at 4.5μ, and the carbonyl band at 6.0μ. The NMR confirmed that the product was the desired material.
Reaction SMILES: [CH:1]1([C@@:4]([OH:24])([CH3:23])[CH2:5][NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12](Br)=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1.[N:25]1[CH:30]=[CH:29][CH:28]=[N:27][C:26]=1[CH2:31][OH:32]>>[CH:1]1([C@@:4]([OH:24])([CH3:23])[CH2:5][NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12]([O:32][CH2:31][C:26]3[N:27]=[CH:28][CH:29]=[CH:30][N:25]=3)=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: OCc1ncccn1
Reactant: C[C@@](O)(CNC(=O)c1cnc(Br)c(-c2ccc(Cl)cc2)n1)C1CC1
Product: C[C@@](O)(CNC(=O)c1cnc(OCc2ncccn2)c(-c2ccc(Cl)cc2)n1)C1CC1

Procedure:
In analogy to example 26, however by starting from 5-bromo-6-(4-chloro-phenyl)-pyrazine-2-carboxylic acid ((S)-2-cyclopropyl-2-hydroxy-propyl)-amide and pyrimidin-2-yl-methanol the title compound was obtained as light yellow solid. MS (ISP) (M+H+)=440.2.
Reaction SMILES: IC.[C:3]([O-])([O-])=O.[K+].[K+].[Br:9][C:10]1[C:11]([OH:20])=[C:12]([C:16]([O:18][CH3:19])=[O:17])[S:13][C:14]=1[Br:15]>CN(C=O)C.C(OCC)C>[Br:9][C:10]1[C:11]([O:20][CH3:3])=[C:12]([C:16]([O:18][CH3:19])=[O:17])[S:13][C:14]=1[Br:15]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1sc(Br)c(Br)c1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1sc(Br)c(Br)c1OC
Reaction time: 18 h
Yield: 80 %

Procedure:
9.97 ml of a solution of iodomethane and then 29.44 g of K2CO3 are added, dropwise, to a solution of 34.35 g of methyl 4,5-dibromo-3-hydroxythiophene-2-carboxylate in 150 ml of DMF and the mixture is left to stir for 18 hours at AT. After cooling, the reaction mixture is diluted in 100 ml of ethyl ether and filtered, and the filtrate is concentrated under vacuum. The reaction crude is purified by silica gel chromatography, elution being carried out with heptane and then with a heptane/EtOAc mixture (85/15; v/v). 28.70 g of the expected compound are obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([OH:12])(=[O:11])=[O:10].[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>[Cu](I)I.[Cu]>[N:13]1([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[S:9]([OH:12])(=[O:11])=[O:10])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: C1CNCCN1
Reactant: Cc1ccc(F)c(S(=O)(=O)O)c1
Agent: I[Cu]I
Agent: [Cu]
Product: Cc1ccc(N2CCNCC2)c(S(=O)(=O)O)c1
Yield: 65.4 %

Procedure:
After the reaction was carried out between 0.76 g of 2-fluoro-5-methylbenzenesulfonic acid and 3.44 g of piperazine in the co-presence of 0.76 g of copper iodide and 0.26 g of copper powder in a sealed tube at 160° C. for 8 hours, the reaction product was purified by silica gel column chromatography (eluant:chloroform:methanol:acetic acid =100:100:3) to give 0.67 g (yield: 65.0%) of the above title product having the following physical property.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([Cl:11])[CH:3]=1.O.[OH-].[Cs+].[CH3:15]I.O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:15])=[C:4]([Cl:11])[CH:3]=1
Reactant: CI
Reactant: Clc1cc(Br)cc2[nH]ncc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncc2c(Cl)cc(Br)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
To a mixture of 6-bromo-4-chloro-1H-indazole (4.0 g, 17.4 mmol), cesium hydroxide monohydrate (23.3 g, 139 mmol), tetrabutylammonium hydrogensulfate (1.36 g, 3.99 mmol) in anhydrous THF (80 mL) was added a solution of methyl iodide (9.86 g, 69.4 mmol) in THF (10 mL) dropwise at r.t. The reaction mixture was stirred for 15 min at r.t. Water was added to the reaction mixture, and the aqueous layer was extracted with EtOAc. The organic layer was concentrated, and the crude reside was purified by silica gel column chromatography (EtOAc/Heptane 0 to 100% gradient as eluent) to afford 6-Bromo-4-chloro-1-methyl-1H-indazole (2.65 g, 62%). 1H NMR (600 MHz, methanol-d4) δ 4.05 (s, 3H), 7.32 (d, 1H), 7.79 (s, 1H), 8.03 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=2)[C:3]=1[C:21]#[N:22].C(COC)[O:24]C>O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Ru]>[NH2:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=2)[C:3]=1[C:21]([NH2:22])=[O:24]
Reactant: COC(=O)c1ccc(-c2nn(C(C)(C)C)c(N)c2C#N)cc1
Reactant: COCCOC
Agent: [Ru]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: COC(=O)c1ccc(-c2nn(C(C)(C)C)c(N)c2C(N)=O)cc1

Procedure:
A mixture of 5-amino-1-tert-butyl-4-cyano-3-(4-methoxycarbonylphenyl)pyrazole (448 mg, 1.5 mmol) and tetrakis(triphenylphosphine)ruthenium dihydride in dimethoxyethane (1 ml) and water (54 μl) was heated at 120° under a nitrogen atmosphere in a sealed tube for 18 h. The reaction was concentrated under reduced pressure and the residue subjected to column chromatography (silica 4% methanol-CH2Cl2) to give the title compound (170 mg) after recrystallisation from ethyl acetate as a colourless solid m.p. 237-239°. δH (CDCl3) 1.67 (9H, s), 4.39 (3H, s), 5.10 (2H, br s), 5.69 (2H, br s), 7.66 (2H, d, J 8.2 Hz), and 8.11 (2H, d, J 8.3 Hz).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[OH:24][C@@H:25]1[CH2:29][O:28][CH2:27][C@H:26]1[NH:30][C:31]1[CH2:35][S:34][C:33](=[O:36])[N:32]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:35]2/[C:31]([NH:30][C@H:26]3[C@H:25]([OH:24])[CH2:29][O:28][CH2:27]3)=[N:32][C:33](=[O:36])[S:34]/2)[CH2:8][CH2:7]1
Reactant: O=C1N=C(N[C@@H]2COC[C@H]2O)CS1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(N[C@@H]2COC[C@H]2O)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 80 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (649 mg) in 2-propanol (10 mL) were added 4-[trans-(4-hydroxytetrahydrofuran-3-yl)amino]-1,3-thiazol-2(5H)-one (580 mg) and piperidinium acetate (283 mg). The reaction mixture was stirred at 80° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (469 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Cl.[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20]Cl>CN(C=O)C>[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: CN(C)CCCl
Reactant: O=Cc1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
To a mixture of 3-hydroxybenzaldehyde (5.44 g, 44.55 mmol), K2CO3 (13.6 g) and DMF (50 ml) was added in portions 2-dimethylaminoethylchloride hydrochloride (7.1 g). The reaction mixture was stirred at room temperature overnight, filtered and the filtrate was stripped. The residue was diluted with 1N HCl (300 ml), and extracted with ether, and the ether layer was dried over MgSO4 and stripped. The acidic aqueous layer was cooled and then treated with 8N NaOH till basic, then it was extracted with ether (3×150 ml). The ether layers were combined, dried over MgSO4, filtered and stripped to afford, as an oily liquid, 1.43 g of 3-[2-(dimethylamino)ethoxy]benzaldehyde.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:17]=[CH:18]/[C:19]([NH:21][CH3:22])=[O:20])=[CH:4][N:3]=1>[Pd].CO.CN(C=O)C>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([CH2:17][CH2:18][C:19]([NH:21][CH3:22])=[O:20])=[CH:4][N:3]=1
Reactant: CNC(=O)/C=C/c1cnc(N)c2c(-c3ccccc3)csc12
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: CNC(=O)CCc1cnc(N)c2c(-c3ccccc3)csc12
Yield: 83.5 %

Procedure:
A mixture of Example 14 (30 mg, 0.1 mmol) and 10% Pd on carbon (30 mg) in 1:1 methanol/DMF (4 mL) was stirred under an atmosphere of hydrogen overnight. The suspension was filtered through diatomaceous earth (Celite®). The pad was washed with methanol and the filtrate was concentrated to half its original volume. The residue was diluted with diethyl ether and filtered. The filter cake was dried to provide 26 mg of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.47 (m, 2H), 2.58 (d, J=4.6 Hz, 2H), 2.91 (t, J=7.9 Hz, 2H), 5.21 (s, 1H), 7.50 (m, 6H), 7.66 (s, 1H), 7.81 (m, J=4.3 Hz, 1H); MS (ESI(+)) m/e 312 (M+H)+.