Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH3:4])=[C:2]=S.[Br:5][C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([NH2:13])=[C:8]([CH3:14])[CH:7]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CO>[Br:5][C:6]1[CH:7]=[C:8]([CH3:14])[C:9]2[NH:13][C:2]([NH:1][CH3:4])=[N:12][C:10]=2[CH:11]=1
Reactant: Cc1cc(Br)cc(N)c1N
Reactant: CN=C=S
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: CNc1nc2cc(Br)cc(C)c2[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 71 %

Procedure:
Isothiocyanatomethane (0.055 g, 0.746 mmol) in N,N-dimethylformamide (1.0 mL) was added dropwise slowly to a stirred solution of 5-bromo-3-methylbenzene-1,2-diamine (0.150 g, 0.746 mmol) in N,N-dimethylformamide (1.5 mL) at 0° C. The cold bath was removed, the reaction mixture was capped and stirred at room temperature for 48 h. N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.157 g, 0.821 mmol) was added and the reaction mixture capped and heated at 40° C. overnight. The resulting mixture was diluted with methanol, filtered and purified using reverse-phase preparatory HPLC (10-50% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Fractions containing the desired product were combined and most of the solvent removed under reduced pressure. Acetonitrile was added and the resulting mixture loaded on a Strata ion exchange column. The column was washed successively with water, acetonitrile, methanol and 5% ammonium hydroxide in methanol. The product eluted with the 5% ammonium hydroxide in methanol and was concentrated under reduced pressure and dried under high vacuum to give the desired product (0.128 g, 0.53 mmol, 72% yield) as a slightly yellow waxy solid. MS (ESI) m/z 240 [M]+, 242 [M+2]+.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[CH3:9][O-].[Na+].CI>CO>[CH3:9][S:3][C:2]1[NH:1][CH:8]=[CH:7][C:5](=[O:6])[N:4]=1
Reactant: C[O-]
Reactant: O=c1cc[nH]c(=S)[nH]1
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: CSc1nc(=O)cc[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
20 g (153 mmol) 2-thiouracil are suspended in 250 mL MeOH and then 8.7 g (152.9 mmol, 1 eq) sodium methoxide are added. The solution is stirred for 5 min at RT and then 12.4 mL (198.8 mmol, 1.3 eq) methyl iodide are added dropwise. The reaction mixture is stirred overnight, then poured onto water and extracted 3× with approx. 150 mL chloroform. The combined organic phases are dried on MgSO4, the solvent is eliminated in vacuo and 16 g E-1 are obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([NH2:8])[CH2:4][CH2:3]1.[CH2:9]([O:11][C:12]([C:14]1[C:19]([O:20][CH2:21][CH3:22])=[C:18]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:17]=[C:16]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36](OC3C=CC=CC=3)=[O:37])=[CH:31][CH:30]=2)[N:15]=1)=[O:13])[CH3:10].CCN(CC)CC>O1CCOCC1>[CH2:9]([O:11][C:12]([C:14]1[C:19]([O:20][CH2:21][CH3:22])=[C:18]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[N:17]=[C:16]([C:29]2[CH:30]=[CH:31][C:32]([NH:35][C:36]([NH:8][N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:37])=[CH:33][CH:34]=2)[N:15]=1)=[O:13])[CH3:10]
Reactant: CCOC(=O)c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)nc(N2CCOCC2)c1OCC
Reactant: CN1CCN(N)CC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(-c2ccc(NC(=O)NN3CCN(C)CC3)cc2)nc(N2CCOCC2)c1OCC
Yield: 45 %

Procedure:
4-methyl-piperazin-1-ylamine (0.52 ml, 2 eq.) was added to a stirred solution of 5-ethoxy-6-morpholin-4-yl-2-(4-phenoxycarbonylamino-phenyl)-pyrimidine-4-carboxylic acid ethyl ester (100 mg, 1 eq.) and Et3N (0.085 ml, 3 eq.) in dioxane (3 ml), the mixture was reacted at 80° C. overnight. The reaction mixture was concentrated, and purified by flash chromatography to give a product (49.2 mg, 45%).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.[CH2:42]([N:44]=[C:45]=[O:46])[CH3:43].CCN(C(C)C)C(C)C.[N-]=C=O.C(O)C(N)(CO)CO>C(Cl)Cl>[CH2:42]([NH:44][C:45](=[O:46])[NH:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:3]=1)[CH3:43]
Reactant: CCN=C=O
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Agent: NC(CO)(CO)CO
Agent: [N-]=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=O)Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an 8 mL vial charged with (R)-1-(3-amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (25 mg, 0.046 mmol) in DCM (1 ml) was added ethyl isocyanate (5.51 μl, 0.070 mmol) and DIEA (0.024 ml, 0.139 mmol). The vial was capped and the contents stirred at room temperature for 16 h. The course of reaction was followed by LCMS analysis. Only minor product formation was observed. Excess isocyanate (1.5 eq) was added and the reaction mixture heated to 40° C. for a further 16 h. Unreacted isocyanate was quenched by adding MP-Trisamine (229 mg, 0.464 mmol) and tumbling the vial for 3 h. The resin was filtered and the volatiles removed in vacuo to afford crude (R)-1-(3-(3-ethylureido)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea which was taken forward without purification. MS ESI calc'd. For C37H36N7O2 [M+H]+ 610. found 610.
Reaction SMILES: [NH2:1][CH:2]([C@H:4]1[C@@H:7]([CH2:8][CH2:9][O:10][C:11](=[O:13])[CH3:12])[NH:6][C:5]1=[O:14])[CH3:3].N1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N+:32]([O-:34])=[O:33])=[O:23]>C(Cl)Cl>[N+:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][C:22]([NH:1][CH:2]([C@H:4]1[C@H:7]([CH2:8][CH2:9][O:10][C:11](=[O:13])[CH3:12])[NH:6][C:5]1=[O:14])[CH3:3])=[O:23])([O-:34])=[O:33]
Reactant: CC(=O)OCC[C@H]1NC(=O)[C@H]1C(C)N
Reactant: O=C(Cl)OCc1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCC[C@@H]1NC(=O)[C@H]1C(C)NC(=O)OCc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 63 %

Procedure:
Trans and cis-3-(1-aminoethyl)-4-(2'-acetoxyethyl)-2-azetidinone (0.6575 g, 0.00328 mole) is dissolved in 10 ml CH2Cl2, cooled to 0° C., and treated with 1.1 mole each of pyridine and o-nitrobenzyl chloroformate. The reaction mixture is stirred at 0° for 20 min, the ice bath is removed and stirring continued for another 30 min. The solution is diluted with CH2Cl2, washed with H2O, dried and evaporated in vacuo. Column chromatography ##STR207## of the residue gives 0.7790 g (0.00206 mole, 63% yield) of the product.
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-])=O)=[C:5]([C:10]([NH2:12])=[O:11])[NH:4][N:3]=1.[CH2:13]([OH:15])C.O>C(O)=O.[Pd]>[CH:13]([NH:7][C:6]1[C:2]([CH3:1])=[N:3][NH:4][C:5]=1[C:10]([NH2:12])=[O:11])=[O:15]
Reactant: CCO
Reactant: Cc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: O
Solvent: O=CO
Product: Cc1n[nH]c(C(N)=O)c1NC=O
Reaction time: 8 h

Procedure:
A mixture of 3-methyl-4-nitropyrazole-5-carboxamide (17.0 g, 0.1 mol) in a mixture of 20 ml of 97-100% formic acid, 160 ml of ethanol and 30 ml of water was hydrogenated overnight at 40°-60° using 150 mg of 5% palladium-on-charcoal at 50 psi. Filtration of the hot solution through Celite and evaporation gave 17.8 g of crude, ochre-colored product which was recrystallized from ethanol: 1st crop 9.3 g colorless, 2nd crop 6.7 g brownish, total yield, 16.0 g (95%).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[C:29]([CH3:36])[C:3]=1[O:4][C:5]1[CH:19]=[CH:18][C:8]([O:9]COCC[Si](C)(C)C)=[C:7]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:6]=1.C1COCC1.S(=O)(=O)(O)O>CO>[Cl:1][C:2]1[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[C:29]([CH3:36])[C:3]=1[O:4][C:5]1[CH:19]=[CH:18][C:8]([OH:9])=[C:7]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH:6]=1
Reactant: Cc1cc([N+](=O)[O-])cc(Cl)c1Oc1ccc(OCOCC[Si](C)(C)C)c(COc2ccc(F)cc2)c1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc([N+](=O)[O-])cc(Cl)c1Oc1ccc(O)c(COc2ccc(F)cc2)c1
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a stirred solution of {2-[4-(2-chloro-6-methyl-4-nitro-phenoxy)-2-(4-fluoro-phenoxymethyl)-phenoxymethoxy]-ethyl}-trimethylsilane (280 mg) in MeOH (2.5 mL)/THF (0.2 mL) was added 6% sulfuric acid in MeOH (2.5 mL) and the resulting solution was stirred for 1 h. The reaction was quenched with 1 N aqueous sodium bicarbonate, extracted with ethyl acetate, the organic layer dried over sodium sulfate and concentrated in vacuo. Flash chromatography (15% ethyl acetate/hexanes) afforded 4-(2-chloro-6-methyl-4-nitro-phenoxy)-2-(4-fluorophen-oxymethyl)-phenol (170 mg) as a yellow semi-solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:18])[C:13]=2[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.ClCC(=O)C[C:23]([O:25][CH3:26])=O.FC1C=CC(N=C=O)=CC=1.COCCO>O1CCOCC1.[Zn]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:18])[C:13]=2[C:14]([O:16][CH2:17][CH2:23][O:25][CH3:26])=[O:15])=[CH:6][CH:7]=1
Reactant: COC(=O)CC(=O)CCl
Reactant: COC(=O)C1=C(Nc2ccc(F)cc2)OCC1=O
Agent: O=C=Nc1ccc(F)cc1
Agent: [Zn]
Solvent: COCCO
Solvent: C1COCCO1
Product: COCCOC(=O)C1=C(Nc2ccc(F)cc2)OCC1=O
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A solution of methyl 2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.063 g, 0.25 mmol) which similarly prepared according to the procedure described in the Example 2, First step using methyl 4-chloroacetoacetate and 4-fluorophenyl isocyanate, 2-methoxyethanol (0.2 mL, 2.5 mmol) and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.0048 g, 0.0050 mmol) in anhydrous dioxane (1.0 mL) was stirred with the microwave synthesizer (Biotage Initiator™) at 120° C. for 1 h. Cooled to ambient temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on silica gel(chloroform/ethyl acetate) to afford 2-methoxyethyl 2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.024 g, y. 33%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:16]([CH3:17])[C:15](=[O:18])[N:14]2[C@@H:19]([CH2:22][C:23]([OH:25])=O)[CH2:20][O:21][CH:13]2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:27]1[C:29]2([CH2:34][CH2:33][NH:32][CH2:31][C@H:30]2[OH:35])[CH2:28]1.CN1CCOCC1>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[C@@H:16]([CH3:17])[C:15](=[O:18])[N:14]2[C@@H:19]([CH2:22][C:23]([N:32]3[CH2:33][CH2:34][C:29]4([CH2:27][CH2:28]4)[C@H:30]([OH:35])[CH2:31]3)=[O:25])[CH2:20][O:21][CH:13]2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@@H]1CNCCC12CC2
Reactant: C[C@H]1C(=O)N2C(CN1C(=O)OCc1ccccc1)OC[C@@H]2CC(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@H]1C(=O)N2C(CN1C(=O)OCc1ccccc1)OC[C@@H]2CC(=O)N1CCC2(CC2)[C@H](O)C1
Yield: 96.5 %

Procedure:
-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (138 mg, 0.36 mmol) was added to a solution of (3S,6S)-3-carboxymethyl-6-methyl-5-oxo-hexahydro-oxazolo[3,2-a]pyrazine-7-carboxylic acid benzyl ester (84 mg, 0.24 mmol), (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (39 mg, 0.24 mmol) and 4-methylmorpholine (73 mg, 0.73 mmol) in DMF(1 mL), then after 16 h the reaction mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; DCM→DCM/MeOH/25% aq. ammonia solution 90:10:0.25) afforded the title compound (106 mg, 96%). Colourless gum, MS: 458.5 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][N:4]([CH2:11][C:12]1[S:16][C:15]([Cl:17])=[N:14][C:13]=1[Cl:18])[CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[C:20]([OH:29])(=[O:28])[C@@H:21]([C@H:23]([C:25]([OH:27])=[O:26])[OH:24])[OH:22].C1COCC1>O>[OH2:22].[C:25]([CH:23]([CH:21]([C:20]([OH:29])=[O:28])[OH:22])[OH:24])([OH:27])=[O:26].[CH3:1][CH:2]([CH3:19])[CH2:3][N:4]([CH2:11][C:12]1[S:16][C:15]([Cl:17])=[N:14][C:13]=1[Cl:18])[CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH3:1][CH:2]([CH3:19])[CH2:3][N:4]([CH2:11][C:12]1[S:16][C:15]([Cl:17])=[N:14][C:13]=1[Cl:18])[CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[C:25]([CH:23]([CH:21]([C:20]([OH:29])=[O:28])[OH:22])[OH:24])([OH:27])=[O:26]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: CC(C)CN(Cc1sc(Cl)nc1Cl)C1CCNCC1
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(O)C(O)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-(2-methylpropyl)-N-[(2,4-dichloro-1,3-thiazol-5-yl)methyl]piperidin-4-amine (193.6 g, 0.6 mol) in 2 L THF at 65° C. are added seed crystals and L-tartaric acid (90.15 g, 0.6 mol, 1 equiv.) solution in 100 ml water dropwise over 5 min (after 15 min the solution becomes turbid and the product begins to crystallize). After 3 h at 64° C., the mixture is cooled down to room temperature, and then stirred for an additional 20 h. The reaction mixture is then cooled down to 10° C. and filtered; the solid is washed with cold THF/water 95/5 and dried under vacuum to afford 245.8 g of N-(2-methylpropyl)-N-[(2,4-dichloro-1,3-thiazol-5-yl)methyl]piperidin-4-amine tartrate hemihydrate (87% yield). 1H NMR (250 MHz, DMSO d6): δ=3.97 (2H, s), 3.69 (2H, s), 3.24 (2H, brd), 2.77 (3H, m), 2.20 (2H, d), 1.63 (5H, m), 0.80 (6H, d); 13C NMR (62 MHz, DMSO d6): δ=175.09, 149.48, 138.32, 131.24, 72.39, 58.12, 55.08, 47.04, 43.29, 26.72, 24.60, 20.81.
Reaction SMILES: FC1C=CC(C2N=CC=CN=2)=C(C=1)C(O)=O.[CH3:17][C:18]1[N:23]=[C:22]([C:24]([OH:26])=O)[C:21]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)=[CH:20][CH:19]=1.C(OC(N1[C@@H]2CC[C@H]1[C@H](COC1C=CC=CN=1)C2)=O)(C)(C)C.[Br:54][C:55]1[CH:56]=[CH:57][C:58]([O:61][CH2:62][CH:63]2[CH2:68][CH:67]3[NH:69][CH:64]2[CH2:65][CH2:66]3)=[N:59][CH:60]=1>>[Br:54][C:55]1[CH:56]=[CH:57][C:58]([O:61][CH2:62][CH:63]2[CH2:68][CH:67]3[N:69]([C:24]([C:22]4[C:21]([N:27]5[N:31]=[CH:30][CH:29]=[N:28]5)=[CH:20][CH:19]=[C:18]([CH3:17])[N:23]=4)=[O:26])[CH:64]2[CH2:65][CH2:66]3)=[N:59][CH:60]=1
Reactant: Brc1ccc(OCC2CC3CCC2N3)nc1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)n1
Agent: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1[C@H](COc1ccccn1)C2
Agent: O=C(O)c1cc(F)ccc1-c1ncccn1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2C3CCC2C(COc2ccc(Br)cn2)C3)n1

Procedure:
Prepared analogous to Example 1 substituting 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid and (1S,2R,4R)-tert-butyl-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate with the title compound of Step A. MS (ESI) mass calcd. for C21H21BrN6O2, 468.1; m/z found 469.1, 471.1 [M+H]+. 1H NMR (CDCl3): 8.20 (d, J=2.6 Hz, 0.4H), 8.16 (d, J=2.6 Hz, 0.6H), 8.13 (d, J=8.3 Hz, 0.4H), 8.10 (d, J=8.4 Hz, 0.6H), 7.82-7.77 (m, 2H), 7.64 (dd, J=8.8, 2.6 Hz, 0.4H), 7.60 (dd, J=8.8, 2.6 Hz, 0.6H), 7.33-7.29 (m, 0.4H), 7.22 (d, J=8.4 Hz, 0.6H), 6.69 (d, J=8.8 Hz, 0.4H), 6.50 (d, J=8.8 Hz, 0.6H), 4.84 (dd, J=11.1, 5.2 Hz, 1H), 4.30-4.04 (m, 2H), 3.93-3.85 (m, 1H), 2.62 (s, 1.3H), 2.38-2.17 (m, 2.7H), 2.11-1.95 (m, 1H), 1.94-1.77 (m, 1H), 1.77-1.40 (m, 4H).
Reaction SMILES: [N:1]([C:12]1[NH:13][C:14]([C:19]#[N:20])=[C:15]([C:17]#[N:18])[N:16]=1)=[N:2][C:3]1[NH:4][C:5]([C:10]#[N:11])=[C:6]([C:8]#[N:9])[N:7]=1.N1C=CC=CC=1>[Zn].C(O)(=O)C>[NH:2]([C:3]1[NH:7][C:6]([C:8]#[N:9])=[C:5]([C:10]#[N:11])[N:4]=1)[NH:1][C:12]1[NH:13][C:14]([C:19]#[N:20])=[C:15]([C:17]#[N:18])[N:16]=1
Reactant: N#Cc1nc(N=Nc2nc(C#N)c(C#N)[nH]2)[nH]c1C#N
Agent: [Zn]
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: N#Cc1nc(NNc2nc(C#N)c(C#N)[nH]2)[nH]c1C#N

Procedure:
2.65 g of 2,2'-azobis(4,5-imidazoledicarbonitrile) was placed in a flask with 65 ml of pyridine and 25 ml of galcial acetic acid. The slurry was then purged and deoxygenated thoroughly with a stream of nitrogen. Then 3 equivalents (1.95 g) of zinc dust was added. An immediate green/black solution was formed characteristic of a radical anion species. This slowly faded to a pale green as the last of the intermediate reacted. The mixture was filtered under nitrogen to remove excess zinc salts. This gave a pale yellow solution of 2,2'-hydrazobis(4,5-imidazoledicarbonitrile). Exposure of an aliquot to the air caused immediate air oxidation back to the bright yellow azo compound which precipitated as the bis pyridinium salt.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[I:28]C1C=C(C=CC=1)C(C(=CNC1C=CC=CC=1)C#N)=O.CCN(C(C)C)C(C)C>C(O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:14][CH2:15]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([I:28])[CH:26]=1
Reactant: N#CC(=CNc1ccccc1)C(=O)c1cccc(I)c1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2ccccc2)c1N
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(I)c2)c1N
Temperature: 160 °C
Yield: 70 %

Procedure:
To a stirred solution of N-cyclopropyl-3-hydrazino-4-methyl-benzamide, trifluoroacetic acid salt 6 (648 mg, 1.74 mmol, 1.0 eq) in 2 mL of ethanol was added 2-(3-iodo-benzoyl)-3-phenylamino-acrylonitrile 2 (550 mg, 1.74 mmol, preparation: International Patent Application Publication No. WO 02/57101 A1, pg. 84) and DIEA (0.50 mL, 2.9 mmol). The mixture was heated to 160° C. for 40 min using microwave. The mixture was concentrated in vacuo. The crude product was purified by silica gel column chromatography (EtOAc/hex, gradient 1/1 to 2/1) to give 3-[5-Amino-4-(3-iodo-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide 7 (589 mg, 70%) as a white solid. MS m/z 497 [M+H]+; 1H NMR (300 MHz, CDCl3) δ0.60 (m, 2H), 0.86 (m, 2H), 2.24 (s, 3H), 2.87 (m, 1H), 5.81 (bs, 2H), 6.35 (bs, 1H), 7.25 (dd, J1=J2=7.8 Hz, 1H), 7.45 (d, J=8.1 Hz, 1H), 7.69 (d, J=1.7 Hz, 1H), 7.80 (m, 3H), 7.89 (m, 1H), 8.00 (s, 1H) ppm.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16]Cl)=[CH:9][C:8]1([CH3:20])[CH3:19])(=[O:3])[CH3:2].[C:21]1([C:27]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[OH:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])O.[K+].[I-].[K+]>O.C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16][N:32]2[CH2:33][CH2:34][CH:29]([C:27]([OH:28])([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:30][CH2:31]2)=[CH:9][C:8]1([CH3:20])[CH3:19])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC1C=CC(C(=O)CCCCl)=CC1(C)C
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)OCCC1C=CC(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)=CC1(C)C

Procedure:
Mix 4-(4-chloro-1-oxobutyl)-2,2-dimethylphenethyl acetate (99.5 g, 0.335 mol), α,α-diphenyl-4-piperidinemethanol (101.8 g, 0.335 mol), potassium hydrogen carbonate (83.8 g, 0.838 mol), potassium iodide (1.00 g, 0.006 mol), toluene (600 mL) and water (220 mL). Stir at reflux for 72 hours, add toluene (200 mL) and deionized water (100 mL). Filter through filter aid while at 80° C. and separate the organic phase. Dry (MgSO4), filter and purify by chromatography (ethyl acetate) to give 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-2,2-dimethylphenethyl acetate as an oily solid.
Reaction SMILES: [C:1]([NH:4][C:5]([CH:16]=[CH:17][CH2:18][CH2:19][CH3:20])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].C[N+]1([O-])CC[O:25]CC1.S([O-])([O-])=O.[Na+].[Na+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[CH2:9]([O:8][C:6](=[O:7])[C:5]([NH:4][C:1](=[O:3])[CH3:2])([CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[O:25])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:10]
Reactant: CCCC=CC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(CCCCC=O)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Diethyl 2-acetamido-2-pentenylmalonate (4.0 g) was dissolved in 210 ml of acetone and 3.3 g of N-methylmorpholine-N-oxide and 36 ml of a 1% aqueous osmium tetraoxide solution were added thereto. The mixture was stirred at room temperature for 2 hours. A solution of 700 mg of sodium sulfite in 20 ml of water was added thereto and the mixture was stirred for 15 minutes. The reaction mixture was concentrated and subjected to silica gel column chromatography using chloroform/methanol (10:1) as an eluent and a fraction having an Rf value: 0.3 (chloroform:methanol=10:1) was concentrated. The residue was dissolved in 630 ml of 1,4-dioxane and 70 ml of a 0.2 M aqueous meta-sodium periodate solution was added thereto. The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtrated, concentrated, extracted with ethyl acetate and washed with water. The hexane layer was dried and concentrated to give 4.17 g of colorless, oily diethyl-2-acetamido-2-(4-formylbutyl)malonate.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1B1OC(C)(C)C(C)(C)O1>>[F:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[C:2]1[S:3][CH:4]=[CH:5][N:6]=1
Reactant: Brc1nccs1
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Product: O=[N+]([O-])c1ccc(F)c(-c2nccs2)c1

Procedure:
2-Bromothiazole (2.1 ml, 22.9 mmol) was coupled to 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (3.0 g, 11.6 mmol) using the method in Example 47. Purification by chromatography on silica gel eluting with dichloromethane then recrystallisation from toluene/isohexane gave 2-(2-fluoro-5-nitrophenyl)thiazole as a brown solid: δH (360 MHz, CDCl3) 7.38 (1H, t, J 9), 7.58 (1H, d, J 3), 8.03 (1H, t, J 3), 8.26-8.31 (1H, m), 9.26 (1H, d, J 6 and 3).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:20])[N:6]2[CH2:16][CH2:17][CH2:18][NH2:19].[CH3:21][O:22][C:23](=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]=O)[CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>CN1C(=O)CCC1>[CH3:21][O:22][C:23](=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][NH:19][CH2:18][CH2:17][CH2:16][N:6]2[C:5](=[O:20])[NH:4][C:3]3[C:7]2=[N:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[N:10][C:2]=3[NH2:1])[CH:26]=1
Reactant: COC(=O)Cc1cccc(C=O)c1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCc3cccc(CC(=O)OC)c3)c2n1
Reaction time: 0.25 h

Procedure:
The product from step (ii) (3.1 g) and methyl(3-formylphenyl)acetate (1.6 g) were dissolved in NMP (30 ml) and stirred for 15 min. Sodium triacetoxyborohydride (3.7 g) was added and the mixture stirred at rt for 20 h. After addition of methanol (1 ml), the mixture was purified by SCX, which afforded the subtitle compound. Yield 3.1 g.