Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:25])([F:24])[C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9]4=[C:10]([C:19](=[O:23])[NH:20][C:21](=[O:22])[N:8]4[C:7]=2[CH:6]=1)[CH:11]=[CH:12][CH:13]=3.Br[CH2:27][CH2:28][OH:29]>CN(C)C=O>[OH:29][CH2:28][CH2:27][N:20]1[C:19](=[O:23])[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[S:15][C:16]4[CH:17]=[CH:18][C:5]([C:4]([F:24])([F:3])[F:25])=[CH:6][C:7]=4[N:8]([C:9]=23)[C:21]1=[O:22]
Reactant: OCCBr
Reactant: O=c1[nH]c(=O)n2c3c(cccc13)Sc1ccc(C(F)(F)F)cc1-2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2cccc3c2n(c(=O)n1CCO)-c1cc(C(F)(F)F)ccc1S3
Reaction time: 1 h

Procedure:
57% Sodium hydride in mineral oil (8.4 g., 0.200 mol.) was added to a stirred solution of 28.0 g (0.0834 mol.) of 10-trifluoromethyl-1H-pyrimido[5,4,3-kl]phenothiazine -1,3(2H)-dione in 220 ml. of dry dimethylformamide. The mixture was stirred for 1 hour at 25°, then 54.0 g. (0.432 mol.) of 2-bromoethanol was added. The resulting mixture was stirred for 4.5 hours at 25°, then filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed on silica gel with chloroform and 90% chloroform-methanol as eluants to give the title compound, m.p. 90°-93° (methanol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[C@@H:14]([OH:37])[C@H:15]([N:23]=[C:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:38][CH:39]([CH3:43])[CH2:40][CH:41]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:41][CH2:40][CH:39]([CH3:43])[CH3:38])[CH2:10][C@@H:9]1[C@@H:14]([OH:37])[C@H:15]([N:23]=[C:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1[C@@H](O)[C@@H](Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)CCN1CCN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](Cc2ccccc2)N=C(c2ccccc2)c2ccccc2)C1
Reaction time: 0.08 h
Yield: 87.8 %

Procedure:
Dissolve (2-(R)-[2-(R)-(benzhydrylidene-amino)-1-(S)-hydroxy-3-phenylpropyl]-piperazine-1-carboxylic acid tert-butyl ester (167 mg, 0.33 mmol) in 1,2-dichloroethane (2.5 mL) and add 3-methylbutyraldehyde (0.042 mL, 0.41 mmol). After 5 min, add sodium triacetoxyborohydride (100 mg, 0.47 mmol) and stir for 1 h. Add saturated aqueous sodium bicarbonate solution (5 mL) and stir for 10 min. Add ethyl acetate and separate the layers. Extract the aqueous layer with ethyl acetate, combine the organic layers, wash the organic layer with saturated aqueous sodium chloridesolution, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with ethyl acetate) to give the title compound as a colorless oil (165 mg, 87%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].Cl>C(Cl)Cl.CCCCCCC.O>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Temperature: 2.5 °C
Yield: 83.4 %

Procedure:
To a solution of 216 g of N-BOC-3(R,S)-hydroxypiperidine in 51 of CH2Cl2 222 ml of triethylamine are added at 0-5° C. 137 g of methanesulfonyl chloride in 300 ml of CH2Cl2 are added dropwise over a period of 45 min, maintaining the temperature at 0-5° C. After additional stirring for 70 minutes 2 l of deionised water are added and the pH is adjusted to 5.9 by addition of about 90 ml of 2 n HCl. The aqueous phase is separated and the organic phase is washed with water. The solution is evaporated to dryness and 270-280 g of an oily residue are obtained. After treating with 1 l of n-heptane crystallization occurs. Crystals are isolated and dried in vacuo. 250 g of N-BOC-3(R,S)-methylsulfonyloxy-piperidine are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][O:24][CH2:25][CH3:26]>CN(C=O)C>[CH2:25]([O:24][CH2:23][O:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1)[CH3:26]
Reactant: CCOC(=O)c1cnc2cc(O)ccn12
Reactant: CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCOc1ccn2c(C(=O)OCC)cnc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11 %

Procedure:
Ethyl 7-hydroxyimidazo[1,2-a]pyridine-3-carboxylate (100 mg, 0.38 mmol) was dissolved in DMF (3 mL) and treated with potassium carbonate (79 mg, 0.57 mmol). The mixture was stirred at ambient temperature for 30 minutes before adding chloromethylethyl ether (40 mg, 0.42 mmol) and heating mixture to 60° C. for 1 hour. The crude mixture was purified by reverse phase chromatography to give ethyl 7-(ethoxymethoxy)imidazo[1,2-a]pyridine-3-carboxylate (11 mg).
Reaction SMILES: N([O-])=O.[Na+].[Cl:5][C:6]1[CH:7]=[C:8]([CH:19]=[CH:20][C:21]=1[Cl:22])[O:9][C:10]1[CH:16]=[CH:15][C:13](N)=[CH:12][C:11]=1[O:17][CH3:18].[I-:23].[K+]>O.S(=O)(=O)(O)O>[Cl:22][C:21]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[CH:16]=[CH:15][C:13]([I:23])=[CH:12][C:11]=2[O:17][CH3:18])=[CH:7][C:6]=1[Cl:5]
Reactant: COc1cc(N)ccc1Oc1ccc(Cl)c(Cl)c1
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: COc1cc(I)ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 0 °C

Procedure:
A solution of sodium nitrite (14.4 g, 208.70 mmol, 1.98 equiv) in water (500 mL) was added dropwise into a solution of 4-(3,4-dichlorophenoxy)-3-methoxyaniline (30 g, 105.58 mmol, 1.00 equiv) in sulfuric acid (1000 mL) with stirring at 0° C. and the mixture was stirred for 30 min at 0° C. The above mixture was added dropwise to a solution of potassium iodide (1000 mL, 5%) in water with stirring at 50° C. The reaction was completed immediately. The reaction mixture was cooled to room temperature, extracted with 3×500 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×500 mL of saturated aqueous sodium bicarbonate and 3×500 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to give 24 g (crude) of 1,2-dichloro-4-(4-iodo-2-methoxyphenoxy)benzene as red oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][CH:8]2[CH:13]([CH3:14])[C:12]([CH3:16])([OH:15])[CH2:11][CH2:10][NH:9]2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].[CH2:24](Br)[CH:25]1[O:29][CH2:28][CH2:27][CH2:26]1>CN(C)C=O>[CH2:24]([N:9]1[CH2:10][CH2:11][C:12]([CH3:16])([OH:15])[CH:13]([CH3:14])[CH:8]1[CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][CH:17]=1)[CH:25]1[O:29][CH2:28][CH2:27][CH2:26]1
Reactant: COc1ccc(CC2NCCC(C)(O)C2C)cc1
Reactant: BrCC1CCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CC2C(C)C(C)(O)CCN2CC2CCCO2)cc1

Procedure:
24.9 gm (0.1 mol) of 2-(p-methoxybenzyl)-3,4-dimethyl-4-hydroxy-piperidine were stirred in 200 ml of dimethylformamide in the presence of 12.6 gm of sodium bicarbonate for 24 hours at 100° C with 19.7 gm (0.12 mol) of tetrahydrofurfuryl bromide. Subsequently, the reaction mixture was evaporated in vacuo, and the residue shaken with a mixture of 150 ml of chloroform and 100 ml of water. After isolation in a separating funnel, the aqueous phase was extracted once more with 50 ml of chloroform. The combined chloroform extracts were washed with water, dried with sodium sulfate and evaporated in vacuo. In analogy to the procedure described in Example 1, the residue was purified by column-chromatography on aluminum oxide (700 gm, activity stage III, neutral), using chloroform as the flow agent. After evaporation of the combined eluates comprising the pure product, a residue of 16 gm was obtained, which was further reacted as such in the following step.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:22][C@H:23]1[NH:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1>>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([N:28]4[CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:24][C@H:23]4[CH3:22])=[O:18])=[CH:13][CH:12]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Yield: 91.8 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.2 g, 0.69 mmol) and (R)-tert-butyl 3-methylpiperazine-1-carboxylate (0.139 g, 0.69 mmol) according to the example 1, which was given (R)-tert-butyl 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-3-methylpiperazine-1-carboxylate as a white solid (0.297 g, 91.0% yield).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=O)=O.[CH:18]1[C:23]([NH:24][NH2:25])=[CH:22][CH:21]=[C:20]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:19]=1.Cl>C(O)C>[F:1][C:2]([F:17])([F:16])[C:3]1[C:5]2[C:6](=[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]3=[CH:13][CH:14]=2)[N:24]([CH:23]2[CH2:22][CH:21]=[C:20]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:19]=[CH:18]2)[N:25]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C1c2ccccc2CCC1C(=O)C(F)(F)F
Agent: Cl
Solvent: CCO
Product: NS(=O)(=O)C1=CCC(n2nc(C(F)(F)F)c3ccc4ccccc4c32)C=C1

Procedure:
A 100 mL one necked round bottomed flask equipped with reflux condenser, nitrogen inlet and provisions for magnetic stirring was charged with 2-trifluoroacetyl-1-tetralone (1.21 g, 5.0 mmol), 4-sulfonamido phenylhydrazine hydrochloride (1.12 g, 5.0 mmol) and 25 mL of absolute ethanol. The solution was then warmed to reflux for 15 h and then concentrated in vacuo. The residue was dissolved in ethyl acetate and then washed with water, brine, dried over anhyd. MgSO4, filtered and concentrated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and isooctane to give g, 71% of pure produce with mp 257°-258° C. 1H NMR (CDCl3 /CD3OD, 4:1) δ2.7 (m, 2H), 2.9 (m, 2H), 6.6 (m, 1H), 6.9 (m, 1H), 7.1 (m, 1H), 7.16 (m, 1H), 7.53 (m, 2H), 7.92 (m, 2H); 19 F NMR CDCl3 δ-62.5. FAB-MS M+H=394.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1Cl.P.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:17][C:18]([CH3:20])=[O:19]>C(Cl)C=CC1C=CC=CC=1.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:17][C:18](=[O:19])[CH3:20]
Reactant: Cc1cccc(C)c1Cl
Reactant: CC(C)=O
Agent: [Pd]
Agent: ClCC=Cc1ccccc1
Agent: O=C([O-])[O-]
Product: CC(=O)Cc1c(C)cccc1C
Yield: 84 %

Procedure:
This reaction is carried out in the same manner as the reaction in example 3. The difference is that, the reactants are 2,6-dimethylphenyl chloride (142.4 mg, 1.0 mmol), palladium cinnamyl chloride (7.8 mg, 0.015 mmol), 2-Methoxy-6-(N-methyl-N-phenyl-amino)phenyldicyclohexyl)phosphine (24.4 mg, 0.060 mmol), Cs2CO3 (651.9 mg, 2.0 mmol) in 4.0 mL acetone at 90° C. for 22 h. 1-(2′,6′-Dimethylphenyl)-2-propanone (138.4 mg) was obtained with a yield of 84% as liquid. 1H NMR (300 MHz, CDCl3) δ 7.15-7.03 (m, 3H, ArH), 3.79 (s, 2H, CH2), 2.27 (s, 6H, 2×ArCH3), 2.17 (s, 3H, COCH3); 13C NMR (75 MHz, CDCl3) δ 206.2, 136.7, 132.1, 128.1, 126.9, 45.0, 29.2, 20.2; IR (neat) v (cm−1) 3021, 2922, 2867, 1715, 1589, 1470, 1446, 1415, 1379, 1357, 1317, 1223, 1158, 1095, 1053, 1031; MS (70 eV, EI) m/z (%): 163 (M++1, 3.30), 162 (M+, 27.85), 119 (100); HRMS calcd for C11H14O (M+): 162.1045. Found: 162.1046.
Reaction SMILES: [NH2:1][C:2]1[C:10]([I:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:13]([NH2:15])=O>CN1C(=O)CCC1>[I:11][C:10]1[C:9]([CH3:12])=[CH:8][CH:7]=[C:3]2[C:2]=1[N:1]=[CH:13][NH:15][C:4]2=[O:5]
Reactant: NC=O
Reactant: Cc1ccc(C(=O)O)c(N)c1I
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(=O)[nH]cnc2c1I
Temperature: 210 °C
Yield: 88 %

Procedure:
2-Amino-3-iodo-4-methylbenzoic acid (8.00 g, 29 mmol), formamide (11 mL, 289 mmol) and NMP (11 ml) were added to an 80 mL microwave vessel. The mixture was heated for 15 min at 210° C. The mixture was diluted with ice water and the precipitated solid collected by filtration. The solid was washed with water and dried to give 8-iodo-7-methylquinazolin-4(3H)-one (7.3 g, 88%) as a light brown solid. MS (M+H)+ 287.
Reaction SMILES: BrCCBr.Cl[C:6]1([F:18])[C:11](Cl)([F:12])[O:10][C:9]([F:15])([F:14])[C:8]([F:17])([F:16])[O:7]1>CN(C=O)C.[Zn]>[F:15][C:9]1([F:14])[C:8]([F:16])([F:17])[O:7][C:6]([F:18])=[C:11]([F:12])[O:10]1
Reactant: FC1(F)OC(F)(Cl)C(F)(Cl)OC1(F)F
Agent: [Zn]
Solvent: BrCCBr
Solvent: CN(C)C=O
Product: FC1=C(F)OC(F)(F)C(F)(F)O1
Yield: 45.1 %

Procedure:
A suspension of 39.2 g (0.60 mol) of zinc dust in 300 mL of dry DMF was stirred under N2 while 5 mL of 1,2-dibromoethane was added. Then a small portion of 74.0 g (0.28 mol) of dichloride 5 was added, and the mixture was stirred and heated. When an exothermic reaction started (about 75° C.), the rest of 5 was added dropwise at a rate sufficient to maintain 110°-120° C. in the pot while product was collected in a -80° C. trap. When the addition was completed, the mixture was heated to reflux to drive out the last of the product. Fractionation of the crude volatile product gave 24.5 g (45%) of pure perfluoro-2,3-dihydro-1,4-dioxin (7), bp 18°-19.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]C)=O.[CH3:12][C:13]([CH3:15])=[O:14].C[O-].[Na+]>C1COCC1>[NH2:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[CH2:12][C:13](=[O:14])[CH3:15])[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)CC(=O)c1cccc(N)c1
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
To a solution of methyl 3-aminobenzoate (7 g, 46.36 mmol) in THF (150 mL) was added acetone (7.5 g, 102 mmol). The solution was warmed to 35° C. where sodium methoxide (3 g, 55.63 mmol) was added sequentially over 20 minutes. The mixture was stirred for 30 minutes, and then brought to reflux for 3 hours. The solvent was removed under reduced pressure and the residue taken up in ethyl acetate. The resulting solution was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 1-(3-aminophenyl)-1,3-butanedione as a brown oil (3.1 g, 37%). This oil was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[OH:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:39][C:40]2[C:41]([O:55][CH3:56])=[N:42][CH:43]=[C:44](B3OC(C)(C)C(C)(C)O3)[CH:45]=2)(=[O:38])=[O:37])=[CH:32][C:31]=1[CH3:57].C(=O)([O-])[O-].[Cs+].[Cs+]>>[NH2:1][C:2]1[C:3]([C:44]2[CH:45]=[C:40]([NH:39][S:36]([C:33]3[CH:34]=[CH:35][C:30]([OH:29])=[C:31]([CH3:57])[CH:32]=3)(=[O:38])=[O:37])[C:41]([O:55][CH3:56])=[N:42][CH:43]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(=O)(=O)c1ccc(O)c(C)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ncc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1NS(=O)(=O)c1ccc(O)c(C)c1
Yield: 52.4 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (63 mg, 0.14 mmol) was treated with 4-hydroxy-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-3-methylbenzenesulfonamide (90 mg, 0.21 mmol), 2M cesium carbonate (430 μl, 0.86 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (12 mg, 0.01 mmol) according to the method described in Example 3 to give 48 mg (51% yield) of the title compound. Purity 100%.
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:1][C:8]#[N:9]
Reactant: Brc1ccccn1
Reactant: N#CCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#CCc1ccccc1-c1ccccn1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
To a solution of benzylcyanide (12.33 g) in tetrahydrofuran (85 ml) was added dropwise, at -70° C. in argon streams, a hexane solution (65 ml) of n-butyl lithium. The mixture was then stirred for 30 minutes at -50° C., to which was then added dropwise 2-bromopyridine (9.7 ml). The reaction temperature was gradually raised up to 0° C. Fifteen minutes later, a saturated ammonium chloride solution was added to the reaction mixture, which was subjected to extraction with ethyl acetate. The extract solution was washed with water, dried over anhydrous sodium sulfate and concentrated to dryness. The concentrate was purified by means of a silica gel column chromatography to give the title compound (6.59 g).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].CC(C)=O.[ClH:27]>C(O)C.O>[ClH:27].[O:14]([CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOc2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCOc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The above ester (3.5 g, 13 mmol) was dissolved in ethanol (35 ml) and 4N sodium hydroxide (3.2 ml) was added. The mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water and 4M hydrochloric acid (6.3 ml) was added. The mixture was concentrated in vacuo and dichloromethane (50 ml) and acetone were added to the residue. The mixture was concentrated in vacuo to give a solid residue which was heated at reflux with acetone (500 ml). The mixture was filtered while still hot and the filtrate was left overnight for crystallisation. The solid which formed was isolated by filtration and dried to give 1.0 g of the title compound as a solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])[CH:3]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].[NH2:36][C:37]1[C:38]([C:44]([NH:46][NH2:47])=[O:45])=[N:39][C:40](Br)=[CH:41][N:42]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[NH2:36][C:37]1[C:38]([C:44]([NH:46][NH2:47])=[O:45])=[N:39][C:40]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]([C:9]#[N:10])([CH3:12])[CH3:11])[CH:3]=2)=[CH:41][N:42]=1
Reactant: NNC(=O)c1nc(Br)cnc1N
Reactant: CC(C)(C#N)c1cc(I)ccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C#N)c1cc(-c2cnc(N)c(C(=O)NN)n2)ccn1
Temperature: 110 °C
Yield: 58.9 %

Procedure:
2-(4-iodo-2-pyridyl)-2-methyl-propanenitrile (100 mg, 0.3675 mmol), PdCl2(PCy3)2 (20.87 mg, 0.02827 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (96.90 mg, 0.3816 mmol), potassium acetate (83.23 mg, 0.8481 mmol) in 1,4-dioxane (1.615 mL). The reaction mixture was degassed with 5× vacuum/nitrogen cycles then heated at 110° C. for 4 hours. 3-amino-6-bromo-pyrazine-2-carbohydrazide (65.60 mg, 0.2827 mmol), potassium carbonate (136.7 mg, 0.9894 mmol), [PdCl2(dppf)].dichloromethane (23.09 mg, 0.02827 mmol) and water (0.89 mL) was added and the mixture was heated at 100° C. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between dichloromethane and water. Combined organic extract were dried over MgSO4 and concentrated in vacuo yielding an oil. Purified by silica gel chromatography eluted with 5% methanol/dichloromethane. Product fractions were combined and concentrated in vacuo to yield 3-amino-6-[2-(1-cyano-1-methyl-ethyl)-4-pyridyl]pyrazine-2-carbohydrazide as a beige solid (49.5 mg, 57.1%) LC/MS m/z 298.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27](C(OCC)C)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([CH:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH:41](OC)[O:42]C)[N:36]=2)[OH:34])=[C:7]([Cl:46])[N:6]=1)[CH2:2][CH2:3][CH3:4].Cl.[OH-].[Na+]>O1CCCC1>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([CH:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH:41]=[O:42])[N:36]=2)[OH:34])=[C:7]([Cl:46])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C(O)c2cccc(C(OC)OC)n2)n1Cc1ccc(-c2ccccc2-c2nnnn2C(C)OCC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCc1nc(Cl)c(C(O)c2cccc(C=O)n2)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.2 %

Procedure:
150 mg (0.23 mmole) of the compound obtained in step 1 of Example 1 was dissolved in 3 ml of tetrahydrofuran and to the resulting solution was added 2 ml of aqueous 4N HCl solution. The resultant was stirred for 15 hours at room temperature, neutralized with aqueous 4N NaOH solution, concentrated under reduced pressure and purified with silica gel column chromatography to obtain 101 mg of the title compound (yield 83%).
Reaction SMILES: [CH2:1]([C:3]1([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:8][CH2:7][CH:6]([O:9][C:10]2[C:21]3[C:20]4[C@@H:19]([CH2:22][CH2:23][OH:24])[CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1)[CH3:2].C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-:45][Cr](O[Cr]([O-])(=O)=O)(=O)=O>CN(C)C=O>[C:28]([O:27][C:26]([NH:25][C:3]1([CH2:1][CH3:2])[CH2:8][CH2:7][CH:6]([O:9][C:10]2[C:21]3[C:20]4[C@@H:19]([CH2:22][C:23]([OH:45])=[O:24])[CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1)=[O:32])([CH3:31])([CH3:30])[CH3:29]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CCC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CCO)CC4)CC1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CCC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(=O)O)CC4)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 53.9 %

Procedure:
To a 50-mL round-bottom flask containing a solution of tert-butyl N-(1-ethyl-4-[[(3R)-3-(2-hydroxyethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)carbamate (180 mg, 0.39 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL) was added PDC (716 mg, 1.90 mmol, 4.88 equiv) and the resulting solution was stirred for 14 hrs at 25° C. The reaction was then quenched by the addition of 20 mL of water and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1) to give the desired 2-[(3R)-12-[(4-[[(tert-butoxy)carbonyl]amino]-4-ethylcyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-3-yl]acetic acid (100 mg, 54%) as a colorless oil. MS (ES): m/z 476 [M+H]+.