Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([N:11]2[CH2:42][CH2:41][C:14]3([C:19](=[O:20])[N:18]([CH2:21][C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24](S(C5C=CC(C)=CC=5)(=O)=O)[CH:23]=4)[CH2:17][CH2:16][CH2:15]3)[CH2:13][CH2:12]2)[CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CO.C(OCC)(=O)C>[NH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([CH2:21][N:18]2[CH2:17][CH2:16][CH2:15][C:14]3([CH2:13][CH2:12][N:11]([C:3]4[CH:2]=[N:1][C:10]5[C:5]([CH:4]=4)=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH2:42][CH2:41]3)[C:19]2=[O:20])=[CH:23]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(CN3CCCC4(CCN(c5cnc6ccccc6c5)CC4)C3=O)c3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1N(Cc2c[nH]c3ccccc23)CCCC12CCN(c1cnc3ccccc3c1)CC2
Yield: 73 %

Procedure:
The mixture of 9-(quinolin-3-yl)-2-((1-tosyl-1H-indol-3-yl)methyl)-2,9-diazaspiro[5.5]undecan-1-one (60 mg, 0.1 mmol) and Cs2CO3 (150 mg, 0.46 mmol) in methanol (2 mL) was heated under reflux for 18 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (31 mg, 71%). [1H NMR (600 MHz, DMSO-d6) ♀ ppm 10.94 (br. s., 1H), 8.86 (d, 1H), 7.86-7.83 (m, 1H), 7.77-7.75 (m, 1H), 7.56-7.52 (m, 2H), 7.48-7.43 (m, 2H), 7.34 (d, 1H), 7.28 (d, 1H), 7.06 (t, 1H), 6.95 (t, 1H), 4.64 (s, 2H), 3.77-3.68 (m, 2H), 3.19-3.13 (m, 2H), 3.06 (t, 2H), 2.30-2.19 (m, 2H), 1.80-1.72 (m, 2H), 1.72-1.63 (m, 2H), 1.60-1.50 (m, 2H); LCMS RtA=1.05 min, [M+H]+=425.3].
Reaction SMILES: C(=O)([O-])O.[Na+].I[C:7]1[C:12]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]=[C:9]([CH3:28])[N:8]=1.[C:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O)(=[O:31])[CH3:30].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][CH:15]=[C:14]2[O:13][C:12]1[C:7]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[C:29](=[O:31])[CH3:30])=[N:8][C:9]([CH3:28])=[CH:10][CH:11]=1
Reactant: CC(=O)c1ccccc1B(O)O
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccccc3C(C)=O)c2cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
Toluene (1 ml) and a saturated aqueous sodium hydrogencarbonate solution (0.5 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 2-acetylphenylboronic acid (97 mg) under an argon atmosphere, and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, a 1 N aqueous sodium hydroxide solution was then added, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (10 mg, yield 20%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>>[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:9]1[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]1)[NH:20][C:19]2=[O:29]
Reactant: OB(O)c1ccccc1Cl
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Product: O=C(O)c1cnn(-c2nc3ccc(-c4ccccc4Cl)cc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 2-chlorophenylboronic acid in step C. MS (ESI): mass calcd. for C18H11ClN4O3, 366.1; m/z found, 367.0 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 12.99 (s, 2H), 8.98 (d, J=0.6 Hz, 1H), 8.27 (s, 1H), 8.13 (d, J=2.1 Hz, 1H), 7.91 (dd, J=8.4, 2.1 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.64-7.61 (m, 1H), 7.55-7.52 (m, 1H), 7.47 (pd, J=7.4, 1.8 Hz, 2H).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[S:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](N1C=CN=C1)(N1C=CN=C1)=O.C[O-].[Na+]>CN(C)C=O.CO>[C:1]1([CH2:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([O:12][CH3:17])=[S:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OC(=S)c1cccnc1Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=S)c1cccnc1Cc1ccccc1
Temperature: 25 °C
Yield: 95.3 %

Procedure:
A solution of 18.3 g (75 mmol) of 2-phenylmethylthionicotinic acid and 16.2 g (100 mmol) of carbonyldiimidazole in 250 mL of dry dimethylformamide was stirred at room temperature for 2 hours. The solution was cooled to 0° and 25 mL of 4M sodium methoxide in methanol was added. After warming to room temperature the solution was partitioned between ether and water and the aqueous layer was washed with two portions of ether. The ether extracts were washed with brine, dried over MgSO4, and concentrated. The residue was crystallized from ether-hexane to afford 17.4 g (89%) of fine white needles, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:20])[CH2:18][OH:19])=[CH:13][C:10]=3[C:11](=[O:12])[C:5]2=[CH:4][C:3]=1[C:21]([O:23]CC)=[O:22].C(O)C.[OH-].[Na+]>O>[NH2:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:20])[CH2:18][OH:19])=[CH:13][C:10]=3[C:11](=[O:12])[C:5]2=[CH:4][C:3]=1[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)c1cc2c(=O)c3cc(C(C)CO)ccc3oc2nc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(CO)c1ccc2oc3nc(N)c(C(=O)O)cc3c(=O)c2c1
Temperature: 50 °C
Yield: 87.6 %

Procedure:
A mixture of ethyl 2-amino-7-(2-hydroxy-1-methylethyl)-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylate (480 mg), ethanol (40 ml), water (5 ml) and 1N sodium hydroxide (5 ml) was heated at 50° C. for 80 minutes, which was then concentrated. The concentrate was dissolved in water, which was made acid with 10% hydrochloric acid. Resulting precipitates were collected by filtration, washed with water, and recrystallized from dimethylformamide-ethanol-water to yield colorless crystals (386 mg) of 2-amino-7-(2-hydroxy-1-methylethyl)-5-oxo-5H-[1]benzopyrano-[2,3-b]pyridine-3-carboxylic acid, m.p. >300° C.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:26](=[O:45])[CH2:27][C@@H:28]([O:43][CH3:44])[C@@H:29]([N:34]([CH3:42])[C:35](=[O:41])[C@H:36]([CH:38]([CH3:40])[CH3:39])[NH2:37])[C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@@H:4]([CH3:20])[C:5]([NH:7][C@H:8]([C:16]([O:18]C)=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6].[CH3:46][N:47]1[CH2:54][CH2:53][CH2:52][C@@:48]1([CH3:55])[C:49](O)=[O:50].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Li+].[OH-]>ClCCl.O>[CH3:46][N:47]1[CH2:54][CH2:53][CH2:52][C@@:48]1([CH3:55])[C:49]([NH:37][C@H:36]([C:35]([N:34]([C@@H:29]([C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@H:28]([O:43][CH3:44])[CH2:27][C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:21]1[C@H:3]([O:2][CH3:1])[C@@H:4]([CH3:20])[C:5]([NH:7][C@H:8]([C:16]([OH:18])=[O:17])[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:6])=[O:45])[CH3:42])=[O:41])[CH:38]([CH3:39])[CH3:40])=[O:50]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](N)C(C)C
Reactant: CN1CCC[C@@]1(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(C)CCCN1C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring mixture of #114 (125 mg, 0.198 mmol, 1.0 eq), #150 (37 mg, 0.26 mmol, 1.3 eq.), and HATU (98 mg, 0.26 mmol, 1.3 eq.) in 5 mL of dichloromethane, Hunig's base (0.14 mL, 0.80 mmol, 4.1 eq.) was added. The reaction was allowed to stir at room temperature for 1 hour. Reaction was concentrated in vacuo. THF (6 mL) was added to crude material. To this stirring mixture LiOH (14 mg, 0.59 mmol, 3.0 eq) dissolved in 2 mL of water was added. Reaction was allowed to stir at room temperature for 90 minutes. Reaction was concentrated in vacuo and residue was purified by medium pressure reverse phase C18 chromatography (Gradient: 5% to 40% acetonitrile in water with 0.02% TFA in each phase) #151 (147 mg, 69%) as a white solid. LC-MS (Protocol Q): m/z 744.3 [M+H+], retention time=1.19 minutes; HPLC (Protocol A at 45° C.): m/z 744.4 [M+H+], retention time=6.631 minutes (purity >98%). 1H NMR (400 MHz, DMSO-d6), δ 9.57-9.71 (m), 8.75 (d), 8.42 (d), 8.15 (d), 7.14-7.29 (m), 4.70-4.79 (m), 4.40-4.68 (m), 3.95-4.03 (m), 3.73-3.80 (m), 3.37-3.61 (m), 2.97-3.31 (m), 2.79-2.88 (m), 2.66-2.76 (m), 2.54-2.58 (m), 2.31-2.43 (m), 1.94-2.29 (m), 1.57-1.91 (m), 1.21-1.52 (m), 0.85-1.10 (m), 0.74-0.82 (m)
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:29]=[CH:28][C:11]([C:12]([C:14](=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=O)=[CH:10][CH:9]=2)[N:3]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:37](=[O:42])/[CH:38]=[C:39](\[NH2:41])/[CH3:40]>C(O)C>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH:20]1[C:38]([C:37](=[O:42])[NH:36][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=2)=[C:39]([CH3:40])[NH:41][C:12]([C:11]2[CH:28]=[CH:29][C:8]([N:4]3[C:5]([CH3:7])=[N:6][C:2]([CH3:1])=[N:3]3)=[CH:9][CH:10]=2)=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(=Cc1ccccc1Cl)C(=O)c1ccc(-n2nc(C)nc2C)cc1
Reactant: C/C(N)=C/C(=O)Nc1ccccn1
Solvent: CCO
Product: CCOC(=O)C1=C(c2ccc(-n3nc(C)nc3C)cc2)NC(C)=C(C(=O)Nc2ccccn2)C1c1ccccc1Cl
Yield: 6.4 %

Procedure:
A mixture of the product from step (a) (566 mg, 1.38 mol) and N-(2-pyridyl)-3-aminocrotonamide (245 mg, 1.38 mmol) in ethanol (10 ml) was heated at reflux under nitrogen for 8 hours. The solvent was removed and the residue purified by flash chromatography (eluting with 2% diethylamine in ethyl acetate) to afford the title compound (50 mg, 6%) as a white solid, m.p. 130° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([NH:23][CH2:14][C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Product: Cc1noc(-c2ccc(Br)cc2)c1CNCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and benzylamine.
Reaction SMILES: [C@@H:1]12[C:10](=[O:11])[O:9][C:7](=O)[C@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.Cl.[NH2:13][CH2:14][C:15]#[N:16].C(N(CC)CC)C.ClC(OCC(C)C)=O.[BH4-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.O.ClCCl>[C:14]([CH2:15][NH:16][C:10]([C@@H:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:7][OH:9])=[O:11])#[N:13]
Reactant: N#CCN
Reactant: O=C1OC(=O)[C@H]2CCCC[C@H]12
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: N#CCNC(=O)[C@@H]1CCCC[C@H]1CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
trans-1,2-Cyclohexanedicarboxylic anhydride (19.64 g, 127 mmol) and aminoacetonitrile hydrochloride (12.05 g, 130 mmol) were weighed into a dry 500 mL flask fitted with a stir bar and nitrogen inlet. After adding anhydrous dichloromethane (200 mL), triethylamine (39.1 mL, 281 mmol) was added at a moderate rate, allowing the reaction to warm the solution to near boiling point. The reaction mixture was allowed to cool to room temperature over 1 h, after which it was cooled to −10° C. and isobutyl chloroformate (18.2 mL, 140 mmol) was added dropwise, keeping the reaction temperature below 0° C. After the addition was complete, the reaction was allowed to warm to room temperature. After 1 h, the reaction mixture was diluted with anhydrous tetrahydrofuran (200 mL) and stired at 0° C. for 1 h. The precipitate were filtered and washed with cold anhydrous tetrahydrofuran (100 mL). The filtrate was taken in a 1000 mL flask and fitted with a stir bar and a 50 mL addition funnel. The solution was cooled to −25° C. and a solution of sodium borohydride (6.90 g, 182 mmol) in water (30 mL) was added at a slow dropping rate, keeping the reaction temperature below −15° C. After the addition was complete, the reaction mixture was stirred for 1 h between −20° C. and −10° C. After warming the reaction mixture to warm to room temperature and stirring for an additional 1 h, anhydrous magnesium sulfate was added and stirring was continured for additional 30 min, filtered and the filtrate was concentrated on a rotary evaporator. Product was purified from the residue by chromatography using 9:1 dichloromethane:methanol eluent. The product fractions were concentrated on a rotary evaporator and dried under high vacuum to give trans-N-cyanomethyl-2-hydroxymethyl-cyclohexanecarboxamide as a white solid.
Reaction SMILES: [CH2:1](C(C(OCC)=O)C(OCC)=O)CCC.[CH3:16][O:17][CH2:18][C:19]#[C:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]23[O:34][CH2:33][C:30]([CH2:35][CH2:36][CH3:37])([CH2:31][O:32]2)[CH:29]([C:38]([F:41])([F:40])[F:39])[O:28]3)=[CH:23][CH:22]=1>>[CH2:35]([C:30]12[CH2:33][O:34][C:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]#[C:19][CH2:18][O:17][CH3:16])=[CH:26][CH:25]=3)([O:32][CH2:31]1)[O:28][CH:29]2[C:38]([F:41])([F:39])[F:40])[CH2:36][CH2:37][CH3:1]
Reactant: CCCC12COC(c3ccc(C#CCOC)cc3)(OC1)OC2C(F)(F)F
Reactant: CCCCC(C(=O)OCC)C(=O)OCC
Product: CCCCC12COC(c3ccc(C#CCOC)cc3)(OC1)OC2C(F)(F)F

Procedure:
4-n-Butyl-1-[4-(3-methoxyprop-1ynyl)phenyl]-3-trifluoromethyl-2,6,7-trioxabicyclo[2,2,2]octane was prepared from diethyl n-butyl-malonate in a manner analogous to the synthesis of 1-[4-(3-methoxyprop-1-ynyl)phenyl]-4-n-propyl-3-trifluoromethyl-2,6,7-trioxabicyclo[2,2,2]octane.
Reaction SMILES: CP(C)C.O1CCCC1.[CH2:10]([O:12][C:13]([C@:15]1([N:28]=[N+]=[N-])[C@@H:20]([OH:21])[CH2:19][C@@H:18]2[C@H:16]1[C@@:17]2([F:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:14])[CH3:11].C(=O)([O-])O.[Na+]>O1CCCC1.O.C(OCC)C>[CH2:10]([O:12][C:13]([C@:15]1([NH2:28])[C@@H:20]([OH:21])[CH2:19][C@@H:18]2[C@H:16]1[C@@:17]2([F:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:14])[CH3:11]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@H](O)[C@@](N=[N+]=[N-])(C(=O)OCC)[C@@H]21
Agent: CP(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@]1(N)[C@H]2[C@@H](C[C@@H]1O)[C@]2(F)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
0.89 mL of a solution of 1M trimethylphosphine/tetrahydrofuran was added to 245 mg of (1R,2R,3S,5R,6R)-2-azido-6-fluoro-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in 7.0 mL of tetrahydrofuran and 0.7 mL of water, and the mixture was stirred for 12 hours at room temperature. After the mixture was diluted with 14 mL of diethyl ether, a saturated aqueous solution of sodium hydrogen carbonate was added thereto, and the mixture was stirred for 1 hour at room temperature. After separation, the aqueous layer was extracted twice with chloroform. The organic layers were combined, washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure The residue was purified by column chromatography (silica gel: Wako gel C200 (made by Wako Pure Chemical Industries Ltd.), eluent: chloroform-ethanol=50:1), thereby yielding 163 mg of (1R,2R,3S,5R,6R)-2-amino-6-fluoro-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: [C:1]1(=[O:21])[N:5]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:2]12.[Cl:22][CH:23]([CH3:27])[C:24](Cl)=[O:25]>>[C:4]1(=[O:16])[N:5]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:24](=[O:25])[CH:23]([Cl:22])[CH3:27])=[CH:12][CH:11]=2)[C:1](=[O:21])[C:2]2=[CH:20][CH:19]=[CH:18][CH:17]=[C:3]12
Reactant: CC(Cl)C(=O)Cl
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1ccccc1
Product: CC(Cl)C(=O)c1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1

Procedure:
By treating [3-(phthalimido)propoxy]benzene and 2-chloropropionyl chloride in the same manner as in Example 79-(1), 4-[3-(phthalimido)propoxy]-1-(2-chloropropionyl)benzene was obtained.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[OH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1>>[CH3:7][N:6]1[C:2]([O:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)C1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Product: Cn1ncc([N+](=O)[O-])c1O[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Yield: 97 %

Procedure:
Following the procedure for Example 230, reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate gave (S)-tert-butyl 3-(1-methyl-4-nitro-1H-pyrazol-5-yloxy)piperidine-1-carboxylate as a pale yellow oil (0.35 g, 97%). 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 5.15-4.85 (m, 1H), 3.84-3.72 (m, 2H), 3.69 (s, 3H), 3.41 (d, J=14.2 Hz, 1H), 3.30-3.13 (m, 1H), 2.11-2.02 (m, 1H), 1.94-1.82 (m, 2H), 1.63-1.52 (m, 1H), 1.42 (s, 9H)
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13]C=C[N:10]=2)[CH:6]=[C:5]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)[CH:20]=2)[CH:4]=1.BrC1C=C(C2C=C(C3C=CN(C)N=3)N=C(NC)C=2)[CH:36]=[N:37]C=1>>[CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)[CH:20]=2)[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][N:37]([CH3:36])[N:10]=2)[N:8]=1
Reactant: CNc1cc(-c2cncc(-c3cnn(C4CCNCC4)c3)c2)cc(-c2ccccn2)n1
Reactant: CNc1cc(-c2cncc(Br)c2)cc(-c2ccn(C)n2)n1
Product: CNc1cc(-c2cncc(-c3cnn(C4CCNCC4)c3)c2)cc(-c2ccn(C)n2)n1

Procedure:
This compound is prepared analogously to Methyl-[5″-(1-piperidin-4-yl-1H-pyrazol-4-yl)-[2,2′;4′,3″]terpyridin-6′-yl]-amine (Example 2.183) by replacing (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-methyl-amine (Example 2.1; step1) by [5-Bromo-6′-(1-methyl-1H-pyrazol-3-yl)-[3,4′]bipyridinyl-2′-yl]-methyl-amine (Example 2.178, step 1).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[OH:33][CH2:32][C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]3=[N:6][CH:7]=2)=[N:31][CH:30]=1
Reactant: Nc1ccc(CO)cn1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(CO)cn3)nc12
Temperature: 110 °C
Yield: 45.3 %

Procedure:
To a 35 ml seal tube, 1-(2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl)-2,2-dimethylpropane-1-one (1.0 g, 0.00242 mole) and (6-aminopyridin-3-yl)methanol (0.36 g, 0.00291 mole) was taken in toluene (10.0 ml). The reaction mixture was purged with argon for 15 min at RT followed by Cs2CO3 (3.1 g, 0.0097 mole) was added and further purged for 30 min with argon. BINAP (0.03 g, 0.000048 mole) and Pd(OAc)2 (0.01 g, 0.000048 mole) were added and the reaction mixture was heated to 110° C. for 16 hrs. After completion of the reaction, the reaction mixture was filtered through celite bed and washed with ethyl acetate. Filtrate was collected and concentrated to afford crude product which was purified using column purification by eluting the compound with 20-25% ethyl acetate in hexanes to yield 0.5 g of 1-(2-(5-(hydroxymethyl)pyridin-2-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethylpropan-1-one.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:16])[CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[CH:31])=[N:28][CH:29]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[C:31][C:2]3[CH:3]=[CH:4][C:5]([N:8]([CH3:16])[CH2:9][CH2:10][N:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)=[N:6][CH:7]=3)=[N:28][CH:29]=2)=[CH:22][CH:23]=1
Reactant: CN(CCN1CCCC1)c1ccc(I)cn1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: CN(CCN1CCCC1)c1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cn1

Procedure:
Prepared according to general working method I from (5-iodo-pyridin-2-yl)-methyl-(2-pyrrolidin-1-yl-ethyl)-amine (100 mg, 0.30 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (65 mg, 0.30 mmol).
Reaction SMILES: [Li]CCCC.[CH2:6]([O:9][CH2:10][C:11]([O:13]CC)=O)[CH:7]=[CH2:8].I[CH2:17][Cl:18].CC(O)=O>C1COCC1.CCOCC>[CH2:6]([O:9][CH2:10][C:11]([CH2:17][Cl:18])=[O:13])[CH:7]=[CH2:8]
Reactant: ClCI
Reactant: C=CCOCC(=O)OCC
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCOCC(=O)CCl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of iPr2Net (3.1 eq) in THF at −78° C. was added dropwise BuLi (1.4 M. in hexanes, 3.1 eq). The resulting mixture was stirred at 0° C. for 15 min, cooled again to −78° C. and added via cannula to a solution of ethyl (allyloxy)acetate from Step 1(1 eq) and iodochloromethane (2.5 eq) in Et2O at −78° C. After stirring 30 min at −78° C., a solution of AcOH (25 eq.) in THF was added dropwise and the resulting mixture was stirred at RT for 15 min and partitioned between Et2O and brine. The organic layer was washed with sat. aq. NaHCO3, brine, dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by SiO2 gel chromatography (hexane/Et2O=9/1) to give the title compound as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 5.90 (m, 1H), 5.35-5.25 (m, 2H), 4.30 (s, 2H), 4.24 (s, 2H), 4.07 (d, J 5.5, 2H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([NH:9][CH2:10][C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([Cl:22])=[CH:17][CH:18]=3)[N:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:12]=2)=[O:8])=[CH:5][N:6]=1.Cl.[CH3:30][S:31]([CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[Cl:22][C:16]1[CH:15]=[C:14]2[C:19]([C:20](=[O:21])[C:11]([CH2:10][NH:9][C:7]([C:4]3[S:3][C:2]([N:37]4[CH2:38][CH2:39][CH:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:35][CH2:36]4)=[N:6][CH:5]=3)=[O:8])=[CH:12][N:13]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1
Reactant: CS(=O)(=O)C1CCNCC1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cnc(Br)s1
Agent: Cl
Product: CS(=O)(=O)C1CCN(c2ncc(C(=O)NCc3cn(-c4ccccc4)c4cc(Cl)ccc4c3=O)s2)CC1

Procedure:
2-(4-Methanesulfonyl-piperidin-1-yl)-thiazole-5-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate F and 4-methanesulfonyl piperidine hydrochloride. MS calcd. for C26H25ClN4O4S2 [(M+H)+] 557.1, obsd. 557.