Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Li+].[CH3:3][N:4]([CH3:16])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[N:9]=1)=[O:6].[ClH:17].[CH:18]([N:21]([CH:25]([CH3:27])[CH3:26])[CH2:22][CH2:23][Cl:24])([CH3:20])[CH3:19]>O1CCOCC1>[ClH:24].[ClH:17].[CH3:3][N:4]([CH3:16])[C:5]([N:7]([CH2:23][CH2:22][N:21]([CH:25]([CH3:27])[CH3:26])[CH:18]([CH3:20])[CH3:19])[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[N:9]=1)=[O:6]
Reactant: CC(C)N(CCCl)C(C)C
Reactant: Cc1cc(C)nc(NC(=O)N(C)C)c1
Agent: Cl
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: Cc1cc(C)nc(N(CCN(C(C)C)C(C)C)C(=O)N(C)C)c1
Yield: 44.1 %

Procedure:
To a suspension of lithium hydride (0.65 g, 80 mmoles) in dry dioxane (65 ml) under nitrogen atmosphere is added N,N-dimethyl-N'-(4,6-dimethyl-2-pyridyl)urea (5.8 g, 30 mmoles) and the mixture is heated to reflux for three hours. 2-Diisopropylaminoethyl chloride hydrochloride (6.0 g, 30 mmoles) is added cautiously in small portions and refluxing continued for twenty-four hours. The reaction mixture is cooled, salts filtered off and solvent evaporated. The residue is dissolved in methylene chloride and the product is extracted into dilute aqueous hydrochloric acid (10%). This solution is filtered through charcoal, made basic with saturated sodium carbonate, and extracted with methylene chloride. The extract is dried over anhydrous sodium sulfate, filtered and evaporated. The crude product (8.3 g) is taken up in diethyl ether, insoluble material is removed by filtration and hydrogen chloride gas is bubbled into the filtrate. The precipitated salt is collected and recrystallized from isopropanol to give 5.2 g (44.0% yield) of product, m.p. 182°-186° C.
Reaction SMILES: [NH:1]([C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]2[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:5]=2[N:4]=1)[NH2:2].[C:24]([O-])([O-])(OCC)[CH3:25].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:24][C:25]1[N:4]2[C:5]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:6]=3[C:7]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[N:8][CH2:9][C:3]2=[N:1][N:2]=1
Reactant: CCOC(C)([O-])[O-]
Reactant: NNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2)=NC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1)=NC2

Procedure:
To a mixture of 9,5 parts of 2-hydrazino-5-phenyl-7-trifluoromethyl-3-H-1,4-benzodiazepine prepared in Example 4, 29 parts of ethyl orthoacetate and 150 parts by volume of chloroform, is added dropwise 23 parts of p-toluenesulfonic acid with stirring under ice-cooling below 10° C and then the mixture is stirred at room temperature for 7 hours. After completion of the reaction, the reaction mixture is neutralized with a saturated aqueous solution of sodium bicarbonate and the chloroform layer is separated, washed with water and dried over sodium sulfate. After evaporation of the solvent, the residue is treated with a mixture of benzene and isopropyl ether, whereby 1-methyl-6-phenyl-8-trifluoromethyl-4H-s-triazolo [4,3-a] [1,4] benzodiazepine is yielded as crystals containing benzene of crystallization. Recrystallization from a mixture of benzene and n-hexane yields colorless needless melting at 129° C to 130° C (sintering), 133° C to 134° C (effervescence).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]2[CH:15]=1.[C:16](Cl)(=[O:20])[O:17][CH2:18][CH3:19]>C1COCC1>[Cl:6][C:7]1[N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]2[C:15]=1[C:16]([O:17][CH2:18][CH3:19])=[O:20]
Reactant: Clc1cn2ccccc2n1
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Cl)nc2ccccn12
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
n-Butyllithium (1.6M in hexane, 45.1 mL) was added to a solution of 2-chloroimidazo[1,2-a]pyridine (10 g) in THF (120 mL) at −78° C. After stirring for 30 min, ethyl chlorocarbonate (7.82 g) in THF (10 ml) was added to the mixture at the same temperature and stirred for 1 h and then 10 h at room temperature. The mixture was quenched with water, and extracted with ethyl acetate, and the extract was washed with brine, and dried over magnesium sulfate. The residue was purified by column chromatography (silica gel, eluted with 10%-50% EtOAc in hexane) to give ethyl 2-chloroimidazo[1,2-a]pyridine-3-carboxylate (13.20 g) as an off-white solid.
Reaction SMILES: [C:1]1([C:7]([N:9]=[C:10]=[S:11])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[C:29]([CH3:34])[CH:28]=1.C1(C)C=CC=CC=1>C(O)C>[C:7]([NH:9][C:10]([NH:31][C:30]1[CH:32]=[CH:33][C:27]([O:26][C:17]2[C:16]3[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([O:13][CH3:12])[CH:15]=3)[N:20]=[CH:19][CH:18]=2)=[CH:28][C:29]=1[CH3:34])=[S:11])(=[O:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
Commercially available 1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (44 mg, yield 58%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.O1CCCC1.[CH2:24]([CH:27]1[CH2:32][CH2:31][CH:30](O)[CH2:29][CH2:28]1)[CH2:25][CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[CH3:18][C@@:12]1([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH:30]4[CH2:31][CH2:32][CH:27]([CH2:24][CH2:25][CH3:26])[CH2:28][CH2:29]4)[CH:3]=3)[CH:8]=2)[CH2:16][O:15][C:14](=[O:17])[NH:13]1
Reactant: CCCC1CCC(O)CC1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Temperature: 25 °C
Yield: 109 %

Procedure:
(R)-4-(6-Hydroxynaphthalen-2-yl)-4-methyl-oxazolidin-2-one (Example 4, 0.301 g, 0.00124 mol) was dissolved in tetrahydrofuran (5.00 mL, 0.0616 mol). 4-Propylcyclohexanol (0.211 g, 0.00148 mol) and triphenylphosphine polymer-bound (1.07 g, 0.00198 mol) were added and the mixture was stirred at room temperature. Diisopropyl azodicarboxylate (0.390 mL, 0.00198 mol) was then added and the mixture was stirred for 2 days at room temperature. The mixture was filtered through CELITE™, concentrated and purified by flash chromatography (0-30% EtOAc in methylene chloride) to give 0.4942 g of to the title product (109% yield).
Reaction SMILES: [C:1]([NH:18][CH2:19][CH2:20][C:21](O)=[O:22])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:57][C:58]1[C:59]([NH:76][CH:77]2[CH2:82][CH2:81][N:80]([CH2:83][CH2:84][C:85]#[N:86])[CH2:79][CH2:78]2)=[C:60]2[CH:66]=[CH:65][N:64]([S:67]([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)(=[O:69])=[O:68])[C:61]2=[N:62][CH:63]=1>CN(C=O)C>[CH:7]1[C:6]2[CH:5]([CH2:4][O:3][C:1](=[O:2])[NH:18][CH2:19][CH2:20][C:21](=[O:22])[NH:57][C:58]3[C:59]([NH:76][CH:77]4[CH2:78][CH2:79][N:80]([CH2:83][CH2:84][C:85]#[N:86])[CH2:81][CH2:82]4)=[C:60]4[CH:66]=[CH:65][N:64]([S:67]([C:70]5[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=5)(=[O:69])=[O:68])[C:61]4=[N:62][CH:63]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: N#CCCN1CCC(Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Reactant: O=C(O)CCNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CCCN1CCC(Nc2c(NC(=O)CCNC(=O)OCC3c4ccccc4-c4ccccc43)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 97 %

Procedure:
Fmoc-beta-Alanine (3.1 g, 9.90 mmol), HATU (3.8 g, 9.90 mmol), and diisopropylethylamine (2.1 ml, 12.0 mmol) were added sequentially to a solution of 3-[4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidin-1-yl]-propionitrile (4.2 g, 9.90 mmol) in DMF (100 ml) at 25° C. The reaction mixture was stirred for 14 h at 25° C., then was concentrated under reduced pressure. The residue was partitioned between half-saturated NaHCO3 (200 ml) and EtOAc (2×200 ml). the combined organic layers were dried over Mg2SO4, filtered, and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient: 0 to 7% CH3OH in CH2Cl2) afforded (2-{1-benzenesulfonyl-4-[1-(2-cyano-ethyl)-piperidin-4-ylamino]-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamoyl}-ethyl)-carbamic acid 9H-fluoren-9-ylmethyl ester (6.89 g, 97%) as a white foam. LCMS (Method G, ESI): RT=0.85 min, m+H=718.5. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 8.14 (t, J=10.3 Hz), 7.84 (s), 7.75 (dd, J=15.2, 7.5 Hz), 7.60-7.54 (m), 7.50 (d, J=4.1 Hz), 7.44 (t, J=7.8 Hz), 7.37 (t, J=7.4 Hz), 7.28 (t, J=5.8 Hz), 6.52 (t, J=4.7 Hz), 5.50 (d, J=11.4 Hz), 4.70 (s), 4.40 (s), 4.33 (d, J=7.1 Hz), 4.19 (t, J=6.6 Hz), 3.64 (td, J=13.3, 6.7 Hz), 3.51 (d, J=21.9 Hz), 3.39 (d, J=5.4 Hz), 2.80-2.47 (m), 2.35 (s), 2.30-2.07 (m), 1.93 (d, J=12.0 Hz), 1.51 (dt, J=13.5, 6.8 Hz).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH2:6][O:7][CH3:8])=[CH2:5].B.C1C[O:13]CC1.B(O[O-])=O.[Na+]>C1COCC1.C(Cl)Cl>[CH3:1][O:2][CH2:3][CH:4]([CH2:6][O:7][CH3:8])[CH2:5][OH:13]
Reactant: C=C(COC)COC
Reactant: C1CCOC1
Agent: B
Agent: O=BO[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COCC(CO)COC
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 48 %

Procedure:
To a solution of the 3-methoxy-2-methoxymethyl-1-propene (3.5 g, 30 mmol, 1.0 eq.) in THF (10 mL) at 0° C. was added BH3.THF (1M in THF, 18 mL, 0.6 eq.) and the resulting mixture was stirred for 40 min. The reaction was quenched with water followed by sodium perborate (10.6 g, 2.3 eq.), warmed to room temperature, stirred overnight, diluted with CH2Cl2 and filtered through celite. The filtrate was diluted with brine and the separated aqueous layer was extracted with CH2Cl2. The combined extracts were dried over Na2SO4 and filtered. The filtrate was distilled at atmospheric pressure to give light yellow liquid residue. Fractional distillation of the residue at 40 milliTorr gave 3-methoxy-2-methoxymethypropan-1-ol (1.93 g, 48%). b.p.=90-110° C.
Reaction SMILES: [Si:1]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH:10]=[CH2:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:19][O:20][SiH:21]([O:24][CH3:25])[O:22][CH3:23]>[Pt].C([Si](C)(C)O[Si](C=C)(C)C)=C.C1(C)C=CC=CC=1>[Si:1]([N:8]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:9][CH2:10][CH2:11][Si:21]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:19])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C=CCN(Cc1ccccc1)[Si](C)(C)C(C)(C)C
Reactant: CO[SiH](OC)OC
Agent: [Pt]
Agent: C=C[Si](C)(C)O[Si](C)(C)C=C
Solvent: Cc1ccccc1
Product: CO[Si](CCCN(Cc1ccccc1)[Si](C)(C)C(C)(C)C)(OC)OC
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 26.2 g (0.1 mol) of N-t-butyldimethylsilyl-N-benzyl-N-allylamine and 0.07 g of a toluene solution of platinum/1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex (Pt concentration 3 wt %) and heated at 50° C. Once the internal temperature became steady, 12.2 g (0.1 mol) of trimethoxysilane was added dropwise over 1 hour. Stirring was continued at the temperature for a further 1 hour. The reaction solution was distilled, collecting 32.6 g of a fraction having a boiling point of 165-166° C./0.4 kPa.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=3)[CH2:9][CH2:8]2)[C:3]1=[O:24].C(N(C(C)C)C(C)C)C.Cl[C:35]1[N:40]=[N:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=1>CN(C=O)C.CCOC(C)=O>[Cl:19][C:18]1[C:13]([N:10]2[CH2:11][CH2:12][CH:7]([N:4]3[CH2:5][CH2:6][C@H:2]([NH:1][C:35]4[N:40]=[N:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=4)[C:3]3=[O:24])[CH2:8][CH2:9]2)=[N:14][CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=1
Reactant: N#Cc1ccc(Cl)nn1
Reactant: N[C@H]1CCN(C2CCN(c3ncc(C(F)(F)F)cc3Cl)CC2)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N[C@H]2CCN(C3CCN(c4ncc(C(F)(F)F)cc4Cl)CC3)C2=O)nn1
Temperature: 90 °C
Yield: 14.6 %

Procedure:
To a solution of (S)-3-amino-1-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)pyrrolidin-2-one (0.15 g, 0.41 mmol) in DMF (10 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.160 g, 1.24 mmol) and 6-chloropyridazine-3-carbonitrile (0.173 g, 1.24 mmol) and the reaction was heated to 90° C. overnight. The reaction was diluted with EtOAc (150 mL) and washed with water (100 mL), and brine (10 mL), dried over MgSO4, filtered and concentrated under vacuum. The material was purified on silica, using 1:1 EtOAc:DCM as eluent to yield a solid, which was further triturated with diethyl ether to yield (S)-6-(1-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-ylamino)pyridazine-3-carbonitrile (0.028 g, 0.060 mmol, 14% yield). Mass spectrum (apci) m/z=466.0, 467.9 (M+H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5](O)=[S:6].S(=O)(=O)(O)O.N[C:23](N)=[O:24].N(O)=[O:27].S([O-])([O-])(=O)=O.[Na+].[Na+]>O>[OH:27][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([O:24][CH3:23])=[S:6]
Reactant: O=NO
Reactant: Nc1cc(C(O)=S)ccc1-c1ccccc1
Reactant: NC(N)=O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=S)c1ccc(-c2ccccc2)c(O)c1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
Adding 110.27 g of 3-amino-4-phenylthiobenzoic acid to 400 ml heated water solution of concentrated sulfuric acid (81 ml), the mixture was heated and stirred for 2 hours, and cooled with ice-salt bath to -5° C. To this solution, a 80 ml water solution of 36.25 g of sodium nitride which was ice-cooled was added in about 1 hour. Further stirring for 30 minutes at 0 ° to 5° C., 2 g of urea was added and stirred for 30 minutes, and the unreacted nitrous acid was decomposed, the obtained mixture was gradually added to a mixture of 121 ml of concentrated sulfuric acid, 168 g of anhydrous sodium sulfate and 112 ml of water, while stirring, in 75 minutes at 100° to 110° C. After addition, the mixture was further stirred for 1 hour at the same temperature. The reaction mixture was cooled, and precipitating brown granules were filtered, washed with water, and dried overnight at 50° C. The obtained product was added to the mixture of 1.4 liters of methanol and 70 ml of concentrated sulfuric acid, and the mixture was refluxed for 2 hours while stirring. After termination of reaction, the reaction mixture was concentrated in vacuo, and 1.5 liters of water was added to the residue, and the product was extracted with ethyl acetate (500 ml×3). The extract was dried in anhydrous sodium sulfate, and concentrated in vacuo. The residue was extracted in 4.2 liters of hot hexane, and cooled, and precipitating yellow matter was filtered, and 49.37 g of methyl 3-hydroxy-4-phenylthiobenzoate was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:24][CH2:25][CH2:26]OS(C1C=CC(C)=CC=1)(=O)=O.O>C(Cl)(Cl)Cl>[F:24][CH2:25][CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]3[CH:17]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2cn3cc(I)ccc3n2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: FCCOc1ccc(-c2cn3cc(I)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 52.7 %

Procedure:
368 mg (corresponding to 1.1 mmol) of 2-(4′-hydroxyphenyl)-6-iodoimidazo[1,2-a]pyridine that was sufficiently dried to remove moisture was dissolved in 15 mL of N,N-dimethylformamide, and 453 mg (corresponding to 3.3 mmol) of potassium carbonate was added thereto. The mixture was supplemented with 280 μL (corresponding to 1.6 mmol) of 2-fluoroethyl-p-toluenesulfonate, and then the solution was stirred at room temperature for 22 hours. After the completion of the reaction, the reaction solution was poured into water and extracted three times with chloroform. The combined chloroform layer was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified by flash silica gel column chromatography (elution solvent: hexane/ethyl acetate=1/1), and further by recycle preparative HPLC (HPLC apparatus: LC-908 (under trade name; manufactured by Japan Analytical Industry Co., Ltd.); column: two JAIGEL 2H (under trade name; manufactured by Japan Analytical Industry Co., Ltd.) connected together; mobile phase: chloroform), to obtain 222 mg (corresponding to 0.580 mmol) of 2-[4′-(2″-fluoroethoxy)phenyl]-6-iodoimidazo[1,2-a]pyridine (FIG. 1-7, Step 3).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Cl-].[Cl:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[CH:16]=[N+:17]([CH3:19])[CH3:18].ClC1C=C(C=CC=1)C=O.CNC>>[Cl:12][C:13]1[CH:14]=[C:15]([CH:16]([N:17]([CH3:19])[CH3:18])[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Cn1ccc2ccccc21
Reactant: C[N+](C)=Cc1cccc(Cl)c1
Agent: CNC
Agent: O=Cc1cccc(Cl)c1
Agent: [Cl-]
Product: CN(C)C(c1cccc(Cl)c1)c1cn(C)c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-methylindole and (3-chloro-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 3-chloro-benzaldehyde and dimethylamine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[NH:25][N:24]([CH3:26])[NH:23][N:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[Cl:34]CCl>>[ClH:34].[CH3:26][N:24]1[NH:23][N:22]=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([NH:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:16][CH:17]=2)[NH:25]1.[ClH:34]
Reactant: CN1NN=C(c2ccc(NC3CCN(C(=O)OC(C)(C)C)CC3)cc2)N1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1NN=C(c2ccc(NC3CCNCC3)cc2)N1
Product: Cl

Procedure:
4-[4-(1-Methyl-1H-tetrazol-5-yl)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (401 mg; 1.12 mmol, prepared in accordance with Example 19) is dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) is slowly added under stirring. After 60 minutes reaction time, the mixture is concentrated under reduced pressure and co-evaporated twice with dichloromethane (10 mL). The crude residue is then diluted in dioxane (2 mL) and a 4N solution of hydrochloric acid in dioxane (3 mL) is added under stiffing. The solid formed is filtered and is dried under high vacuum to afford the desired product as hydrochloride (257 mg; 0.87 mmol).
Reaction SMILES: [CH:1]1([NH:5][C:6]2[C:7]3[CH:32]=[CH:31][NH:30][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:23][C:24]([O:26]CC)=[O:25])[C:18](=[O:29])[CH2:17][CH2:16]4)[N:11]=2)[CH2:4][CH2:3][CH2:2]1>C1COCC1.O.[OH-].[Na+]>[CH:1]1([NH:5][C:6]2[C:7]3[CH:32]=[CH:31][NH:30][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:23][C:24]([OH:26])=[O:25])[C:18](=[O:29])[CH2:17][CH2:16]4)[N:11]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)CN1C(=O)CCc2cc(Nc3nc(NC4CCC4)c4cc[nH]c4n3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CN1C(=O)CCc2cc(Nc3nc(NC4CCC4)c4cc[nH]c4n3)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 2-(6-(4-(cyclobutyamino)-7H-pyrrolo[2,3-d]pyrimidine-2-ylamino)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate (10 mg, 0.023 mmol) in THF (0.6 mL) and H2O (0.4 mL) was added NaOH (5N, 2 drops). After stirring for 3 h at room temperature, the reaction mixture was purified by preparative HPLC to yield 2-(6-(4-(cyclobutyamino)-7H-pyrrolo[2,3-d]pyrimidine-2-ylamino)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetic acid (MS calcd for C21H22N6O3 406.2, found [MH] 407.0; UV 207.5, 304.5 nm).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22](O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:11][C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])c(F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.1 %

Procedure:
To a mixture of 5.0 g (31.80 mmole) of 3-fluoro-4-nitrophenol, 8.32 g (41.31 mmole) of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester and 14.32 g (54.06 mmole) of triphenylphosphine in 100 mL of tetrahydrofuran was added 8.4 mL (54.06 mmole) of diethyl azodicarboxylate. The mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexanes (gradient 0:100-40:60) to give 6.94 g of 4-(3-fluoro-4-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (IV.21a).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH2:26][CH2:27][C@H:28]([OH:30])[CH3:29]>>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][NH:26][CH2:27][C@H:28]([OH:30])[CH3:29])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)=[O:5]
Reactant: C[C@@H](O)CN
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCCl)ccc1Cl
Product: C[C@@H](O)CNCCOc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Product: Cl

Procedure:
Prepared according to the method of Example 4 using 2-chloro-5-(2-chloroethoxy)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 11a, 0.17 g) and (R)-1-amino-2-propanol (0.11 ml). The reaction mixture was partitioned between ethyl acetate and sodium hydrogencarbonate solution, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by RPHPLC (eluting with 25-95% MeCN in 0.1% AcONH4 aqueous) to give the title compound as the acetate salt. This was converted to the hydrochloride salt by stirring with 4M HCl in dioxane and concentration under reduced pressure. Trituration with diethyl ether gave the title compound as a solid (0.055 g).