Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:11][N:12]1[C:21]2[C:16](=[CH:17][C:18]([N:26]3[CH:30]=[CH:29][N:28]=[CH:27]3)=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=2)[N:15]=[C:14](Cl)[C:13]1=[O:32])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>ClCCl>[CH2:4]([O:11][N:12]1[C:21]2[C:16](=[CH:17][C:18]([N:26]3[CH:30]=[CH:29][N:28]=[CH:27]3)=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=2)[N:15]=[C:14]([NH:2][NH2:3])[C:13]1=[O:32])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NN
Reactant: O=c1c(Cl)nc2cc(-n3ccnc3)c(C(F)(F)F)cc2n1OCc1ccccc1
Solvent: O
Solvent: ClCCl
Product: NNc1nc2cc(-n3ccnc3)c(C(F)(F)F)cc2n(OCc2ccccc2)c1=O
Temperature: 0 °C
Yield: 90.9 %

Procedure:
Hydrazine hydrate (2.7 ml, 55 mmol) was added to a solution of 5.9 g (14 mmol) of 1-benzyloxy-3-chloro-6-(1H-imidazol-1-yl)-7-trifluoromethylquinoxalin-2(1H)-one in 100 ml of dichloromethane with stirring at 0° C. After 1 h the mixture was evaporated to dryness and the residue was triturated with water and dried to give 5.3 g (90%) of crude title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:18](Cl)=[N:19][CH:20]=[C:21]([F:23])[CH:22]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:18]([O:32][C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=3)=[N:19][CH:20]=[C:21]([F:23])[CH:22]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc(F)cnc2Cl)CC1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)CC1
Yield: 53.4 %

Procedure:
4-[(2-Chloro-5-fluoro-pyridine-3-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (4.0 g, 11.18 mmol) (see Preparation 27), 4-fluorophenol (1.378 g, 12.3 mmol) and caesium carbonate (7.29 g, 33.54 mmol) were stirred in N,N-dimethylformamide (40 ml) at 55° C. under an atmosphere of nitrogen for 18 hours. The reaction mixture was then partitioned between ethyl acetate (50 ml) and water (30 ml) and the organic layer separated. The organic layer was then washed with a saturated aqueous solution of sodium chloride (40 ml), dried over anhydrous magnesium sulphate and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane. The product was finally triturated with diethylether (25 ml) giving 4-{[5-fluoro-2-(4-fluorophenoxy)-pyridine-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (2.59 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)=[O:4].S([O-])([O-])(=O)=O.OO.C(=O)([O-])[O-].[K+].[K+].[CH:28]([NH2:30])=[O:29]>CO.C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:28]([NH2:30])=[O:29])[CH:9]=[CH:8]2)=[O:4]
Reactant: NC=O
Reactant: COC(=O)c1ccc2ncccc2c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: OO
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc2nc(C(N)=O)ccc2c1
Temperature: 80 °C
Reaction time: 0.83 h

Procedure:
4.0 g of 6-quinolinecarboxylic acid were suspended in 30 ml of MeOH, 2.0 ml of conc. sulfate was added under ice cooling, and the mixture was stirred at 70° C. for 22 hours. The reaction solution was concentrated under reduced pressure, and the residue was mixed with water and neutralized with potassium carbonate. The thus-precipitated solid was filtered and dried to obtain 4.28 g of 6-quinolinecarboxylic acid methyl ester. 0.5 g of the obtained ester body was dissolved in 5 ml of formamide, 0.15 ml of conc. sulfate, 0.05 g of ferrous sulfate hepta-hydrate, and 0.4 ml of 31% hydrogen peroxide were sequentially added thereto, and the mixture was stirred at 80° C. for 50 minutes. The reaction solution was mixed with water and alkalinized with potassium carbonate. 10% MeOH-chloroform was added, and insoluble matter was filtered using celite. The obtained filtrate was separated, the obtained organic layer was dried over anhydrous sodium sulfate and concentrated, and the obtained residue was washed with EtOH to obtain 0.15 g of 6-methoxycarbonyl-2-quinolinecarboxamide.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][NH:14][C:15]2[C:16](=[O:32])[N:17]([C:28]([CH3:31])([CH3:30])[CH3:29])[S:18](=[O:27])(=[O:26])[C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=O)=O)=CC=1.[CH3:33][S:34]([O:37][C:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=1)(=[O:36])=[O:35].C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH3:33][S:34]([O:37][C:38]1[CH:39]=[CH:40][C:41]([O:11][CH2:12][CH2:13][NH:14][C:15]2[C:16](=[O:32])[N:17]([C:28]([CH3:29])([CH3:30])[CH3:31])[S:18](=[O:27])(=[O:26])[C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:42][CH:43]=1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Oc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)N1C(=O)C(NCCOc2ccc(OS(C)(=O)=O)cc2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 39.4 %

Procedure:
2-[(2-tert-Butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]ethyl 4-methylbenzenesulfonate (150 mg, 0.313 mmol) was dissolved in dry MeCN (3 mL) under nitrogen atmosphere. 4-Hydroxyphenyl methanesulfonate (65 mg, 0.345 mmol) was added followed by potassium carbonate (217 mg, 1.567 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 15 mins. Potassium carbonate was filtered off and the reaction mixture was evaporated to dryness in a vacuum centrifuge. The crude product was purified by preparative HPLC affording the title compound (61 mg, 38.5%). 1H NMR (CDCl3, 500 MHz): δ 1.73 (s, 9H), 3.11 (s, 3H), 3.23-3.27 (m, 2H), 3.83-3.86 (m, 2H), 5.65 (bs, 1H), 6.83 (d, 2H), 7.20 (d, 2H), 7.43-7.46 (m, 3H), 7.50-7.54 (m, 2H); 13C NMR (CDCl3, 125 MHz): δ 27.83, 37.34, 43.30, 61.85, 66.50, 108.27, 115.77, 123.48, 125.07, 129.07, 130.06, 131.68, 135.18, 143.35, 157.21, 159.65; Mass Spectrum: M+NH4+511.8.
Reaction SMILES: C1C=CC=CC=1.[Cl:7][C:8]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:9]=1[C:10]([C:12]1[CH:13]=[N:14][N:15]([CH3:18])[C:16]=1[OH:17])=[O:11].[C:24]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1)(=[O:26])[CH3:25]>C(N(CC)CC)C>[Cl:7][C:8]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:9]=1[C:10]([C:12]1[CH:13]=[N:14][N:15]([CH3:18])[C:16]=1[O:17][CH2:31][C:30]1[CH:33]=[CH:34][C:27]([C:24](=[O:26])[CH3:25])=[CH:28][CH:29]=1)=[O:11]
Reactant: Cn1ncc(C(=O)c2ccc(Cl)cc2Cl)c1O
Reactant: CC(=O)c1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(=O)c1ccc(COc2c(C(=O)c3ccc(Cl)cc3Cl)cnn2C)cc1
Yield: 83 %

Procedure:
In 30 ml of dry benzene containing 0.50 g (0.005 mol) of triethylamine was dissolved 1.36 (0.005 mol) of 4-(2,4-dichlorobenzoyl)-1-methyl-5-hydroxypyrazole, and then 1.07 g (0.005 mol) of p-acetylbenzylbromide was added thereto. The resulting mixture was heated under reflux for 3 hours. After cooling the reaction mixture, the salt precipitated was filtered off and the solvent was distilled off therefrom under reduced pressure. The resulting oil was purified through column chromatography on silica gel using benzene/ethyl acetate 8:1 as an eluent to give 1.67 g of the title compound (yield 83%).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Cl:8].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[S:17](Cl)(=[O:19])=[O:18]>>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[S:17]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Cl:8])(=[O:18])=[O:19]
Reactant: Cc1ccc(C)c(S(=O)(=O)Cl)c1
Reactant: Cc1noc(N)c1Cl
Product: Cc1ccc(C)c(S(=O)(=O)Nc2onc(C)c2Cl)c1
Yield: 82 %

Procedure:
2,5-Dimethyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-chloro-3-methylisoxazole and 2,5-dimethylbenzenesulfonyl chloride according to the procedures described in Example 25b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a light yellow solid, m.p. 92-93° C., yield 82%.
Reaction SMILES: OS(O)(=O)=O.[NH2:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:22])[C:11]=2[C:10]([Br:23])=[CH:9][C:8]=1[Br:24].S([O-])(O)(=O)=O.C1([N+]#N)C2C(=O)C3C(=CC=CC=3)C(=O)C=2C=CC=1.[N-]=[N+]=[N-].[Na+]>O>[Br:24][C:8]1[C:7]2=[N:6][O:21][C:19]3=[C:20]2[C:11]([C:12](=[O:22])[C:13]2[C:18]3=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:10]([Br:23])[CH:9]=1
Reactant: Nc1c(Br)cc(Br)c2c1C(=O)c1ccccc1C2=O
Agent: N#[N+]c1cccc2c1C(=O)c1ccccc1C2=O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])O
Solvent: O
Product: O=C1c2ccccc2-c2onc3c(Br)cc(Br)c1c23
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 76.1 %

Procedure:
3,5-dibromo-6H-anthra[1,9-cd]isoxazol-6-one (1)—Sodium nitrite (993 mg, 14.4 mmol) was added with stirring to conc. H2SO4 (25 mL) at 30-40° C. over 10 min then stirred for an additional 30 min. Next 1-amino-2,4-dibromoanthraquinone (5.0 g, 13.1 mmol) was added over 15 min and the mixture was stirred overnight (16 h) at 50-55° C. The heated solution was poured directly over ice and the resulting yellow precipitate was filtered, washed with cold water, and a 1:1 mixture of ethanol-ether. The moist anthraquinonediazonium hydrogensulfate was added to a solution of NaN3 (1.37 g, 21.0 mmol) in water (25 mL) and stirred overnight (16 h). The light orange solid was filtered off and washed with water followed by a 9:1 mixture of acetone-water. The moist azide was suspended in toluene (40 mL) and heated to 70° C. with stirring. Water and acetone were slowly distilled (using a Dean-Stark apparatus) over a 12 h period. The yellow-orange crystals were filtered and washed with methanol to give 3.78 g (76%) of 3,5-dibromo-6H-anthra[1,9-cd]isoxazol-6-one. 1H NMR (500 MHz, CDCl3) δ 8.44 (d, J=7.8 Hz, 1H), 8.07 (d, J=7.4 Hz, 1H), 7.97 (s, 1H), 7.80 (t, J=7.0 Hz, 1H), 7.71 (t, J=7.4 Hz, 1H). Reference: Sutter, P; Weis, C. D. J. Heterocyclic Chem. 1982, 19, 997-1011.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>O>[OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:17][CH3:18])=[O:6]
Reactant: Cc1c(O)cccc1C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1cccc(O)c1C
Temperature: 90 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
To a solution of 3-hydroxy-2-methylbenzoic acid (2.0 g, 13 mmol) in absolute ethanol (20 mL) was added sulfuric acid (2.0 mL, 37 mmol). The resulting mixture was stirred at 90° C. for 16 hours. The reaction was cooled to room temperature then diluted with water (20 mL). The mixture was extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate and concentrated under vacuum to give ethyl 3-hydroxy-2-methylbenzoate (116a, 2.4 g, 99% yield) as yellow oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:37][C:18]3=[N:19][CH:20]=[C:21]([C:23]4[CH:24]=[C:25]([CH:33]=[CH:34][C:35]=4[CH3:36])[C:26]([O:28]C(C)(C)C)=O)[CH:22]=[C:17]3[C:16]=2[C:38](=[O:41])[NH:39][CH3:40])=[CH:11][CH:10]=1.CCN(C(C)C)C(C)C.Cl.[N:52]1[CH:57]=[CH:56][CH:55]=[N:54][C:53]=1[C:58]1([NH2:61])[CH2:60][CH2:59]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCCl>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:37][C:18]3=[N:19][CH:20]=[C:21]([C:23]4[CH:24]=[C:25]([C:26](=[O:28])[NH:61][C:58]5([C:53]6[N:54]=[CH:55][CH:56]=[CH:57][N:52]=6)[CH2:60][CH2:59]5)[CH:33]=[CH:34][C:35]=4[CH3:36])[CH:22]=[C:17]3[C:16]=2[C:38]([NH:39][CH3:40])=[O:41])=[CH:11][CH:10]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ncc(-c3cc(C(=O)OC(C)(C)C)ccc3C)cc12
Reactant: NC1(c2ncccn2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ncc(-c3cc(C(=O)NC4(c5ncccn5)CC4)ccc3C)cc12
Reaction time: 2 h
Yield: 61 %

Procedure:
TFA (544 μL, 7.06 mmol) was added to a stirring solution of tert-butyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)-4-methylbenzoate (65 mg, 0.141 mmol) in DCE (1.4 mL) at rt. It was allowed to stir for 2 hours then concentrated. The white solid was taken up in DMF (1.5 mL) and treated with DIEA (123 μL, 0.706 mmol), 1-(pyrimidin-2-yl)cyclopropanamine hydrochloride (29.1 mg, 0.169 mmol) followed by HATU (81 mg, 0.212 mmol) at rt. The reaction was allowed to stir for 1 hour and then was purified by preparative reverse phase HPLC on a C18 column using a TFA buffered H2O/MeOH gradient, and concentrated to give the expected product 2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)furo[2,3-b]pyridine-3-carboxamide (45 mg, 0.086 mmol, 61.1% yield) consistent by LCMS and NMR. 1H NMR (300 MHz, DMSO-d6) d ppm 9.19 (1H, s), 8.66 (2H, d, J=4.76 Hz), 8.45-8.57 (1H, m), 8.40 (1H, d, J=1.83 Hz), 8.10 (1H, d, J=1.83 Hz), 8.00-8.08 (2H, m), 7.85-7.94 (2H, m), 7.35-7.50 (3H, m), 7.26 (1H, t, J=4.76 Hz), 2.83 (3H, d, J=4.39 Hz), 2.31 (3H, s), 1.55-1.67 (2H, m), 1.27-1.39 (2H, m). LC-MS retention time: 1.75 min; m/z (MH'): 522. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:30])=[C:8]2[C:14]([C:15]#[N:16])=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[N:12]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Br:38])C(=O)C1.C(OOC(C1C=CC=CC=1)=O)(C1C=CC=CC=1)=O>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:30])=[C:8]2[C:14]([C:15]#[N:16])=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[N:12]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:9]2=[C:10]([Br:38])[N:11]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ncc2c(c1O)c(C#N)c(-c1ccc(F)cc1)n2-c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CCOC(=O)c1nc(Br)c2c(c1O)c(C#N)c(-c1ccc(F)cc1)n2-c1ccccc1

Procedure:
Prepared in analogy to that of Example 103(a) from 3-cyano-2-(4-fluoro-phenyl)-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, NBS and BzOOBz. The title compound, ESI MS (m/z): 480 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3]([C:5]1[N:30]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:28][CH:27]5[CH2:29][CH:24]([CH2:25][NH:26]5)[CH2:23]4)=[O:21])=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].CCN(C(C)C)C(C)C.C(=O)([O-])[O-].[K+].[K+].[F:52][C:53]([F:64])([F:63])[CH2:54]OS(C(F)(F)F)(=O)=O>O1CCOCC1.C(Cl)Cl>[CH3:1][N:2]([CH3:36])[C:3]([C:5]1[N:30]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:28][CH:27]5[CH2:29][CH:24]([CH2:25][N:26]5[CH2:54][C:53]([F:64])([F:63])[F:52])[CH2:23]4)=[O:21])=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CNC(C5)C4)cn3)nc2n1C1CCCC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CC(C4)N(CC(F)(F)F)C5)cn3)nc2n1C1CCCC1
Temperature: 50 °C
Yield: 58.4 %

Procedure:
In a 100 ml round bottom flask was combined 7-Cyclopentyl-2-[5-(3,6-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (165 mg, 0.294 mmol) and DIPEA (0.128 ml, 0.735 mmol) which were diluted in Dioxane (6.00 ml) gave a yellowish heterogeneous solution. To this mixture was then added potassium carbonate (406 mg, 2.94 mmol) and trifluoroethyltriflate (0.106 ml, 0.735 mmol). The reaction was heated to 50° C. for 18 h. LCMS showed 100% conversion. The mixture was diluted in DCM, and washed with sat'd aq solution of NaHCO3, followed by a brine wash. The organic layer was then separated, dried over MgSO4 and evaporated to give a yellowish solid. This solid was triturated with EtOAc to give 98 mg of 7-Cyclopentyl-2-{5-[6-(2,2,2-trifluoro-ethyl)-3,6-diaza-bicyclo[3.2.1]octane-3-carbonyl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide in 58% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.95 (1H, s), 8.84 (1H, s), 8.30-8.40 (2H, m), 7.81-7.83 (1H, d), 6.65 (1H, s), 4.71-4.78 (1H, quin.), 3.23-3.42 (7H, m), 3.06 (7H, br. s.), 2.30-2.45 (2H, br. s.), 1.99 (4H, br. s.), 1.55-1.75 (4H, d), 1.24-1.35 (2H, br. s). MS (ESI) m/e (M+H+): 570.9
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:21][CH2:20]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCNCC3)c2n1
Reactant: IC1CCCCC1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCN(C4CCCCC4)CC3)c2n1

Procedure:
Prepared similarly to Example 112 from 2-(butyloxy)-8-(methyloxy)-9-[4-(4-piperidinyl)butyl]-9H-purin-6-amine and iodocyclohexane.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5](I)=[CH:4][N:3]=1.[CH2:13]([N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])[CH2:14][CH2:15][C:16]#[CH:17].O.C(OCC)(=O)C>CN(C)C=O.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5]([C:17]#[C:16][CH2:15][CH2:14][CH2:13][N:18]2[C:19](=[O:28])[C:20]3[C:21](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:23])=[CH:4][N:3]=1
Reactant: CCCNc1nc(Cl)ncc1I
Reactant: C#CCCCN1C(=O)c2ccccc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCNc1nc(Cl)ncc1C#CCCCN1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 107.2 %

Procedure:
To a solution of 2-chloro-5-iodo-N-propylpyrimidin-4-amine (F1, 1.45 g), N-(4-pentynyl)phthalimide (2.08 g), bis(triphenylphosphine)palladium(II) dichloride (171 mg) and copper(I) iodide (47 mg) in N,N-dimethylformamide (15 mL), triethylamine (3.4 mL) was added at room temperature, and the mixture was stirred at 60° C. for 1 hour and 15 minutes. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed successively with saturated aqueous sodium hydrogencarbonate, water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent, 70 to 40% hexane in ethyl acetate) to obtain 2-(5-(2-chloro-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)isoindoline-1,3-dione (K1, 2.00 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:7]=[C:8]=[S:9])=[CH:4][S:5][CH:6]=1.[NH2:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[NH2:17]>>[NH2:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[NH:17][C:8]([NH:7][C:3]1[C:2]([CH3:1])=[CH:6][S:5][CH:4]=1)=[S:9]
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: Cc1cscc1N=C=S
Product: Cc1cscc1NC(=S)N[C@@H]1CCCC[C@H]1N

Procedure:
is obtained analogously to the reaction described in example 1 b) from 4-methyl-3-thienyl isothiocyanate and racemic trans-1,2-diaminocyclohexane. Crystalline solid, m.p. 205-210° C.,
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[C:3]1=[O:13].[BH4-].[Na+]>CO>[CH3:1][CH:2]1[CH2:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[CH:3]1[OH:13]
Reactant: CC1CCCc2ccccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1CCCc2ccccc2C1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-methyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one (24.93 g, 143.1 mmol) in methanol (150 ml) was added sodium borohydride (5.41 g, 143 mmol) by small portions under ice-cooling and the mixture was stirred at room temperature for 1 hr. The solvent of the reaction solution was evaporated under reduced pressure, water was added, and the mixture was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give the objective substance.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29]Cl>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[N:3]=1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(I)c2c1
Reactant: COCCOCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCn1nc(I)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46 %

Procedure:
To a solution of 3-iodo-5-nitro-1H-indazole (10.0 g, 34.6 mmol) in THF (50 ml) was added sodium bis(trimethylsilyl)amide (1M in THF, 48.4 mmol, 48.4 ml) and the solution stirred at room temperature for 20 minutes. 2-methoxyethoxymethyl chloride (4.9 g, 39.1 mmol, 4.5 ml) was added and the solution stirred at room temperature for 15 hours. The reaction was quenched with ammonium chloride (30 ml, saturated aqueous) and extracted into ethyl acetate (3×50 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (1:1 EtOAc:hexanes) to give the title compound as an orange solid (6.0 g). 1H NMR (400 MHz, CDCl3) δ 3.35 (3H, s), 3.50–3.52 (2H, m), 3.68–3.70 (2H, m), 5.86 (1H, s), 7.69 (1H, d), 8.38 (1H, d), 8.53 (1H, s). MS (ES+) m/e=378.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C-:17]#[N:18].[K+]>O1CCCC1.O.O1CCOCCOCCOCCOCCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:17]#[N:18])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [C-]#N
Reactant: Fc1ccc(CCl)cc1Oc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#CCc1ccc(F)c(Oc2ccccc2)c1
Yield: 113.2 %

Procedure:
A stirred mixture of 5.0 grams (0.021 mole) of 4-fluoro-3-phenoxyphenylmethyl chloride, 4.1 grams (0.063 mole) of potassium cyanide and 0.6 gram (0.002 mole) of 1,4,7,10,13,16-hexaoxacyclooctadecane in 180 ml of tetrahydrofuran was heated at reflux for about four hours. After this time the reaction mixture was diluted with 180 ml of water, and then extracted with two 100 ml portions of diethyl ether. The combined ether extracts were washed with five 200 ml portions of water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 5.4 grams of 4-fluoro-3-phenoxyphenylacetonitrile. The nmr spectrum was consistent with the proposed structure.