Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].C(N(CC)CC)C.C1(C)C=CC=CC=1.[C:30]([O:34][CH3:35])(=[O:33])[CH:31]=[CH2:32]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.O>[C:5]([C:4]1[CH:3]=[C:2]([CH:15]=[CH:14][CH:13]=1)[CH:32]=[CH:31][C:30]([O:34][CH3:35])=[O:33])(=[O:6])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C=CC(=O)OC
Reactant: O=C(c1ccccc1)c1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1cccc(C(=O)c2ccccc2)c1
Temperature: 100 °C
Yield: 90.9 %

Procedure:
To a mixture of 3-bromobenzophenone (5.0 g, 19 mmol), palladium acetate (215 mg, 0.958 mmol), and tri-o-tolylphosphine (290 mg, 0.953 mmol) was added triethylamine (3.3 mL, 45 mmol), toluene (4 mL), and methyl acrylate (2.2 mL, 27 mmol). The mixture was heated at 100° C. for 18 hours at which time—TLC analysis showed the reaction was still incomplete. Additional portions of palladium acetate (215 mg, 0.958 mmol), tri-o-tolylphosphine (290 mg, 0.953 mmol), triethylamine (3.3 mL, 45 mmol) and methyl acrylate (2.2 mL, 27 mmol) were added, and the mixture was heated at 110° for a further 18 hours. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed sequentially with water and brine, and then dried (MgSO4) and concentrated to a brown oil (5.3 g). The oil was chromatographed over silica gel. Elution with ethyl acetate/hexanes (1:9) afforded methyl 3-benzoylcinnamate (4.6 g, 91%) as a yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11](Cl)=[O:12])=[CH:2]1.[CH3:15][OH:16]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11]([O:16][CH3:15])=[O:12])=[CH:2]1
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Reactant: CO
Product: COC(=O)C(=O)c1c[nH]c2ccccc12

Procedure:
reacting the 3-indoleglyoxalyl chloride with methanol to give methyl 3-indoleglyoxylate, and
Reaction SMILES: [CH2:1]([CH:5]1[CH2:10][C:9](=[O:11])[CH2:8][C:7](=[O:12])[N:6]1C(OC(C)(C)C)=O)[CH:2]([CH3:4])[CH3:3]>O1CCOCC1.Cl>[CH2:1]([CH:5]1[NH:6][C:7](=[O:12])[CH2:8][C:9](=[O:11])[CH2:10]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CC1CC(=O)CC(=O)N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)CC1CC(=O)CC(=O)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.6 %

Procedure:
To a solution of tert-butyl 2-isobutyl-4,6-dioxopiperidine-1-carboxylate (30 g, 0.114 mol) in dry 1,4 dioxane (300 mL), HCl (3 M in 1,4 dioxane, 100 mL) was added and stirred at room temperature for 3 h. The reaction mixture was concentrated and purified by crystallization using diethyl ether to yield 6-isobutyl-piperidine-2,4-dione (14 g, 74%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH:9]=[O:10])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccnc(CO)c1Br
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1ccnc(C=O)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.1 %

Procedure:
A mixture of (3-bromo-4-methyl-2-pyridyl)methanol (600 mg, 2.97 mmol) and Dess-Martin Periodinane (1688 mg, 3.86 mmol) in DCM (20 mL) was stirred at room temperature for 3 hours. The reaction mixture was diluted with dichloromethane (50 mL) and washed with saturated aqueous sodium bicarbonate (2×25 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by flash chromatography (12 g, Silica, 0-80% ethyl acetate in heptane). Desired fractions were combined and evaporated in vacuo to afford the title compound as pale yellow solid (470 mg, 79%), which was used in the next step without further purification.
Reaction SMILES: [ClH:1].[CH:2]1([C:6]2[NH:7][N:8]=[C:9]3[C:14]=2[C:13]([CH3:15])=[CH:12][C:11](=[O:16])[NH:10]3)[CH2:5][CH2:4][CH2:3]1.Cl>CO.[Pd]>[ClH:1].[CH:2]1([C:6]2[NH:7][N:8]=[C:9]3[C:14]=2[CH:13]([CH3:15])[CH2:12][C:11](=[O:16])[NH:10]3)[CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cc(=O)[nH]c2n[nH]c(C3CCC3)c12
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC1CC(=O)Nc2n[nH]c(C3CCC3)c21
Temperature: 60 °C
Reaction time: 12 h
Yield: 9.5 %

Procedure:
To an aliquot of 3-cyclobutyl-4-methyl-2,7-dihydro-pyrazolo[3,4-b]pyridin-6-one hydrochloride salt (0.20 mg, 0.83 mmol) in MeOH (50 mL) was added 10% Pd/C (100 mg). The reaction mixture was placed in a hydrogenation bottle, pressured with 45 psi H2, and then heated to 60° C. (internal temp). After 12 hr, the reaction was cooled to room temperature, 100 μL of conc. HCl was added, followed by an additional 100 mg of Pd/C. The bottle was re-pressurized with 45 psi H2, and then reheated to 60° C. (internal temp). The reaction mixture was cooled to room temperature after 12 hr, filtered through a plug of diatomaceous earth, and concentrated under pressure. Partial purification of this material was accomplished by MPLC using a 15 g ISCO column (ISCO, Inc., Lincoln, Nebr.), eluting with 2% MeOH/CH2Cl2 with 0.2% NH4OH. The product-containing fractions were collected and concentrated. This material was re-chromatographed using a 15 g ISCO column, eluting with 4% MeOH/CH2Cl2 with 0.2% NH4OH. The product-containing fractions were collected and concentrated to afford the title compound (19.0 mg, 11% yield). The monohydrochloride salt was formed using 1M HCl in Et2O. 400 MHz 1H NMR (CD3OD) free base d 3.60 (dddd, J=9.5,9.5, 9.5, 0.8 Hz, 1H), 3.10 (ddddd, J=10.8, 6.6, 6.6, 6.6, 4.2 Hz, 1H), 2.72 (dd, J=15.8, 6.6 Hz, 1H), 2.36-2.23 (M, 5H), 2.07 (dddd, J=19.9, 9.5, 9.5, 9.5 Hz, 1H), 1.94-1.89 (m, 1H), 1.15 (d, J=7.0 Hz, 3H). LRMS m/z (APCI+) 206 (M+1).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:25][C:17]3=[C:18]4[C:22](=[CH:23][CH:24]=[C:16]3[O:15][CH2:14]2)[NH:21][CH:20]=[CH:19]4)(=O)=O)=CC=1.[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[C:36]1[CH2:37][CH2:38][NH:39][CH2:40][CH:41]=1>CS(C)=O.C(OCC)(=O)C>[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[C:36]1[CH2:37][CH2:38][N:39]([CH2:12][CH:13]2[O:25][C:17]3=[C:18]4[C:22](=[CH:23][CH:24]=[C:16]3[O:15][CH2:14]2)[NH:21][CH:20]=[CH:19]4)[CH2:40][CH:41]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4[nH]ccc4c3O2)cc1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Fc1ccc2[nH]cc(C3=CCN(CC4COc5ccc6[nH]ccc6c5O4)CC3)c2c1

Procedure:
A solution of 0.30 g (0.84 mmole) of (2R)-2,3-dihydro-7H-[1,4]dioxino[2,3-e]indol-2-ylmethyl 4-methylbenzenesulfonate and 0.40 g (1.8 mmole) of 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 30 mL of DMSO was heated at 65° C. for 4 hours. The mixture was diluted with 300 mL of ethyl acetate, washed with 200 ml portions of saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with 0-1.5% methanol in methylene chloride as eluant. The product fractions were combined and concentrated in vacuum, and the residue triturated with ether/hexane (1:1) to give 0.10 g of the (S)-enantiomer of the title compound as a yellow solid, m.p. 112° C., with one-quarter mole of ether.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[C:5]([C:9]1[CH:10]=[C:11]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])[CH:12]=[C:13]1[CH2:17][CH2:16][NH:15][C:14]1=[O:18])([CH3:8])([CH3:7])[CH3:6]>>[CH3:1][NH:2][C:3]([N:15]1[CH2:16][CH2:17][C:13](=[CH:12][C:11]2[CH:19]=[C:20]([C:23]([CH3:24])([CH3:25])[CH3:26])[C:21]([OH:22])=[C:9]([C:5]([CH3:8])([CH3:7])[CH3:6])[CH:10]=2)[C:14]1=[O:18])=[O:4]
Reactant: CC(C)(C)c1cc(C=C2CCNC2=O)cc(C(C)(C)C)c1O
Reactant: CN=C=O
Product: CNC(=O)N1CCC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Yield: 70.3 %

Procedure:
Methyl isocyanate (5.0 ml) was added to 3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-one (277 mg, 0.75 mmole) (J. Med. Chem., p1995, 30, 1987) and the mixture was heated under reflux for 15 hours. The reaction mixture was evaporated under reduced pressure to obtain a residue, which was purified by using silica gel chromatography (n-hexane:ethyl acetate=4:1) and recrystallized from dichloromethane-ether, whereby 189 mg of the objective compound was obtained as white crystal in 70.3% yield. The physical constants are described on Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[N:30][CH:31]=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14]([NH:25][C:26]3[CH:31]=[N:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: COc1ccc(N)cn1
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Solvent: O
Product: COc1ccc(Nc2ncc3cc(-c4c(Cl)cccc4Cl)c(=O)n(C)c3n2)cn1
Temperature: 160 °C

Procedure:
A mixture of 0.155 g (0.40 mmol) of 6-(2,6-dichlorophenyl)-2-methanesulfonyl-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 39 and 0.50 g (4.00 mmol) of 5-amino-2-methoxypyridine was heated, with stirring, in a 160° C. oil bath. The resulting solution was heated for 10 minutes and cooled to room temperature. Water (10 mL) was added to precipitate a gum. The mixture was decanted, and the remaining gum was triturated with 5 mL of water. The brown solid that developed was filtered, washed well with water, and dried; wt 0.135 g. Purification was effected by silica gel chromatography eluting with chloroform and then with ethyl acetate to obtain the fraction containing pure product. The eluent was concentrated to 2 mL volume. The crystals that separated on inducement were filtered and washed with 0.2 mL of ethyl acetate and then 0.5 mL of ether; wt 0.045 g; mp 233°-235° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].S(Cl)([Cl:26])=O>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([Cl:26])=[O:23])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: O=S(Cl)Cl
Product: CCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1

Procedure:
10 g of 4-n-heptyloxy-4'-biphenylcarboxylic acid and 50 ml of excess thionyl chloride were heated under reflux for 3 hours and thereafter unreacted thionyl chloride was distilled off to obtain 4-heptyloxy-4'-biphenylcarboxylic acid chloride.
Reaction SMILES: C([O:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][S:14][C:15]2[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])[CH:9]=[CH:10][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][S:14][C:15]2[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccccc1SCCc1cccc(OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccccc1SCCc1cccc(O)c1
Reaction time: 8 h
Yield: 77.3 %

Procedure:
Methyl 2-{[2-(3-tert-butoxyphenyl)ethyl]thio}benzoate (402 mg, 1.167 mmol) was dissolved in DCM (3 ml). Trifluoroacetic acid (3 ml) was added. The mixture was stirred overnight and then evaporated to dryness. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using ethyl acetate/heptane (2.5:97.5, then 5:95, then 10:90 and then 25:75) as eluant gave 260 mg the desired product, yield 77%. 1H NMR (500 MHz, CDCl3): δ 2.94 (t, 2H), 3.17 (t, 2H), 3.95 (s, 3H), 6.18 (s, 1H) 6.77-6.83 (m, 3H), 7.18 (t, 2H), 7.34 (d, 1H), 7.44 (t, 1H) and 7.99 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12]CC)=[O:11])=[CH:7][C:6]=2[CH:15]=1.[S:16]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17]1.C(=O)([O-])[O-].[Na+].[Na+].Cl>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[S:16]1[CH:20]=[CH:19][C:18]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][C:6]=3[CH:15]=2)=[CH:17]1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2o1
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc2cc(-c3ccsc3)ccc2o1
Temperature: 100 °C
Yield: 97.4 %

Procedure:
A mixture of ethyl 5-bromobenzofuran-2-carboxylate 15 (1.0 g, 3.7 mmole), 3-thiopheneboronic acid (0.52 g, 4.1 mmole), tetrakis(triphenylphosphine)palladium (0) (47 mg), sodium carbonate (1.30 g, 12.3 mmole) in water (10 ml), and dioxane (10 ml) was stirred under an atmosphere of argon and heated to 100° C. for 24 hrs. The mixture was cooled, acidified with 1 M HCl, extracted with ethyl acetate, washed with water, dried, and evaporated, to give about 0.88 g of 5-thiophen-3-yl-benzofuran-2-carboxylic acid 21, mp. 215-220° C.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([N+:7]([O-:9])=[O:8])[NH:4][N:3]=1.[OH-].[Na+].S(OC)(O[CH3:16])(=O)=O>CC(C)=O>[Br:1][C:2]1[N:3]([CH3:16])[N:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=[N+]([O-])c1nc(Br)n[nH]1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cn1nc([N+](=O)[O-])nc1Br
Reaction time: 18 h
Yield: 42.7 %

Procedure:
A stirred solution of 3-bromo-5-nitro-1H-1,2,4-triazole (13.1 g) in acetone (100 ml) was cooled to 0° and treated with 10% sodium hydroxide solution (30 ml), followed by dimethyl sulphate (9.5 g). After 18 h at room temperature, the mixture was evaporated in vacuo; the residue was diluted with water and extracted with ethyl acetate. The combined extracts were washed with 2N sodium hydroxide solution, water, and evaporated in vacuo. The resulting solid was recrystallized from a mixture of ethyl acetate and cyclohexane to yield the title compound (6.0 g), m.p. 90.5°-91.5°.
Reaction SMILES: [OH-].[Na+:2].CCO.[C:6](#[N:10])[CH2:7][C:8]#[N:9].[C:11](=[S:13])=[S:12]>>[C:8]([C:7]([C:6]#[N:10])=[C:11]([S-:13])[S-:12])#[N:9].[Na+:2].[Na+:2]
Reactant: S=C=S
Reactant: N#CCC#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#CC(C#N)=C([S-])[S-]
Temperature: 15 °C
Yield: 79 %

Procedure:
Solid NaOH (187.2 g, 4541 mmol) was added to EtOH (2000.0 mL, 34253 mmol) at rt and stirred until disolved. The solution was cooled to 15° C. and malononitrile (150 g, 2300 mmol) was added in one portion and the resulting suspension was stirred until the malononitrile had dissolved (reaction is slightly endothermic). The reaction mixture was stirred for 1 h and carbon disulfide (136.6 mL, 2271 mmol) was added while keeping the temperature between 10 and 20° C. After about half of the carbon disulfide was added the reaction mixture begins to solidify and becomes very difficult to stir. The addition of carbon disulfide was continued and the reaction was stirred mechanically with a spatula. When the addition was complete the reaction mixture was warmed to 30° C. and then cooled to room temperature. The product was filtered and dried under vacuum at 82° C. for 2 days. The solid material obtained was ground up with a mortor and pestal and then dried under vacuum to give the title compound (335 grams, 79%).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:29][CH2:28][C:24]3([CH2:27][O:26][CH2:25]3)[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32][CH:31]=1>>[N:30]1[CH:35]=[C:34]([C:2]2[C:3]([N:22]3[CH2:29][CH2:28][C:24]4([CH2:27][O:26][CH2:25]4)[CH2:23]3)=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])[CH:33]=[N:32][CH:31]=1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC3(COC3)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC3(COC3)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 86 using 5-bromo-6-(2-oxa-6-azaspiro[3.4]octan-6-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 116.1) and pyrimidin-5-ylboronic acid to afford a white solid. UPLC-MS (condition 1) tR=2.35 min, m/z=472.0 [M+H]+, m/z=470.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.00-2.15 (m, 2H) 3.11 (t, J=6.72 Hz, 2H) 3.44 (s, 2H) 4.41-4.45 (m, 2H) 4.45-4.50 (m, 2H) 7.36 (d, J=8.31 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H) 8.11 (d, J=2.45 Hz, 1H) 8.79 (d, J=2.45 Hz, 1H) 8.90 (s, 2H) 9.20 (s, 1H) 10.19 (s, 1H).
Reaction SMILES: [CH2:1]([N:11]=[C:12]=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:14]([O:21][NH2:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCCl.C(Cl)Cl>[CH2:14]([O:21][NH:22][C:12]([NH:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCCCCCCCCCN=C=O
Reactant: NOCc1ccccc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCCCCCCCCNC(=O)NOCc1ccccc1
Yield: 66.3 %

Procedure:
To a solution of decyl isocyanate (19.6 g, 0.11 mol) in 1,2-dichloroethane (100 ml) was added a solution of benzyloxyamine (0.114 mol) in methylene chloride (100 ml). The solution was refluxed for 20 minutes, evaporated, and the residue triturated with pentane to give N-benzyloxy-N'-decylurea as a white solid (22.36 g, 67% yield). This urea (2.95 g, 10 mmol) was dissolved in DMF (30 ml) at 40° C. Sodium hydride (425 mg of a 60% dispersion in oil) was added. Within 15 minutes, a precipitate formed. After 30 minutes, methyl iodide (0.64 ml) was added, and the mixture was stirred for one hour at room temperature. The resulting solution was poured in 1% HCl, and the resulting solid was washed with water, collected by filtration, and air-dried. Recrystallization from pentane provided N-benzyloxy-N-methyl-N'-decylurea as a white solid (2.25 g, 73% yield). Hydrogenolysis as in Example 2 above, and recrystallization from ethanol-water, provided the title compound as a white solid (1.43 g, 91% yield), mp 74°-76° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[CH2:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:16]2[CH2:17][CH2:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15]2)=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=[N+]([O-])c1ccc(OCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCCN2CCc3ccccc3C2)cc1
Reaction time: 24 h
Yield: 73.6 %

Procedure:
A mixture of 1-(3-bromopropoxy)-4-nitrobenzene (10 g), 1,2,3,4-tetrahydroisoquinoline (5.1 g) and potassium carbonate (10.6 g) in DMF (100 ml) was stirred at 70° for 24 h. The mixture was then filtered and the filtrate evaporated. The residue was taken up with water and extracted with dichloromethane. The organic layer was washed with water, dried, evaporated and purified by column chromatography eluting with dichloromethane/methanol (96:4) to give the title compound (8.8 g) as a yellow oil. NMR includes signals at d 3.6 (2H,s,N--CH2Ar), 4.1 (2H,t,O--CH2).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:5]([CH3:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)=[N:27][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:20][O:19][C:17](=[O:18])[CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]#[C:8][C:6]1[C:5]([CH3:21])=[CH:4][N:3]=[C:2]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([CH:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)=[N:27][CH:28]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cn2)CC1
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Cl)ncc1C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)ncc1C
Temperature: 120 °C

Procedure:
To a solution of methyl 2-(2-((2-chloro-5-methylpyrimidin-4-yl)ethynyl)phenyl)acetate (K7) (100 mg, 0.333 mmol) in 1,4-dioxane (8 mL) was added tert-butyl 4-(5-aminopyridin-2-yl)piperidine-1-carboxylate (K4) (92.2 mg, 0.333 mmol), Cs2CO3 (433 mg, 1.33 mmol), Pd2(dba)3 (30 mg, 0.033 mmol) and Xantphos (58 mg, 0.10 mmol). The resulting mixture was degassed with nitrogen for 5 minutes before heating under microwave irradiation for 30 minutes at 120° C. The resulting mixture was diluted with EtOAc (100 mL) then washed with water (2×25 mL), brine (25 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in hexanes) to give the title compound A17 as a yellow foam (112 mg, 62%); 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J=2.4 Hz, 1H), 8.32 (d, J=0.6 Hz, 1H), 8.16 (dd, J=8.5, 2.7 Hz, 1H), 7.66 (dd, J=7.6, 0.9 Hz, 1H), 7.43-7.30 (m, 3H), 7.14 (d, J=8.5 Hz, 1H), 7.10 (s, 1H), 4.25 (br. s, 2H), 3.95 (s, 2H), 3.70 (s, 3H), 2.86-2.78 (m, 3H), 2.35 (d, J=0.4 Hz, 3H), 1.91 (d, J=13.3 Hz, 2H), 1.75-1.63 (m, 2H), 1.47 (s, 9H). LCMS-A: rt 5.462 min; m/z 542 [M+H]+.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[CH3:21][C:17]([N:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1)([CH3:20])[CH2:18][OH:19]
Reactant: CC(C)(CO)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(CO)N1CCNCC1
Yield: 95.1 %

Procedure:
A mixture of 4-(2-hydroxy-1,1-dimethylethyl)piperazine-1-carboxylic acid benzyl ester (3.0 g, 10.3 mmol) in methanol (70 mL) and palladium on charcoal (0.5 g, 10%) was hydrogenated at room temperature at 40 p.s.i. overnight. The mixture was filtered through Celite and the filtrate evaporated under reduced pressure to give the title compound (1.55 g, 98%) as a white solid.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[NH:24][C:25](=[O:28])[NH:26][NH2:27]>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[NH:24][C:25](=[O:28])[NH:26][N:27]=[C:9]1[C:10](=[O:11])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]1=[O:8]
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: COc1ccc(Cl)c(NC(=O)NN)c1
Agent: Cl
Product: COc1ccc(Cl)c(NC(=O)NN=c2c(=O)c3ccccc3c2=O)c1

Procedure:
ninhydrin, 4-(2-chloro-5-methoxyphenyl)-semicarbazide hydrochloride