Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]1.[OH:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:48].Cl>>[ClH:1].[ClH:48].[CH3:24][N:23]([CH2:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([NH:15][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:30]4[CH:31]=[CH:32][C:27]([OH:26])=[CH:28][CH:29]=4)[N:3]=3)[N:8]=[CH:7][C:6]=2[C:12](=[O:14])[CH3:13])[CH2:17][CH2:18]1)[CH3:25]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Reactant: OB(O)c1ccc(O)cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3ccc(O)cc3)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure II, 1-(6-chloro-4-{trans-4-[(dimethylamino)methyl]-cyclohexylamino}-1,5-naphthyridin-3-yl)ethanone (76 g, 0.21 mmol) was reacted with (4-hydroxyphenyl)boronic acid (43 g, 0.32 mmol) followed by formation of the dihydrochloride salt to afford the desired product (35 g, 34%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.11 (s, 1H), 8.41 (d, J=8.9 Hz, 1H), 8.28 (d, J=8.9 Hz, 1H), 8.03-7.97 (m, 2H), 7.04-6.98 (m, 2H), 5.73-5.62 (m, 1H), 3.11 (d, J=6.8 Hz, 2H), 2.94 (s, 6H), 2.75 (s, 3H), 2.50-2.42 (m, 2H), 2.06-1.99 (m, 3H), 1.73-1.61 (m, 2H), 1.40-1.27 (m, 2H); ESI MS m/z 419 [M+H]+; HPLC>99% (AUC), tR=9.24 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[S:22][C:17]2=[N:18][CH:19]=[CH:20][N:21]=[C:16]2[CH:15]=1)=O.P(Cl)(Cl)([Cl:25])=O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1/[N:11]=[C:12](\[Cl:25])/[C:14]1[S:22][C:17]2=[N:18][CH:19]=[CH:20][N:21]=[C:16]2[CH:15]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1NC(=O)c1cc2nccnc2s1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc([N+](=O)[O-])cc1/N=C(\Cl)c1cc2nccnc2s1
Yield: 111.9 %

Procedure:
A solution of N-(2-methyl-5-nitrophenyl)thieno[2,3-b]pyrazine-6-carboxamide 75 (400 mg, 1.273 mmol) in phosphorus oxychloride (15 mL, 161 mmol) was stirred at 105° C. for 7 h. POCl3 was evaporated to dryness and co evaporated with toluene. Triturating with acetonitrile gave crude (Z)—N-(2-methyl-5-nitrophenyl)thieno[2,3-b]pyrazine-6-carbimidoyl chloride 76 (474 mg, 112%) which was used without further purification. (m/z)=333 (M+H)+.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2=[CH:16][S:17][C:18]([CH3:19])=[C:5]12)=[O:3].[N:20]1([CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(OCC)(=O)C>[CH3:19][C:18]1[S:17][CH:16]=[C:6]2[C:7](=[O:15])[NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:4]([C:2]([N:33]3[CH2:32][CH2:31][CH:30]([CH2:29][CH2:28][CH2:27][CH2:26][N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)[CH2:35][CH2:34]3)=[O:3])[C:5]=12
Reactant: C1CCN(CCCCC2CCNCC2)CC1
Reactant: Cc1scc2c1N(C(=O)Cl)c1ccccc1NC2=O
Solvent: CCOC(C)=O
Product: Cc1scc2c1N(C(=O)N1CCC(CCCCN3CCCCC3)CC1)c1ccccc1NC2=O
Yield: 31 %

Procedure:
Prepared analogously to Example 4 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 4-[4-(1-piperidinyl)butyl]piperidine in a yield of 31% of theory. Colourless crystals, m.p. 209°-210° C. (ethyl acetate).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[F:11][C:12]1[CH:39]=[CH:38][C:15]([CH2:16][N:17]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:27][CH2:26][C@@H:25]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[C@H:24]([OH:36])[CH2:23]3)[C:18]2=[O:37])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[F:11][C:12]1[CH:39]=[CH:38][C:15]([CH2:16][N:17]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[C:24](=[O:36])[CH2:23]3)[C:18]2=[O:37])=[CH:14][CH:13]=1
Reactant: COc1ccc([C@@H]2CCN(C3CCN(Cc4ccc(F)cc4)C3=O)C[C@H]2O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(C2CCN(C3CCN(Cc4ccc(F)cc4)C3=O)CC2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of DMSO (0.14 mL, 2 mmol) and DCM (20 mL) at −78° C. under nitrogen was added oxalyl chloride (0.18 mL, 2 mmol) and the reaction mixture was stirred for 10 min. Then 1-(4-fluorobenzyl)-3-(trans-3-hydroxy-4-(4-methoxyphenyl)-piperidin-1-yl)pyrrolidin-2-one (320 mg, 0.8 mmol) was added and the reaction was stirred for one hour at same temperature. Triethylamine (0.56 mL, 4 mmol) was then added, and the reaction mixture was allowed to warm to rt. The mixture was then partitioned between water (100 mL) and DCM (200 mL). The organic layer was separated, dried over Na2SO4, filtered, and evaporated under reduced pressure to give afford the crude product, which was taken on to step D without further purification. LCMS (method Q) RT 0.68 min (47% AP), m/z 397.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:8][C:6]1[CH:5]=[C:4]([O:9][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(C)cc(O)c1
Reactant: Clc1ccccc1
Product: Cc1cc(C)cc(Oc2ccccc2)c1
Yield: 60 %

Procedure:
Following General Procedure C (140° C., 30 hours), 3,5-dimethyl-phenol (183 mg, 1.5 mmol) is coupled with chlorobenzene (102 μL, 1.0 mmol) to give 60% 1,3-dimethyl-5-phenoxybenzene.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>C(Cl)Cl>[Si:14]([O:6][CH2:5][C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[NH2:1])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1cccc(CO)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cccc(N)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.7 %

Procedure:
To a solution of 3-aminobenzyl alcohol (2.00 g, 16.2 mmol) and tertbutyldimethylsilyl chloride (2.90 g, 19.4 mmol) in CH2Cl2 (32.5 mL) was added triethylamine (7.45 mL, 53.5 mmol). The reaction mixture was stirred for 18 hours at ambient temperature and was then partitioned between ethyl acetate and H2O. The organic phase was washed twice with H2O, twice with brine, dried over MgSO4, filtered, and concentrated in vacuo. 3-(O-t-butyldimethylsilyloxymethyl)aniline (2.18 g, 57%) was obtained as a yellow oil by chromatography on silica gel (30% ethyl acetate/hexane). 1H NMR (300 MHz, CDCl3) δ7.10 (1H, t, J=7.5 Hz), 6.67-6.72 (2H, m), 6.56 (1H, br d, J=7.5 Hz), 4.66 (2H, s), 3.63 (2H, br s), 0.94 (9H, s), 0.09 (6H, s). MS m/e 238 (M+H)+, 255 (M+NH4)+.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H].[ClH:24]>C(O)C.O.[Pd]>[ClH:24].[ClH:24].[NH2:1][C:4]1[CH:21]=[CH:20][C:7]([CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(CCN2CCc3ccccc3C2)cc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(CCN2CCc3ccccc3C2)cc1

Procedure:
To a solution of the product of step (a) (11.0 g, 39.0 mmol) in 95% ethanol (150 ml), concentrated hydrochloric acid (7.5 ml) and water (50 ml) was added 10% Pd/C (1.0 g). The mixture was hydrogenated at 50 psig for 2.5 hours, until the theoretical amount of hydrogen was taken up. The catalyst was filtered and the filtrate concentrated to a solid residue. This was digested in absolute ethanol (75 ml), cooled, filtered and air dried; yield 11.4 g (90%) of the dihydrochloride salt.
Reaction SMILES: [CH2:1]([OH:29])[C@@H:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([OH:28])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].N1C=CN=C1.[Si:35](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].CN(C)C=O>O>[Si:35]([O:29][CH2:1][C@@H:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([OH:28])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3])([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H](CO)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)CO[Si](C)(C)C(C)(C)C
Temperature: 60 °C
Yield: 63.9 %

Procedure:
A mixture of (25R)-Cholest-5-ene-3β,26-diol (6.24 g, 15.4 mmol), imidazole (4.21 g, 61 mmol) and tert-butyldimethylsilylchloride (2.34 g, 15.4 mmol) and dimethylformamide was heated to 60° C. for 1.5 hours, then poured into water (300 ml) and extracted with diethyl ether (5×100 ml). Flash chromatography afforded (25R)-26-(tert-butyldimethylsilyloxy)cholest-5-en-3β-ol (5.09 g). Melting point: 93.5° C. The 1H-NMR spectrum (CDCl3, d) showed characteristic signals at: 0.01 (s, 6H), 0.63 (s, 3H), 0.90 (s, 9H), 3.4 (m, 3H, H-26 and H-3), 5.32 (d, 1H, H-6). The 13C-NMR spectrum (CDCl3, d) showed characteristic signals at: 50.1 (C-9), 56.1 (C14), 56.7 (C-17), 68.5 (C-26), 71.7 (C-3), 121.6 (C-6), 140.7 (C-5). The mass spectrum showed characteristic peaks at: 516.5 (M+).
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:17]=[C:18]1[C:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH2:21][CH2:20][N:19]1[CH2:36][C:37](O)=[O:38].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[O:17]=[C:18]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:22][CH2:21][CH2:20][N:19]1[CH2:36][C:37]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2][CH2:3]1)=[O:38]
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
A solution of benzyl piperazine-1-carboxylate (0.196 g, 0.889 mmol), 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (0.250 g, 0.808 mmol; Example 68E) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.186 g, 0.970 mmol) were stirred together overnight in dichloromethane (5 mL). The reaction was concentrated, loaded directly onto a SF15-silica gel column (Analogix®). The product was eluted using a gradient of 5% to 100% ethyl acetate over 30 minutes to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 7.46-7.07 (m, 15H), 5.15 (s, 2H), 4.22 (s, 2H), 3.75-3.30 (m, 10H), 2.73-2.53 (m, 2H), 1.85 (d, J=5.9, 2H); MS (ESI+) m/z 512.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][C@@H:7]([NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[CH2:6][C:5]2=1.[Cu][C:22]#[N:23]>CN1CCCC1=O.O.CCOC(C)=O.C(N)CN.[Cu]I.[Cu]>[C:22]([C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][C@@H:7]([NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[CH2:6][C:5]2=1)#[N:23]
Reactant: N#C[Cu]
Reactant: CC(C)C(=O)N[C@@H]1CCc2[nH]c3ccc(Br)cc3c2C1
Agent: [Cu]
Agent: [Cu]I
Solvent: O
Solvent: NCCN
Solvent: CCOC(C)=O
Product: CC(C)C(=O)N[C@@H]1CCc2[nH]c3ccc(C#N)cc3c2C1
Temperature: 130 °C
Yield: 63.2 %

Procedure:
Dissolve (R)-N-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide (Preparation 21) (1.00 g, 2.98 mmol) in 1-methyl-2-pyrolidinone (30 mL). Sparge the resulting solution with nitrogen for 15 min. Add copper(I) cyanide (801 mg, 8.95 mmol) and copper(I) iodide (1.70 g, 8.95 mmol). Heat to 130° C. for three days, then cool to room temperature. Dilute the reaction mixture with water (100 mL), EtOAc (250 mL), and enough ethylene diamine to dissolve the copper solids (about 70 mL). Separate the layers, then wash the organic layer with water (2×50 mL). Dry the organic portion over MgSO4. Filter, concentrate, and purify on silica gel (80 g) using 50-80% EtOAc/hexanes to afford 530 mg (63%) of the title compound as a white solid. MS (ES): 282 (M+1), 280 (M−1); 1H NMR (CDCl3): δ 8.44 (s, 1H), 7.76 (s, 1H), 7.40 (dd, 1H, J=8.4, 1.3 Hz), 7.37 (d, 1H, J=8.5 Hz), 5.64 (d, 1H, J=7.5 Hz), 4.42 (m, 1H), 3.11 (dd, 1H, J=15.2, 5.1 Hz), 2.98-2.80 (m, 2H), 2.59 (dd, 1H, J=15.4, 7.5 Hz), 2.38 (m, 1H), 2.17 (m, 1H), 2.02 (m, 1H), 1.21 (d, 6H, J=7.0 Hz); Chiral HPLC: Chiralcel OD-H 0.46×15 cm column, 15:85 EtOH/Heptane, 1.0 mL/min, 225 nm detection; Rt=7.37 min; >99% ee.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)=[O:27])=[CH:24][C:23]=4[O:38][CH3:39])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:40].[Na+]>CN(C=O)C>[CH:1]1([N:6]([C:7]2[C:8]([NH:9][CH3:16])=[CH:17][N:18]=[C:19]([NH:21][C:22]3[CH:37]=[CH:36][C:25]([C:26](=[O:27])[NH:28][CH:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[CH:24][C:23]=3[O:38][CH3:39])[N:20]=2)[CH2:12][C:11]([F:14])([F:13])[C:10]([OH:40])=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1cnc(Nc2ccc(C(=O)NC3CCN(C)CC3)cc2OC)nc1N(CC(F)(F)C(=O)O)C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (543 mg, 1 mmol) in 10 ml of DMF, was added 1N NaOH (5 ml) dropwise. The reaction mixture was stirred at rt. for 1 h and then subjected to reverse phase HPLC purification using basic column. The final compound was obtained by lyophilization first and then dried in the vacuum oven at 60° C. for 3 d (380 mg, 68%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47-1.99 (m, 12 H) 2.54 (d, J=2.8 Hz, 2 H) 2.64-2.79 (m, 5 H) 3.00 (d, J=4.6 Hz, 2 H) 3.85-4.10 (m, 6 H) 4.20 (d, J=7.3 Hz, 1 H) 7.42 (s, 2 H) 7.48 (d, J=8.3 Hz, 1 H) 7.61-7.80 (m, 1 H) 8.23 (br. s., 1 H) 8.42 (d, J=8.3 Hz, 1 H). [M+H] calc'd for C27H37F2N7O4, 562; found 562.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([Cl:25])[N:10]=1>COCCOC>[Cl:25][C:11]1[N:10]=[C:9]([N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)[C:18]2[C:13]([C:12]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:14][CH:15]=[CH:16][CH:17]=2
Reactant: Clc1nc(Cl)c2ccccc2c1-c1ccccc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: Clc1nc(-n2ccnc2)c2ccccc2c1-c1ccccc1
Reaction time: 3 h

Procedure:
15 g (0.5 mole) of an 80% suspension of sodium hydride in mineral oil were introduced, while stirring, into a solution of 37.5 g (0.6 mole) of imidazole in 250 ml of absolute 1,2-dimethyoxyethane. The whole was heated for 30 minutes to the boil and then a solution of 109.6 g (0.4 mole) of 1,3-dichloro-4-phenylisoquinoline in 100 ml of absolute 1,2-dimethoxyethane was added dropwise. The mixture was then boiled for 3 hours under reflux, the solvent was distilled off under reduced pressure and the residue was dissolved in a mixture of methylene chloride and water. The organic phase was washed with water, the sol-was removed under reduced pressure and the product was recrystallized from toluene. M.p. 165° to 168°.
Reaction SMILES: O[CH2:2][C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1CCCCC1.[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[CH2:28][CH3:29])[CH:23]=[O:24].CO>O>[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[CH:28]([CH3:2])[CH3:29])[CH:23]=[O:24]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: CCc1ccc(C=O)cc1Br
Solvent: O
Solvent: CO
Solvent: C1CCCCC1
Product: CC(C)c1ccc(C=O)cc1Br
Temperature: 41.79999923706055 °C
Yield: 207.7 %

Procedure:
A one liter four-necked cylindrical shaped reaction flask equipped with a Dean-Stark trap, condenser, thermometer, nitrogen inlet, and a mechanical stirrer was charged with 42 g of D-sorbitol (0.23 mole), 700 mL of cyclohexane, 105 g of 3-bromo-4-ethylbenzaldehyde (0.46 moles), 80 mL of methanol, and 2.5 g of water. The system was then flushed with argon and heated in an oil bath with stirring. The mixture was then heated to a vapor temperature of 41.8° C., at which time 3.0 g of p-toluenesulfonic acid in 40 mL of methanol was slowly added. The reaction was seeded with 1.0 g of 3,4-dimethylbenzylidene sorbitol in 20 mL of methanol. The reaction was then stirred and heated (to about 120° C.) under reflux with removal of water through the Dean Stark trap as cyclohexane was returned to the system. Heating was then recommenced until the vapor temperature reached 70° C., at which time 40 mL of methanol were added slowly. The reaction mixture was allowed to heat up to the same vapor temperature and methanol was added slowly again, and repeated another 5 times. The reaction product (a white gel) was then cooled, neutralized with potassium hydroxide (7 g in 40 mL of methanol), and stripped of the resultant cyclohexane layer (by azeotrope with water). The gel remaining was then filtered and purified in boiling water and boiling methanol, giving 3-bromo-4-isopropylbenzaldehyde as a white solid (108.5 g, 78% yield)(as determined through standard analyses) exhibiting a peak melting transition of 216.3° C. by DSC at 20° C./min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:25]=[CH:24][C:16]([O:17][CH2:18][CH2:19][NH:20][C:21]([NH2:23])=[O:22])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:26]([F:29])([F:28])[F:27])=[N:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>ClCCl>[C:36]([O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:25]=[CH:24][C:16]([O:17][CH2:18][CH2:19][NH:20][C:21]([NH2:23])=[O:22])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:26]([F:28])([F:29])[F:27])=[N:9]2)=[CH:6][CH:7]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)NCCOc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(O)cc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(OCCNC(N)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of N-(2-{4-[1-(4-hydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea obtained by Example 81 (148.5 mg) in dichloromethane (1.5 ml) was added pyridine (163 μL) and acetic anhydride (45 μL), and the mixture was stirred at room temperature for 1 hr and stirred under reflux for 3 hrs.
Reaction SMILES: Br[C:2]1[C:3]([CH:9]=[N:10][C:11]([CH3:14])([CH3:13])C)=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(#N)C.[CH:18]1(C#C)[CH2:23][CH2:22]C[CH2:20][CH2:19]1>ClCCl.[Zn]>[Cl:8][C:5]1[N:6]=[CH:7][C:2]2[C:3]([CH:4]=1)=[CH:9][N:10]=[C:11]([CH:13]1[CH2:22][CH2:23][CH2:18][CH2:19][CH2:20]1)[CH:14]=2
Reactant: C#CC1CCCCC1
Reactant: CC(C)(C)N=Cc1cc(Cl)ncc1Br
Agent: [Zn]
Solvent: CC#N
Solvent: ClCCl
Product: Clc1cc2cnc(C3CCCCC3)cc2cn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
A round-bottom flask containing N-((5-bromo-2-chloropyridin-4-yl)methylene)-2-methylpropan-2-amine (164.5 mg, 0.5969 mmol), DPPPNiCl2 (16.0 mg, 0.0295 mmol) and zinc (84.0 mg, 1.28 mmol) was evacuated and purged with nitrogen 5 times. Acetonitrile (6 mL, 100 mmol) and cyclohexylacetylene (86.0 uL, 0.658 mmol) were added to the flask and the reaction mixture was stirred at 80° C. under a nitrogen balloon for 30 minutes. The reaction mixture was cooled to room temperature, diluted with dichloromethane, and filtered through celite, rinsing with dichloromethane. The filtrate was evaporated in vacuo and the crude product purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-40% ethyl acetate in dichloromethane) to yield 80.4 mg (55%) of 3-chloro-7-cyclohexyl-2,6-naphthyridine. LCMS (ESI): M+H=247.2; 1H NMR (500 MHz, DMSO) δ 9.39 (s, 1H), 9.28 (s, 1H), 8.20 (s, 1H), 7.88 (s, 1H), 2.91-2.81 (m, 1H), 1.97 (d, J=11.3 Hz, 2H), 1.84 (d, J=13.0 Hz, 2H), 1.75 (d, J=12.9 Hz, 1H), 1.58 (ddd, J=24.8, 12.5, 2.9 Hz, 2H), 1.49-1.37 (m, 2H), 1.27 (ddd, J=16.3, 12.6, 9.2 Hz, 1H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:28]2[N:37]=[CH:36][C:35]3[C:30](=[C:31]([F:42])[CH:32]=[C:33]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:34]=3)[C:29]2=[O:43])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[N:13]=[C:14]([NH:20][C:21]2[CH:22]=[N:23][N:24]([CH2:26][CH3:27])[CH:25]=2)[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[C:38]([C:33]1[CH:34]=[C:35]2[C:30](=[C:31]([F:42])[CH:32]=1)[C:29](=[O:43])[N:28]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[N:13]=[C:14]([NH:20][C:21]4[CH:22]=[N:23][N:24]([CH2:26][CH3:27])[CH:25]=4)[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=3)[CH:10]=[CH:9][N:8]=1)[N:37]=[CH:36]2)([CH3:41])([CH3:39])[CH3:40]
Reactant: CCn1cc(Nc2nc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3COC(C)=O)cn(C)c2=O)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: CCn1cc(Nc2nc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
A mixture of 123d (152 mg, 0.26 mmol) and lithium hydroxide (61 mg, 2.56 mmol) in i-propanol/THF (1:1, 10 mL) and water (3 mL) was stirred at room temperature for 1 h. The mixture was evaporated under reduced pressure and the residue was extracted with ethyl acetate (2×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 123 (55 mg, 39%) as a yellow solid. MS-ESI: [M+H]+ 545.2. 1H NMR (500 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.58 (d, J=5.0 Hz, 1H), 8.54 (d, J=2.5 Hz, 1H), 8.18 (s, 1H), 7.90 (d, J=2.0 Hz, 1H), 7.80-7.75 (m, 1H), 7.74 (s, 1H), 7.71 (d, J=5.0 Hz, 1H), 7.51 (s, 1H), 4.90 (t, J=5.0 Hz, 1H), 4.61-4.53 (m, 2H), 4.09 (q, J=7.5 Hz, 2H), 3.54 (s, 3H), 1.41 (s, 9H), 1.35 (t, J=6.0 Hz, 3H).
Reaction SMILES: [CH2:1]([P:9](=O)([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C=CCCCCCC>>[CH2:18]([P:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCP(=O)(CCCCCCCC)CCCCCCCC
Solvent: C=CCCCCCC
Product: CCCCCCCCP(CCCCCCCC)CCCCCCCC

Procedure:
Work up yielded trioctylphosphine oxide, a colourless solid FP 47.0° C., 365 g--75% yield on the octene used.