Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:26]=[CH:25][C:20]([O:21][CH2:22][C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:9]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:40]=[N+:41]=[N-:42].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:26]=[CH:25][C:20]([O:21][CH2:22][C:23]4[NH:42][N:41]=[N:40][N:24]=4)=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[C:9]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCOc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(-c2ccccc2)n3Cc2ccccc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(Cc2c(-c3ccccc3)n(Cc3ccccc3)c3ccc(-c4ccc(OCc5nnn[nH]5)cc4)cc23)cc1

Procedure:
The desired product was prepared using a procedure similar to step 6 of example 3. Thus, [4-(1,3-dibenzyl-2-phenyl-1H-indol-5-yl)-phenoxy]-acetonitrile (0.481 g, 0.953 mmol) was reacted with NaN3 (0.310 g, 4.766 mmol) and NH4Cl (0.255 g, 4.766 mmol) in DMF (5 ml) to give the product (0.394 g, 0.719 mmol, 75%) as an off-white solid, dec. 191-194° C. 1H NMR (DMSO-d6) δ 4.08 (s, 2H), 5.35 (s, 2H), 5.51 (s, 2H), 6.89 (d, J=7.2 Hz, 2H), 7.10-7.25 (m, 10H), 7.37 (dd, J=1.7 Hz, 8.5 Hz, 1H), 7.40-7.54 (m, 8H), 7.61 (s, 1H), 16.80 (broad s, 1H); IR (solid) 3020, 2920, 1605, 1520, 1470, 1450, 1360, and 1240 cm−1; [ESI(−)], m/z 546 (M−H)−; Anal. Calcd. for C36H29N5O: C, 78.95; H, 5.34; N, 12.79; Found: C, 78.53H, 5.25; N, 12.77.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH2:14][C:15](O)=[O:16])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH2:14][C:15]([Cl:22])=[O:16])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1cccc(C(=O)c2ccc(Cl)cc2)c1
Product: O=C(Cl)Cc1cccc(C(=O)c2ccc(Cl)cc2)c1

Procedure:
A solution of 8.235 g of 3-(4-chlorobenzoyl)-benzeneacetic acid in 20 ml of thionyl chloride was heated to reflux and then excess thionyl chloride was removed under reduced pressure. The residue was dissolved in benzene and the solution was evaporated to dryness under reduced pressure. The residue was dissolved in 50ml of anhydrous benzene to obtain a solution of 3-(4-chlorobenzoyl)-benzeneacetic acid chloride which was used as is for the next step.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Li])CCC.[Cl-].[C:17]1([PH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CCCCCC.CCOCC>[C:24]1([P:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][N:2]([CH3:10])[CH3:1])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: CN(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: CN(C)Cc1ccccc1P(c1ccccc1)c1ccccc1
Reaction time: 30 h

Procedure:
A 15.0 ml portion of N,N-dimethylbenzenemethanamine and 300 ml of ether were mixed under a nitrogen atmosphere. A 58 ml portion of 2.6M butyl lithium in hexane was added and this mixture was stirred, under nitrogen for 30 hours. A mixture of 27.0 ml of diphenylphosphine chloride in 60 ml of ether was added dropwise and the mixture was stirred overnight. Water was added, the organic layer was separated and extracted twice with dilute hydrochloric acid. The combined acid extracts were basified with 10% sodium hydroxide, then extracted twice with ether. The ether extracts were combined, dried and evaporated, giving 15.9 of 2-(diphenylphosphino)-N,N-dimethylbenzenemethanamine as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br)([O-:3])=[O:2].[O:12]([S:14]([CH3:16])=[O:15])[Na]>CCO>[CH3:16][S:14]([CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:15])=[O:12]
Reactant: CS(=O)O[Na]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Solvent: CCO
Product: CS(=O)(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 77.3 %

Procedure:
To a mixture of 3-nitrobenzyl bromide (1 g, 4.63 mmol) in EtOH (12 mL) was added NaOSOCH3 (0.61 g, 5.09 mmol). After heating at reflux for 2 h, the mixture was cooled to room temperature, and the precipitates were collected by filtration to give 1-(methylsulfonylmethyl)-3-nitrobenzene (0.77 g).
Reaction SMILES: [CH2:1]([C:3]1([S:6]([O-:9])(=O)=[O:7])[CH2:5][CH2:4]1)[CH3:2].[K+].S(Cl)([Cl:13])=O.O>C(Cl)Cl.CN(C=O)C>[CH2:1]([C:3]1([S:6]([Cl:13])(=[O:9])=[O:7])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1(S(=O)(=O)[O-])CC1
Reactant: O=S(Cl)Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC1(S(=O)(=O)Cl)CC1
Temperature: 80 °C
Yield: 138.3 %

Procedure:
To a mixture of potassium 1-ethylcyclopropane-1-sulfonate (0.420 g, 2.23 mmol, Preparation #JJJ.1) in thionyl chloride (3.58 mL, 49.1 mmol) was added DMF (0.016 mL, 0.20 mmol). The reaction was heated at about 80° C. for about 16 h. The reaction was cooled to 0° C. before the slow addition of water (10 mL). The reaction mixture was diluted with DCM (20 mL). The layers were separated and the aqueous portion was extracted with DCM (3×10 mL). The combined organic layers were separated, dried over anhydrous MgSO4, filtered, and concd under reduced pressure to afford crude 1-ethylcyclopropane-1-sulfonyl chloride (0.52 g, 83% yield, 60% purity) as an orange oil: 1H NMR (400 MHz, DMSO) d 2.09 (q, J=7.4, 2H), 1.62-1.60 (m, 2H), 1.45-1.39 (m, 2H), 0.91 (t, J=7.5, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][CH2:16][C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=1[CH2:23][C:24]([NH:26][CH:27]1[C:44](=[O:45])[N:29]2[C:30]([C:41]([OH:43])=[O:42])=[C:31]([CH2:34][S:35][C:36]3[N:37]=[N:38][NH:39][CH:40]=3)[CH2:32][S:33][C@H:28]12)=[O:25])=O)(C)(C)C>CCOCC>[NH2:15][CH2:16][C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=1[CH2:23][C:24]([NH:26][CH:27]1[C:44](=[O:45])[N:29]2[C:30]([C:41]([OH:43])=[O:42])=[C:31]([CH2:34][S:35][C:36]3[N:37]=[N:38][NH:39][CH:40]=3)[CH2:32][S:33][C@H:28]12)=[O:25]
Reactant: CC(C)(C)OC(=O)NCC1=C(CC(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4c[nH]nn4)CS[C@H]23)CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: NCC1=C(CC(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4c[nH]nn4)CS[C@H]23)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of trifluoroacetic acid (1 ml.) and 5h (0.55 g., 0.98 mmoles) was stirred for 30 min. at room temperature and diluted with ether (50 ml.) to give the precipitate which was collected by filtration and slurried in a small amount of water (2 ml.). The mixture was adjusted to pH 6 with ammonium hydroxide and diluted with acetonitrile (200 ml.) to precipitate 6h which was washed with acetonitrile (50 ml.). Yield 0.36 g. (80%). M.p. 203° - 215° C. (dec.).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:14][C@@H:15]([C@H:17]2[CH2:21][NH:20][C:19](=[O:22])[CH2:18]2)[CH3:16])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[CH:11]2[CH2:13][CH2:12]2)[CH:7]=1.[CH3:23][C:24]1([CH3:43])[C:32]2[C:27](=[CH:28][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:31]=2)[NH:26][C:25]1=[O:42].CC1(C)C2C(=CC=CC=2)NC1=O>>[CH:11]1([C:10]2[CH:9]=[N:8][N:6]3[CH:7]=[C:2]([C:29]4[CH:28]=[C:27]5[C:32]([C:24]([CH3:43])([CH3:23])[C:25](=[O:42])[NH:26]5)=[CH:31][CH:30]=4)[CH:3]=[C:4]([O:14][C@@H:15]([C@@H:17]4[CH2:18][C:19](=[O:22])[NH:20][CH2:21]4)[CH3:16])[C:5]=23)[CH2:13][CH2:12]1
Reactant: CC1(C)C(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: C[C@@H](Oc1cc(Cl)cn2ncc(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: CC1(C)C(=O)Nc2ccccc21
Product: C[C@@H](Oc1cc(-c2ccc3c(c2)NC(=O)C3(C)C)cn2ncc(C3CC3)c12)[C@H]1CNC(=O)C1

Procedure:
Following Steps 7 and 8 from the procedure used to prepare Example 6.53, starting from (R)-4-((R)-1-((6-chloro-3-cyclopropylpyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one 6.53a (55 mg) and 3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one, 13 mg of 6-(3-cyclopropyl-4-4R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3,3-dimethylindolin-2-one was synthesized.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[NH2:15][C@@H:16]1[CH2:25][CH2:24][C:23]2[C:18](=[C:19]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[CH:20]=[CH:21][CH:22]=2)[CH2:17]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:32][N:29]1[CH2:30][CH2:31][N:26]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[CH2:17][C@H:16]([NH:15][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:14][CH:13]=2)[CH2:25][CH2:24]3)[CH2:27][CH2:28]1
Reactant: CS(=O)(=O)Oc1ccc(C(=O)O)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(OS(C)(=O)=O)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 4-methylsulfonyloxybenzoic acid (0.60 g, 2.8 mmol; described in: Looker, J. H.; Hayes, C. H.; Thatcher, D. N. J. Am. Chem. Soc. 1957, 79, 741-4) in thionyl chloride (15 mL) was heated at reflux for 30 min (the mixture became homogeneous). The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (110 mg, 0.47 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (110 mg, 0.45 mmol) and triethylamine (94 μL, 0.68 mmol) in methylene chloride (20 mL). After the addition the reaction was allowed to stir at ambient temperature for 15 min and then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 160 mg (78%) of the title compound as white crystals: mp 199-200° C.; [α]21D −20° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 443 (3, M+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][N:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH:6]=[C:7]([F:17])[C:8]=1[O:9]CC1C=CC=CC=1)#[N:2]>CO.C1COCC1.[C].[Pd]>[C:1]([C:3]1[CH:4]=[C:5]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][N:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH:6]=[C:7]([F:17])[C:8]=1[OH:9])#[N:2]
Reactant: COC(=O)c1ccnc(-c2cc(F)c(OCc3ccccc3)c(C#N)c2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccnc(-c2cc(F)c(O)c(C#N)c2)c1

Procedure:
Methyl 2-(3-cyano-4-benzyloxy-5-fluorophenyl)isonicotinate is stirred at room temperature in methanol-THF (1:1) under a hydrogen atmosphere at normal pressure in the presence of palladium-carbon to obtain methyl 2-(3-cyano-5-fluoro-4-hydroxyphenyl)isonicotinate. FN: 271.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7](O)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=2)[CH2:3][CH2:2]1.O=P(Cl)(Cl)[Cl:17].CC(=O)OCC>CC#N>[Cl:17][C:7]1[C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:11][N:10]=[C:9]([S:12][CH3:13])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1ncc(OCC2CC2)c(O)n1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CSc1ncc(OCC2CC2)c(Cl)n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
To the title compound of step 2 (29.00 g, 136.79 mmol) and N(CH3)4C1 (22.47 g, 205.19 mmol) in anhydrous MeCN (300 mL), was added POCl3 (123.93 g, 820.74 mmol). The mixture was stirred at r.t. for 30 min and at 70° C. for 1 h. After concentration under vacuum, EA extractive work up and silica gel chromatography (PE:EA=50:1-5:1) gave the title compound (20 g, 63.6% yield) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.16 (s, 1H), 3.95 (d, J=6.8 Hz, 2H), 2.56 (s, 3H), 1.33-1.28 (m, 1H), 0.72-0.70 (m, 2H), 0.41-0.37 (m, 2H). LCMS: 230.9 (M+1)+
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([CH2:12][NH2:13])[CH2:4][CH2:3]1.F[C:16]1[CH:24]=[N:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]>>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([CH2:12][NH:13][C:21]2[CH:22]=[N:23][CH:24]=[CH:16][C:17]=2[C:18]([OH:20])=[O:19])[CH2:4][CH2:3]1
Reactant: O=C(O)c1ccncc1F
Reactant: CC1(C)CCC(CN)c2ccccc21
Product: CC1(C)CCC(CNc2cnccc2C(=O)O)c2ccccc21
Yield: 17 %

Procedure:
The title compound was prepared in 17% yield from 1-(4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)methanamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ 13.36 (br s, 1H), 8.37 (s, 1H), 7.83 (d, 1H, J=5.0 Hz), 7.59 (br s, 1H), 7.55 (d, 1H, J=5.0 Hz), 7.38 (d, 1H, J=7.8 Hz), 7.26 (d, 1H, J=6.8 Hz), 7.07-7.19 (m, 2H), 3.47-3.58 (m, 2H), 3.07-3.11 (m, 1H), 1.77-1.90 (m, 3H), 1.51-1.57 (m, 1H), 1.31 (s, 3H), 1.21 (s, 3H). [M+H] calc'd for C19H22N2O2, 311. found 311.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([OH:12])=[CH:7]2.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1.O>CN1C(=O)CCC1.C(Cl)Cl>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:12][C:6]1[CH:7]=[C:8]2[C:3](=[CH:4][CH:5]=1)[C:2]([NH2:1])=[CH:11][CH:10]=[CH:9]2
Reactant: Nc1cccc2cc(O)ccc12
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: O
Product: COc1cc2nccc(Oc3ccc4c(N)cccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-amino-2-naphthol (711 mg, 4.47 mmol) in NMP (3 ml), Cs2CO3 (4.37 g, 13.41 mmol) was added and the reaction was stirred at RT for 15 min. To the mixture, 4-chloro-6,7-dimethoxy-quinoline (500 mg, 2.23 mmol) was added and the vessel was sealed/clamped shut. The reaction was placed in the microwave and heated at 160° C. for 15 min, then 10 additional min with pre-stirring for 60 sec. The mixture was taken up into water and CH2Cl2, and filtered through Celite. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water, 1N NaOH, and brine, dried with Na2SO4, filtered and concentrated in vacuo. The 6-(6,7-dimethoxy-quinolin-4-yloxy)-naphthalen-1-ylamine was purified by column chromatography using 0-10% MeOH in CH2Cl2.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=1)[CH:7]=[CH:6]2.B(Br)(Br)Br>>[OH:19][C:15]1[CH:14]=[C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([OH:2])[CH:4]=3)[N:9]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc(-c2ccc3cc(OC)ccc3n2)c1
Agent: BrB(Br)Br
Product: Oc1cccc(-c2ccc3cc(O)ccc3n2)c1
Yield: 10 %

Procedure:
The compound is prepared by reaction of 6-methoxy-2-(3-methoxyphenyl)quinoline (77 mg, 0.29 mmol, 1 eq) with boron tribromide (15 eq) according to method G. Purification by column chromatography with hexane/ethyl acetate 7/3 as the eluent yields the desired product in a yield of 10%, 7 mg.
Reaction SMILES: [Li][CH2:2]CCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[F:23].CI>C1COCC1>[Cl:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([CH3:2])[C:18]=1[F:23]
Reactant: Fc1cnccc1Cl
Reactant: [Li]CCCC
Agent: CC1(C)CCCC(C)(C)N1
Solvent: CI
Solvent: C1CCOC1
Product: Cc1nccc(Cl)c1F
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 56 %

Procedure:
n-BuLi (8.5 ml of a 1.2 M soln in hexanes, 10.2 mmol) was added dropwise to a solution of 2,2,6,6-tetramethylpiperidine (1.73 ml, 10.2 mmol) in THF (30 ml) at 0° C. The mixture was then cooled to −78° C. and 4-chloro-3-fluoropyridine (1.0 ml, 10.2 mmol) was added dropwise over 15 minutes and then stirred for 25 minutes. MeI (0.64 ml, 10.2 mmol) was added dropwise at −78° C. and the resulting solution was left to warm to room temperature over several hours and quenched with saturated NaHCO3 (5 ml). The reaction was concentrated at reduced pressure, diluted with dichloromethane (50 ml), washed twice with saturated NaHCO3 (25 ml), dried (MgSO4), filtered and concentrated at reduced pressure. The residue was purified by FCC (pentane/diethyl ether with gradient, 9:1 to 8:2) to provide the title compound as colourless oil (833 mg, 56%).
Reaction SMILES: C(N(C1C=CC=CC=1C1CCC2C(=CC=C(OC)C=2)C1)CCC1C=CC(O)=CC=1)C.Cl.ClCCN1CCCC1.[CH2:40]([N:42]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=1[CH:65]1[CH2:74][CH2:73][C:72]2[C:67](=[CH:68][CH:69]=[C:70]([O:75]C)[CH:71]=2)[CH2:66]1)[CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][CH2:53][N:54]2[CH2:58][CH2:57][CH2:56][CH2:55]2)=[CH:47][CH:46]=1)[CH3:41]>>[CH2:40]([N:42]([CH2:43][CH2:44][C:45]1[CH:46]=[CH:47][C:48]([O:51][CH2:52][CH2:53][N:54]2[CH2:55][CH2:56][CH2:57][CH2:58]2)=[CH:49][CH:50]=1)[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=1[CH:65]1[CH2:74][CH2:73][C:72]2[CH:71]=[C:70]([OH:75])[CH:69]=[CH:68][C:67]=2[CH2:66]1)[CH3:41]
Reactant: CCN(CCc1ccc(OCCN2CCCC2)cc1)c1ccccc1C1CCc2cc(OC)ccc2C1
Agent: CCN(CCc1ccc(O)cc1)c1ccccc1C1CCc2cc(OC)ccc2C1
Agent: Cl
Agent: ClCCN1CCCC1
Product: CCN(CCc1ccc(OCCN2CCCC2)cc1)c1ccccc1C1CCc2cc(O)ccc2C1
Yield: 51.9 %

Procedure:
Synthesized from 4-{2-{ethyl[2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amino}ethyl}phenol and 1-(2-chloroethyl)pyrrolidine hydrochloride according to an analogous synthetic method to Preparation Example 40, ethyl[2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]{2-[4-(2-pyrrolidin-1-ylethoxy)phenyl]ethyl}amine (230 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (116 mg).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)[CH3:19]>>[CH2:18]([O:20][C:21]1[CH:26]=[C:25]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)[CH:24]=[CH:23][CH:22]=1)[CH3:19]
Reactant: CCOc1cccc(B(O)O)c1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: CCOc1cccc(-n2cnc(-c3c(-c4ccccc4)noc3C)c2)c1
Yield: 7 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (68 mg, 0.3 mmol) was converted, using 3-ethoxyphenylboronic acid instead of 4-fluorophenylboronic acid, to the tide compound (8 mg, 7%) which was obtained as an off-white solid. MS: m/e=346.5 [M+H]+.
Reaction SMILES: [C:1]12([CH2:11][N:12]=[C:13]=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F:15][C:16]1[C:17](=[O:23])[NH:18][C:19](=[O:22])[NH:20][CH:21]=1>CN(C)C(=O)C.C(OCC)(=O)C>[C:1]12([CH2:11][NH:12][C:13]([N:20]3[CH:21]=[C:16]([F:15])[C:17](=[O:23])[NH:18][C:19]3=[O:22])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: O=C=NCC12CC3CC(CC(C3)C1)C2
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)n1cc(F)c(=O)[nH]c1=O
Reaction time: 3 h

Procedure:
To the above solution of 1-adamantylmethyl isocyanate was added a solution of 5-fluorouracil (2.60 g) in N,N-dimethylacetamide (20 ml) at 80° C. and stirred for further 3 hours at the same temperature. The resultant mixture was diluted with ethyl acetate (200 ml), washed with water (each 30 ml., 3 times), dried over magnesium sulfate, treated with activated charcoal, filtered and evaporated in vacuo. The residue was recrystallized from diethyl ether to give 1-[N-(1-adamantylmethyl)carbamoyl]-5-fluorouracil (1.85 g), as colorless crystalline powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH2:18]([N:21]=[C:22]=[O:23])[CH2:19][CH3:20]>>[CH2:18]([NH:21][C:22]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:23])[CH2:19][CH3:20]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: CCCN=C=O
Product: CCCNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 52.2 %

Procedure:
Beginning with 0.15 gm (0.65 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.073 mL (0.78 mMol) propyl isocyanate, 0.107 gm (52%) of the title compound were recovered essentially by the procedure of Example 122. An analytical sample was crystallized from aqueous ethanol. m.p.=181° C. (dec.) MS(m/e): 315(M+) Calculated for C17H25N5O: Theory: C, 64.74; H, 7.99; N, 22.2. Found: C, 64.51; H, 7.77; N, 22.46.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([NH2:25])=[O:24])[C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:16])=[CH:11][C:12]=3[C:13]=2[N:14]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1COCC1>[N:17]1([C:15]([C:10]2[CH:9]=[CH:8][C:7]3[NH:6][C:5]4[C:4]([C:23]([NH2:25])=[O:24])=[CH:3][C:2]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)=[N:14][C:13]=4[C:12]=3[CH:11]=2)=[O:16])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: NC(=O)c1cc(Br)nc2c1[nH]c1ccc(C(=O)N3CCOCC3)cc12
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1CCOC1
Product: NC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1ccc(C(=O)N3CCOCC3)cc12
Temperature: 85 °C

Procedure:
2-Bromo-8-(morpholine-4-carbonyl)-5H-pyrido[3,2-b]indole-4-carboxamide (100 mg, 0.248 mmol), phenylboronic acid (60.5 mg, 0.496 mmol), potassium phosphate tribasic (168 mg, 0.794 mmol), 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (23.64 mg, 0.050 mmol) and palladium(II) acetate (5.57 mg, 0.025 mmol) were mixed with THF (4 mL) in a sealed microwave tube. The mixture was heated in microwave at 85° C. for 3 hrs. The mixture was concentrated and purified using preparative HPLC to give titled product. MS (ESI) m/z 401.2 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.8 (s, 1H), 8.65 (s, 1H), 8.5 (s, 1H), 8.32 (m, 3H), 7.94 (s, 1H), 7.81(d, 1H, J=8.2), 7.60(m, 3H), 7.44 (t, 1H, J=7), 3.7-3.5 (bm, 8H).
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9](=[C:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=1)[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([NH:39][C:40](=O)[O:41]C2C=CC=CC=2)[CH:34]=1.C(N(CC)CC)C>CS(C)=O>[Br:8][C:9]([C:10]1[CH:26]=[CH:25][CH:24]=[C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][N:15]=2)[CH:11]=1)=[C:27]1[CH2:32][CH2:31][N:30]([C:40]([NH:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)=[O:41])[CH2:29][CH2:28]1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C(Br)=C3CCNCC3)c2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(Nc1cccnc1)N1CCC(=C(Br)c2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
A solution of 2-(3-(bromo(piperidin-4-ylidene)methyl)phenoxy)-5-(trifluoromethyl)pyridine trifluoroacetate (624 mg, 0.995 mmol) and phenyl pyridin-3-ylcarbamate (213 mg, 0.995 mmol) in DMSO (5 mL) was treated with triethyamine (0.28 mL, 201 mg, 1.99 mmol) and the mixture was heated to 60° C. After 4 h, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted again with ethyl acetate. The combine organic layers were washed with brine and dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0-5% MeOH/CH2Cl2) to afford the title compound as a white foam (329 mg, 62% yield). MS (APCI 10V) AP+ 535.15; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (2H) 2.65 (2H) 3.46 (2H) 3.63 (2H) 6.99 (d, J=8.38 Hz, 1H) 7.05 (2H) 7.12 (dd, 1H) 7.35 (1H) 7.62 (1H) 7.87 (dd, J=8.87, 2.05 Hz, 1H) 8.13 (1H) 8.41 (1H) 8.65 (1H) 8.93 (1H) 9.20 (1H)