Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:7]([NH:8][C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[C:6](O)[N:5]=[C:4]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:3]=1.P(Cl)(Cl)([Cl:30])=O>>[Cl:30][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[O:10][C:6]=2[N:5]=[C:4]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:3]=1
Reactant: COc1ccc(CCNc2nc(O)c(NC(=O)c3ccco3)c(O)n2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(CCNc2nc(Cl)c3nc(-c4ccco4)oc3n2)cc1
Temperature: 90 °C
Yield: 83.2 %

Procedure:
A mixture of 4,6-dihydroxy-5-(2-furanylcarbonyl)amino-2-[(4-methoxyphenyl)ethyl]aminopyrimidine (408 mg) and phosphorus oxychloride (5 ml) was heated at 90° C. for 3 hours. The excess phosphorus oxychloride was removed by evaporation, in vacuo, and then by azeotroping with toluene (2×50 ml). The residue was added to water and the resultant precipitate filtered off, washed with water and dried. There was thus produced 7-chloro-2-(2-furyl)-5-[2-(4-methoxyphenyl)ethyl]amino oxazolo[5,4-d]pyrimidine (340 mg, 83.2% yield); m.p.169.5°-171° C.: NMR:DMSO-d6 : 2.80(t,2H,ArCH2), 3.48(q,2H, CH2NH), 3.72(s, 3H, OMe), 6.80(m, 1H, furyl-H), 6.85(d,2H,ArH), 7.16(d,2H,ArH), 7.44(d,1H,furyl-H), 8.07(m, 1H, furyl-H), 8.13(brs,1H,NH).
Reaction SMILES: Br[C:2]1[C:11]([S:12]([N:15]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][C@@H:16]2[CH3:29])(=[O:14])=[O:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[CH3:30]B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.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>[C:25]([O:24][C:22]([N:18]1[CH2:19][CH2:20][CH2:21][N:15]([S:12]([C:11]2[C:2]([CH3:30])=[C:3]3[C:8](=[CH:9][CH:10]=2)[CH:7]=[N:6][CH:5]=[CH:4]3)(=[O:14])=[O:13])[C@@H:16]([CH3:29])[CH2:17]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCCN1S(=O)(=O)c1ccc2cnccc2c1Br
Reactant: CB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(S(=O)(=O)N2CCCN(C(=O)OC(C)(C)C)C[C@@H]2C)ccc2cnccc12
Temperature: 100 °C
Reaction time: 10 h
Yield: 80.8 %

Procedure:
100 mg of (S)-5-bromo-6-(4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl)isoquinoline, 15 mg of methylboronic acid, 12 mg of tetrakis(triphenylphosphine)palladium, and 131 mg of potassium phosphate were suspended in 10 mL of 1,4-dioxane and stirred at 100° C. for 10 hours in an argon gas atmosphere. After the completion of reaction, water was added to the reaction solution, followed by extraction with ethyl acetate (30 mL×2). Then, the extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain 70 mg of the compound of interest as a colorless oil (81%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](Br)[C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=1.[Br-].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Zn+].Cl>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.O>[Br:1][C:2]1[CH:3]=[C:4]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)[C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=1
Reactant: [Zn+]c1ccccn1
Reactant: CCNC(=O)Nc1nc2cc(Br)cc(Br)c2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: O
Product: CCNC(=O)Nc1nc2cc(Br)cc(-c3ccccn3)c2s1
Temperature: 55 °C
Reaction time: 18 h
Yield: 55.2 %

Procedure:
A stirred mixture of the 1-(5,7-dibromo-benzothiazol-2-yl-3-ethyl urea (2.62 g, 0.00687 mol) and Dichlorobis(triphenylphosphine)-palladium (0.48 g 0.000687 mol), under nitrogen, was treated in one portion, via a syringe, with 2-pyridyl zinc bromide solution (0.5M solution in THF, 7.66 g, 0.0344 mol). The reaction mixture was heated, with stirring, at 55° C. for 18 hours, allowed to cool and poured into 500 ml of water containing ˜5 ml of conc hydrochloric acid. The suspension was stirred and the solid filtered off, washed with water, followed by 20 ml of 1:1 DCM/Methanol mixture to give the crude 1-(5-Bromo-7-pyridin-2-yl-benzothiazol-2-yl)-3-ethyl-urea (1.43 g). This was purified by “flash” silica chromatography using 0 to 100% hexane/ethyl acetate followed by 0 to 100% methanol in ethyl acetate to elute the required product as a beige solid (1.1 g).
Reaction SMILES: [C:1]([O-:4])([O-])=O.[Cs+].[Cs+].[CH2:7]([O:14][C:15]1[CH:16]=[C:17](O)[C:18]2[C:19](=[O:31])[C:20]3[C:25]([O:26][C:27]=2[CH:28]=1)=[C:24]([O:29][CH3:30])[CH:23]=[CH:22][CH:21]=3)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CI.CCO>CN(C=O)C>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([O:4][CH3:1])[C:18]2[C:19](=[O:31])[C:20]3[C:25]([O:26][C:27]=2[CH:28]=1)=[C:24]([O:29][CH3:30])[CH:23]=[CH:22][CH:21]=3)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cccc2c(=O)c3c(O)cc(OCc4ccccc4)cc3oc12
Agent: [Cs+]
Solvent: CCO
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccc2c(=O)c3c(OC)cc(OCc4ccccc4)cc3oc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.1 %

Procedure:
Cs2CO3 (27.0 g, 83 mmol) was added in portions to phenol (102) (14.5 g, 42 mmol) and MeI (8.0 mL, 125 mmol) in DMF (400 mL) at rt. After 3 h at 50° C., the reaction was decanted and washed with CH2Cl2 into an erlenmeyer which had been placed in an ice cooled bath. With stirring, 2M HCl was added slowly until acidic by pH paper. After warming to rt, the reaction was diluted with CH2Cl2 (800 mL) and H2O (400 mL). The layers are separated and the aqueous layer was reextracted with CH2Cl2 (300 mL). The organic layers were combined, washed with brine (400 mL), dried (Na2SO4) and concentrated under reduced pressure to provide a red sludge which could be tritrated with EtOH and filtered to afford (9.3 g, 66%) of (103) as a pink solid. Analytically pure material can be obtained at this point by column chromatography with 50% EtOH/hexane. (LH-63-5) 1H NMR (250 MHz, CDCl3) δ 7.84 (d, 1H, J=6.0Hz), 7.42−7.31 (complex, 5H), 7.20−7.07 (complex, 2 H), 6.63 (s, 1H), 6.37 (s, 1H), 5.08 (s, 2H), 3.92 (s, 3H), 3.88 (s, 3H); 13C NMR (62.5 MHz) δ 175.2, 163.8, 161.7, 159.4, 147.8, 144.5, 135.6, 128.6, 128.3, 127.5, 123.9, 123.1, 117.5, 114.3, 106.1, 95.9, 93.6, 70.4, 56.3, 56.2; mass spectrum (CI) m/z+1 363.1242 [C22H19O5 (M+1) requires 363.1232] 363 (base), 339.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:17]([C:18]4[CH:23]=[CH:22][C:21]([O:24]S(C5C=CC(C)=CC=5)(=O)=O)=[CH:20][CH:19]=4)=[CH:16][N:15](S(C4C=CC(C)=CC=4)(=O)=O)[C:12]3=[N:13][CH:14]=2)O1.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+].Br[C:56]1[N:57]([CH3:61])[CH:58]=[CH:59][N:60]=1>CS(C)=O.CO>[CH3:61][N:57]1[CH:58]=[CH:59][N:60]=[C:56]1[C:9]1[CH:10]=[C:11]2[C:17]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)=[CH:16][NH:15][C:12]2=[N:13][CH:14]=1
Reactant: Cn1ccnc1Br
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(B5OC(C)(C)C(C)(C)O5)cc34)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Solvent: CC#N
Product: Cn1ccnc1-c1cnc2[nH]cc(-c3ccc(O)cc3)c2c1
Yield: 52 %

Procedure:
50 mg (80 μmol) of toluene-4-sulfonic acid 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]-phenyl ester and 7 mg of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloride dichloromethane adduct were placed in a Smith® vial. 1 ml of acetonitrile, 1 ml of a 2 M aqueous solution of sodium carbonate and 16 μl of 2-bromo-1-methyl-1H-imidazole were added and the resulting mixture was irradiated in a Personal Chemistry microwave reactor to 165° C. for 20 min. The resulting mixture was diluted with 2 ml of DMSO and 1 ml of methanol and subsequently filtered over sodium sulfate and a 0.45 μm PTFE syringe filter. The filtrate is directly purified via mass-triggered reverse phase HPLC to afford 12 mg (41 μmol, 52% yield) of 4-[5-(1-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]-phenol as a colorless solid. 1H-NMR (d6-DMSO): δ11.97 (s, 1H), 9.40 (s, 1H), 8.53 (d, J=2.0 Hz, 1H), 8.40 (d, J=1.4 Hz, 1H), 8.14 (s, 1H), 7.77 (d, J=2.4 Hz, 1H), 7.54 (d, J=8.3 Hz, 2H), 7.30 (s, 1H), 7.02 (s, 1H), 6.86 (d, J=8.7 Hz, 2H), 3.78 (s, 3H); MS: m/z 291 [MH+].
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:33]=[CH:32][C:8]2[N:9]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:31]=[CH:30][C:25]5[O:26][CH2:27][CH2:28][O:29][C:24]=5[CH:23]=4)[CH2:18][CH2:17]3)[CH:10]=[N:11][C:7]=2[CH:6]=1)=O.N#N.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1COCC1>[OH:2][CH2:3][C:5]1[CH:33]=[CH:32][C:8]2[N:9]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:17][CH2:18][N:19]([C:22]4[CH:31]=[CH:30][C:25]5[O:26][CH2:27][CH2:28][O:29][C:24]=5[CH:23]=4)[CH2:20][CH2:21]3)[CH:10]=[N:11][C:7]=2[CH:6]=1
Reactant: COC(=O)c1ccc2c(c1)ncn2CCCCN1CCN(c2ccc3c(c2)OCCO3)CC1
Agent: N#N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)ncn2CCCCN1CCN(c2ccc3c(c2)OCCO3)CC1
Reaction time: 1 h

Procedure:
A solution of 4.4 g of 6-[4-(4-(5-methoxycarbonylbenzimidazol-1-yl)butyl)piperazino]-1,4-benzodioxane in 40 ml of THF is added dropwise with stirring in an N2 atmosphere at 20° to a suspension of 0.6 g of lithium aluminium hydride in 20 ml of THF. The mixture is stirred at 20° for 1 hour, decomposed with dilute sodium hydroxide solution and filtered, and the filtrate is worked up in the conventional manner and gives 6-[4-(4-(5-hydroxymethylbenzimidazol-1-yl)butyl)piperazino]-1,4-benzodioxane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH2:22][CH:23]=O)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:25](OCC)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:20]([C@H:17]1[CH2:18][CH2:19][C@H:14]([C@H:11]2[CH2:12][CH2:13][C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)[CH2:15][CH2:16]1)[CH2:21][CH2:22][CH:23]=[CH2:25]
Reactant: O=CCCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(F)cc3)CC2)CC1
Reactant: CCOCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Product: C=CCCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(F)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A suspension of 5.19 g of methyl-triphenylphosphonium bromide in 80 ml of diethyl ether was treated with 1.55 g of potassium tert.butylate while gassing with nitrogen. The yellow suspension was stirred at room temperature for a further 45 minutes and then treated dropwise at 0° C. with a solution of 2.3 g of 4-[trans-4-[trans-4-(4-fluorophenyl)cyclohexyl]cyclohexyl]butyraldehyde. The reaction mixture was stirred at 0° C. for a further 2 hours and then diluted with 60 ml of water. The aqueous phase was separated and extracted twice with 60 ml of hexane each time. The combined organic phases were washed neutral with water, dried over sodium sulfate, filtered and concentrated. Chromatographic purification of the residue on silica gel with hexane gave 1.89 g of crude product. After two-fold recrystallization from acetone at -20° C. there were obtained 1.22 g of 1-[trans-4-[trans-4-(4-pentenyl)cyclohexyl]cyclohexyl]-4-fluorobenzene with m.p. (C--N) 65.7° C. and cl.p. (N--I) 129.7° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:36])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[CH2:23][CH2:22]3)[CH:16]=1)[C:11]([CH3:35])([CH3:34])[CH2:10]2)=[O:4].O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[Cl:36][C:7]1[CH:8]=[C:9]2[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1)[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[CH2:25][CH2:26]3)[CH:16]=1)[C:11]([CH3:35])([CH3:34])[CH2:10]2
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(N3CCN(c4ccccc4C)CC3)c1)C(C)(C)C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1N1CCN(c2cccc(C3Nc4c(cc(Cl)cc4C(=O)O)CC3(C)C)c2)CC1
Temperature: 60 °C
Reaction time: 12 h
Yield: 41.9 %

Procedure:
A mixture of 6-chloro-3,3-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (0.36 g, 0.73 mmol), lithium hydroxide hydrate (310 mg, 7.3 mmol), water (2.0 mL) in methanol (3 mL) and tetrahydrofuran (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 6-chloro-3,3-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (150 mg, 42%) as a white solid: LC/MS m/e calcd for C29H32ClN3O2M+: 490.05, observed: 490.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[CH3:27][S:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.C[Al](C)C>C1(C)C=CC=CC=1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([S:28][CH3:27])=[CH:30][CH:31]=3)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: CSc1ccc(N)cc1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)cc1OC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1ccc(SC)cc1
Yield: 42 %

Procedure:
The title compound was prepared according to the procedure as described for step-6 of Intermediate-26 by using methyl 4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-21, 0.150 g, 0.380 mmol), 4-(methylthio)aniline (0.079 g, 0.570 mmol), trimethyl aluminium (2M solution in toluene) (1 mL) and dry toluene (5.0 mL) to afford 0.080 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 2.46 (s, 3H), 3.94 (s, 3H), 7.26 (d, J=8.4 Hz, 2H), 7.69-7.72 (m, 6H), 7.78 (d, J=6.9 Hz, 1H), 7.82 (s, 1H), 10.06 (s, 1H), 12.76 (br s, 1H); MS (m/z): 501.0 (M)+.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[P:38]([O:50][CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][N:56]([CH2:59][CH2:60][C@@H:61]([NH:70][C:71]2[CH:76]=[CH:75][C:74]([S:77](=[O:80])(=[O:79])[NH2:78])=[CH:73][C:72]=2[S:81]([C:84]([F:87])([F:86])[F:85])(=[O:83])=[O:82])[CH2:62][S:63][C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH2:55][CH2:54]1)([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[P:38]([O:50][CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][N:56]([CH2:59][CH2:60][C@@H:61]([NH:70][C:71]2[CH:76]=[CH:75][C:74]([S:77](=[O:79])(=[O:80])[NH:78][C:20](=[O:21])[C:19]3[CH:18]=[CH:17][C:16]([N:13]4[CH2:12][CH2:11][CH:10]([C@@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3])[C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[C:31]5[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=5)[CH2:15][CH2:14]4)=[CH:24][CH:23]=3)=[CH:73][C:72]=2[S:81]([C:84]([F:87])([F:86])[F:85])(=[O:83])=[O:82])[CH2:62][S:63][C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH2:55][CH2:54]1)([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39]
Reactant: CC(C)(C)OP(=O)(OCCN1CCN(CC[C@H](CSc2ccccc2)Nc2ccc(S(N)(=O)=O)cc2S(=O)(=O)C(F)(F)F)CC1)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OP(=O)(OCCN1CCN(CC[C@H](CSc2ccccc2)Nc2ccc(S(=O)(=O)NC(=O)c3ccc(N4CCC([C@@H](O[Si](C)(C)C(C)(C)C)c5ccccc5-c5ccc(Cl)cc5)CC4)cc3)cc2S(=O)(=O)C(F)(F)F)CC1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(R)-4-(4-((tert-butyldimethylsilyloxy)(4 ′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 13, 170 mg, 0.32 mmol), (R)-di-tert-butyl 2-(4-(4-(phenylthio)-3-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino)butyl)piperazin-1-yl)ethyl phosphate (INTERMEDIATE 61, 275 mg, 0.35 mmol), DMAP (116 mg, 0.95 mmol) and EDC (122 mg, 0.63 mmol) were dissolved in DCM (3.2 ml). The reaction mixture was stirred at r.t. for 72 hours. The mixture was diluted with DCM (10 ml) and washed with NaHCO3 solution (saturated, aq., 5 ml) and brine (5 ml). The collected organic layer was dried over Na2SO4 and concentrated to give the title compound (446 mg, yield: almost quantitative). The title compound was used in the preparation of EXAMPLE 10 without further purification.
Reaction SMILES: CC(C1C=CC(Cl)=CC=1)=O.CC1(C2C=CC(Cl)=CC=2)C=CC=C(C=CC#N)C1.[2H][2H].[CH3:31][CH:32]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[CH2:33][CH2:34][NH2:35].[CH3:43][O:44][C:45]1[CH:46]=[C:47]([C:51](=O)[CH3:52])[CH:48]=[CH:49][CH:50]=1.C([BH3-])#N.[Na+]>[OH-].[Pd+2].[OH-].CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)(=O)C>[CH3:31][CH:32]([C:36]1[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=1)[CH2:33][CH2:34][NH:35][CH:51]([C:47]1[CH:48]=[CH:49][CH:50]=[C:45]([O:44][CH3:43])[CH:46]=1)[CH3:52]
Reactant: CC(CCN)c1ccc(Cl)cc1
Reactant: COc1cccc(C(C)=O)c1
Agent: [Pd+2]
Agent: [Ti+4]
Agent: CC(=O)c1ccc(Cl)cc1
Solvent: CC(=O)O
Product: COc1cccc(C(C)NCCC(C)c2ccc(Cl)cc2)c1

Procedure:
In a similar fashion, 4-chloroacetophenone was used to prepare 3-methyl-3-(4-chlorophenyl)cinnamonitrile. The nitrile was catalytically reduced (palladium hydroxide, acetic acid, 60 p.s.i. hydrogen 2 hr) to generate 3-methyl-3-(4-chlorophenyl)propylamine. An equal molar amount of the amine, 3′-methoxyacetophenone and 1.25 molar equivalents titanium(IV) isopropoxide were mixed 4 hr at rt and the intermediate imine treated with an ethanolic sodium cyanoborohydride (5 ml of 1 M, 5 mmol). Work-up and chromatography afforded N-[3-methyl-3-(4-chlorophenyl)propyl]-1-(3-methoxyphenyl)ethylamine, 5B/5C as an oil; m/z (rel. int.) 317 (M+, 12), 302 (74), 210 (2), 182 (4), 164 (12), 135 (100), 121 (25), 103 (40), 91 (19), 77 (28).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:5])[CH3:4].[Cl:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3F)[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:9][C:8]=1[OH:25].ClC1C=C(NC2C3C(=CC=CC=3OCCNC)N=CN=2)C=CC=1OCC1C=CC=CN=1>>[NH2:1][CH2:2][C@@H:3]([CH3:4])[O:5][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:23]=1[C:14]([NH:13][C:11]1[CH:10]=[CH:9][C:8]([OH:25])=[C:7]([Cl:6])[CH:12]=1)=[N:15][CH:16]=[N:17]2
Reactant: C[C@@H](O)CN
Reactant: Oc1ccc(Nc2ncnc3cccc(F)c23)cc1Cl
Agent: CNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: C[C@H](CN)Oc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Yield: 64 %

Procedure:
(R)-1-amino-2-propanol was reacted with 2-chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol (prepared as described in Example 4-4, preparation of starting materials) using an analogous process to that described Example 1 for the preparation of N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(methylamino)ethoxy]quinazolin-4-amine) to give 4-({5-[(1R)-2-amino-1-methylethoxy]quinazolin-4-yl}amino)-2-chlorophenol in 64% yield; NMR spectrum (DMSO-d6) 1.39 (d, 3H), 2.88-3.03 (m, 2H), 3.72-3.85 (m, 1H), 6.95 (d, 1H), 7.15 (d, 1H), 7.29 (d, 1H), 7.45-7.52 (m, 1H), 7.69, (t, 1H), 8.05 (s, 1H), 8.45 (s, 1H) Mass spectrum MH+ 345.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH:13]([C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([OH:23])=O)[C:16]=1[CH3:24])=[O:14].ON1C2C=CC=CC=2N=N1.[CH2:35]([N:42]1[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O.CN(C=O)C.C(N(CC)CC)C>[CH2:35]([N:42]1[CH2:46][CH2:45][CH:44]([NH:47][C:21]([C:17]2[C:16]([CH3:24])=[C:15]([CH:13]=[O:14])[NH:19][C:18]=2[CH3:20])=[O:23])[CH2:43]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: NC1CCN(Cc2ccccc2)C1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1[nH]c(C=O)c(C)c1C(=O)NC1CCN(Cc2ccccc2)C1
Temperature: 0 °C
Yield: 52.4 %

Procedure:
1-Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (268.1 g, 1.4 mol), triethylamine (280.0 mL), 5-formyl-2,4-dimethyl-1H-pyrrole-3-formic acid (167.0 g, 1.0 mol) and 1-hydroxybenzotriazole (189.2 g, 1.4 mol) were added to DMF (500 mL) with stirring at about 0° C. and stirred for 1.5 hrs, then 1-benzylpyrrolidine-3-amine (1.2 mol) was added. The reaction was stirred at room temperature until completion was indicated by thin layer chromatography (TLC). 120 mL of water and 100 mL of saturated salt water were added, and the mixture was extracted with 10% methanol/dichloromethane (300 mL×3), the combined organic phase was washed with saturated salt water (300 mL×3), dried over anhydrous Na2SO4, and the solvent was distilled off under reduced pressure. The residue was then chromatographed on silica gel (eluted with methanol/ethyl acetate=1/1) to give 170.3 g (524 mmol) of N-(1-benzylpyrrolidin-3-yl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-formamide as an off-white solid. Yield 52.4%.
Reaction SMILES: I[C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.C(=O)(O)[O-].[Na+].[CH3:13][O:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[C:18](B(O)O)=[CH:17][N:16]=1.CO>COCCOC.C(Cl)Cl.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>[CH3:13][O:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[C:18]([C:2]2[S:3][CH:4]=[C:5]([CH3:7])[N:6]=2)=[CH:17][N:16]=1
Reactant: Cc1csc(I)n1
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: COCCOC
Product: COc1ncc(-c2nc(C)cs2)c(OC)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 106.2 %

Procedure:
2-iodo-4-methyl-1,3-thiazole (prepared according to procedure described in JACS 123 (6), 1017-1022, (2001), 250 mg, 1.111 mmol) was dissolved in 1,2-Dimethoxyethane (DME) (4.629 ml). Pd(Ph3P)4 (64.2 mg, 0.056 mmol) was added and the mixture was stirred at room temperature for 10 minutes. 1M aqueous sol. Sodium bicarbonate (4.443 ml, 4.44 mmol) and [2,4-bis(methyloxy)-5-pyrimidinyl]boronic acid (409 mg, 2.222 mmol) were added and the resulting mixture was stirred at 85° C. for 2 hours. The mixture was allowed to cool to rt and it was diluted with DCM (5 mL). The aqueous was separated and extracted with DCM (2×5 mL). The organics were combined and dried (Na2SO4 then rotaevaporator) to give a yellow solid that was purified by silica chromatography (Biotage SP1, 25+M), eluting with DCM:MeOH from 100:0 to 9:1 to afford the title compound as a pale yellow solid (280 mg, 78% yield).