Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[S:14][C:13]([CH:15](O)[CH3:16])=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19].[Br:21]P(Br)Br>ClCCl>[Br:21][CH:15]([C:13]1[S:14][C:10]([S:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[C:11]([N+:18]([O-:20])=[O:19])[CH:12]=1)[CH3:16]
Reactant: CC(O)c1cc([N+](=O)[O-])c(Sc2ccc(Cl)cc2Cl)s1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CC(Br)c1cc([N+](=O)[O-])c(Sc2ccc(Cl)cc2Cl)s1
Temperature: 25 °C
Yield: 113.9 %

Procedure:
To a solution of 1-[5-(2,4-dichlorophenyl)sulfanyl-4-nitro-2-thienyl]ethanol from example 26 (0.6 g, 1.7 mmol) in dichloromethane (10 mL), was added tribromophosphane (0.28 mL, 2.55 mmol). The resulting reaction mixture was kept under reflux for 2 hours. After this time, the reaction mixture was cooled to ambient temperature, quenched with sat'd sodium carbonate aqueous solution and extracted with ethyl acetate. The combined organic phase was dried (Na2SO4) and concentrated to afford the title compound (800 mg). The crude product was used as such for the next step.
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:14]=[CH:13][C:8]2[S:9][CH:10]=[C:11]([CH3:12])[C:7]=2[CH:6]=1>CN1CCCC1=O>[C:2]([C:5]1[CH:14]=[CH:13][C:8]2[S:9][CH:10]=[C:11]([CH3:12])[C:7]=2[CH:6]=1)#[N:3]
Reactant: N#C[Cu]
Reactant: Cc1csc2ccc(Br)cc12
Solvent: CN1CCCC1=O
Product: Cc1csc2ccc(C#N)cc12
Reaction time: 17 h
Yield: 90.1 %

Procedure:
To copper (I) cyanide (0.569 g, 6.35 mmol) was added 5-bromo-3-methyl benzo[b]thiophene (1.179 g, 5.19 mmol) in N-methylpyrrolidinone (10 ml) and the mixture was stirred at 180°-190° C. for 17 h. This was then partitioned between ether (75 ml) and ammonia solution (75 ml). The ether layer was separated, washed with more ammonia solution (2×50 ml), dried (Na2SO4) and evaporated in vacuo to leave 0.81 g of an off-white solid. Chromatography on flash silica, eluting with 10% ethyl acetate/petroleum ether yielded 0.76 g (85%) of the title compound as a white solid. δ (CDCl3) 2.47 (3H, s), 7.23 (1H, s), 7.55 (1H, dd, J=8.3 and 1.5 Hz), 7.93 (1H, d, J=8.4 Hz), 8.03 (1H, d, J=1.4 Hz).
Reaction SMILES: CS(O[CH2:6][CH2:7][S:8][CH2:9][C:10]#[C:11][C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)(=O)=O.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>>[CH3:18][C:17]([NH:21][CH2:6][CH2:7][S:8][CH2:9][C:10]#[C:11][C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)([CH3:20])[CH3:19]
Reactant: CS(=O)(=O)OCCSCC#Cc1cccs1
Reactant: CC(C)(C)N
Product: CC(C)(C)NCCSCC#Cc1cccs1

Procedure:
A solution of 400 mg of 9d in 8 ml of tert-butyl amine was stirred for 3 days at RT; conversion was completed after that time. The reaction mixture was concentrated and the residue was treated with 30 ml of water and 30 ml of sat. NaHCO3 and the product was extracted into ethyl acetate. The combined organic layers were washed with water, dried and concentrated to provide 354 mg of 9e as essentially pure material, which was used without further purification in the next step. NMR (CDCl3) δ 1.12 (s, 9, tertC4H9), 2.88 (m, 4, 2×CH2), 3.52 (s, 2, CH2), 6.96, 7.18 and 7.22 (3×m, 3, thiophene-H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[C:18]([NH:25][C:26]3[S:27][C:28]([C:38](=[O:40])[NH2:39])=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=4)[N:30]=3)[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:41](OCC)(OCC)OCC>C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]3[N:22]=[CH:41][N:25]([C:26]4[S:27][C:28]([C:38](=[O:40])[NH2:39])=[C:29]([C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=5)[N:30]=4)[C:18]=3[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc([N+](=O)[O-])c(Nc3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2)CC1
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(N)=O)s4)c3c2)CC1

Procedure:
The crude 4-{3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazole-2-ylamino]-4-nitro-phenoxymethyl}-piperidine-1-carboxylic acid tert-butyl ester (VII.23) was dissolved in 4 mL of acetic acid and 0.14 mL (0.84 mmole) of triethyl orthoformate. The mixture was heated at 70 degrees for 2 hours and then concentrated under reduced pressure. The residue was diluted with ethyl acetate and saturated aqueous sodium carbonate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-dichloromethane (gradient 50:50-100:0) to give 0.13 g of 4-{3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazole-2-yl]-3H-benzoimidazol-5-yloxymethyl}-piperidine-1-carboxylic acid tert-butyl ester (I.23a).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C@@H:13]2[CH2:15][O:14]2)=[CH:5][C:4]=1[N:16]=[CH:17][N:18]([CH3:20])[CH3:19])#[N:2].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(Cl)(Cl)Cl.C(O)C>[C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C@@H:13]([OH:14])[CH2:15][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:5][C:4]=1[N:16]=[CH:17][N:18]([CH3:20])[CH3:19])#[N:2]
Reactant: C1CCNCC1
Reactant: COc1cc(C#N)c(N=CN(C)C)cc1OC[C@@H]1CO1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1cc(C#N)c(N=CN(C)C)cc1OC[C@@H](O)CN1CCCCC1
Yield: 85.7 %

Procedure:
N′-(2-cyano-5-(2S)-oxiranylmethoxy-4-methoxyphenyl)-N,N-dimethylimidoformamide (850 mg, 3.09 mmol) in chloroform (6 ml) and ethanol (12 ml) was irradiated with piperidine (0.46 ml, 4.6 mmol) in a microwave oven at reflux for 10 minutes. The solvent was evaporated and the residue was purified by silica gel chromatography, eluant CH2Cl2/MeOH 90/10 to give title compound (954 mg, 86%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[C:20]([CH:30]=[CH:31][CH:32]=2)[C:21]([N:23]2[CH2:27][CH2:26][CH2:25][C@H:24]2[C:28]#[N:29])=[O:22])=[CH:12][CH:11]=1.[N-:33]=[N+:34]=[N-:35].[Na+].Cl.C([NH+](CC)CC)C>C1(C)C=CC=CC=1>[NH:33]1[C:28]([C@@H:24]2[CH2:25][CH2:26][CH2:27][N:23]2[C:21]([C:20]2[CH:30]=[CH:31][CH:32]=[C:18]([CH2:17][O:16][C:13]3[CH:12]=[CH:11][C:10]([C:3]4[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=4[F:1])=[CH:15][CH:14]=3)[CH:19]=2)=[O:22])=[N:29][N:35]=[N:34]1
Reactant: N#C[C@@H]1CCCN1C(=O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1
Reactant: [N-]=[N+]=[N-]
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(c1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1)N1CCC[C@H]1c1nnn[nH]1
Yield: 81.1 %

Procedure:
(S)-1-[3-(2′,4′,5′-Trifluoro-biphenyl-4-yloxymethyl)-benzoyl]-pyrrolidine-2-carbonitrile (1.56 g, 3.47 mmol), sodium azide (678 mg, 10.43 mmol) and triethylammonium hydrochloride (1.43 g, 10.43 mmol) in toluene were heated at 100° C. for 17 hrs. The reaction mixture was cooled, concentrated and distributed between 20 mL 0.5N HCl and 100 mL ethyl acetate. The ethyl acetate layer was separated, washed with saturated NaCl, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography with a 0-40% gradient of ethyl acetate/MeOH/AcOH (95:5:1) in CH2Cl2 to give 1.35 g (81.2%) of [(S)-2-(1H-tetrazol-5-yl)-pyrrolidin-1-yl]-[3-(2′,4′,5′-trifluoro-biphenyl-4-yloxymethyl)-phenyl]-methanone as a white solid. LC-MS (ES) calculated for C25H20F3N5O2, 479.47; found m/z 480.1 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:3]([CH2:7][CH2:8][C:9]#[CH:10])[C:4]([OH:6])=[O:5].N12CCCN=C1CCCCC2.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>C(#N)C>[Si:28]([O:1][C@H:2]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C@@H:3]([CH2:7][CH2:8][C:9]#[CH:10])[C:4]([OH:6])=[O:5])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CCC[C@@H](C(=O)O)[C@H](O)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C#CCC[C@@H](C(=O)O)[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Reaction time: 4 h
Yield: 86.5 %

Procedure:
To a stirred solution of 32.0 g (147 mmol) of (2R)-2-[(S)-hydroxy(phenyl)methyl]hex-5-ynoic acid from Step C above in 500 mL of anhydrous acetonitrile at ambient temperature under an atmosphere of nitrogen was added 77.0 mL (513 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene 22 mL followed by 66.3 g (440 mmol) of tert-butyldimethylsilyl chloride in three portions over 10 min. The reaction mixture was stirred for 4 h then evaporated in vacuo to remove all volatiles. The residue was diluted with 300 mL of dichloromethane and 100 mL of water. A 1.0 M aqueous hydrogen chloride solution was added to the mixture until a pH of 3 was achieved in the aqueous layer. The phases were separated and the aqueous phase was extracted with dichloromethane (2×100 mL). The combined organics were washed with water (50 mL), brine (50 mL) then dried over magnesium sulfate. After filtration and evaporation in vacuo the residue was dissolved in 350 mL of methanol and 350 mL (280 mmol) of a 0.8 M aqueous potassium carbonate solution was added. The resulting mixture was stirred for 1.5 h then evaporated in vacuo to remove all volatiles. The residue was diluted with 300 mL of dichloromethane and the aqueous phase was acidified with a 5.0 M aqueous hydrogen chloride solution until a pH of 3 was achieved. The phases were separated and the aqueous phase was extracted with dichloromethane (2×100 mL). The combined organics were washed with water (50 mL), brine (50 mL) then dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with a 3-15% ethyl acetate in hexanes gradient to afford the title compound as a colorless solid (42.3 g, 86.6%). 1H NMR (500 MHz, CDCl3): δ 7.36-7.27 (m, 5H), 4.78 (d, J=8.7, 1H), 2.90-2.86 (m, 1H), 2.19-2.11 (m, 1H), 2.10-2.03 (m, 1H), 1.90 (t, J=2.6 Hz, 1H), 1.75-1.67 (m, 1H), 1.41-1.34 (m, 1H), 0.83 (s, 9H), 0.02 (s, 3H), −0.27 (s, 3H). LC-MS: m/z (ES) 333.2 (MH)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:40])[C:8]2[CH:14]=[C:13]([C:15](C)=[CH:16][C:17]3[CH:38]=[CH:37][C:20]([C:21]([NH:23][C@H:24]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:22])=[CH:19][CH:18]=3)[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2].[H][H].F[C:44](F)(F)C(O)=O>[Pd]>[C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:40])[C:8]2[CH2:14][CH:13]([CH2:15][CH:16]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([NH:23][C@H:24]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:22])=[CH:37][CH:38]=3)[CH3:44])[CH2:12][NH:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: [H][H]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(C=C(C)c2cnc3nc(NC(C)=O)nc(O)c3c2)cc1)C(=O)OCC
Agent: [Pd]
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(C(C)CC2CNc3nc(NC(C)=O)nc(O)c3C2)cc1)C(=O)OCC

Procedure:
A solution of 84.4 mg of diethyl N-(4-[2-(2-acetamido-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)prop-1-enyl]benzoyl)-L-glutamate in 30 mL of trifluoroacetic acid was hydrogenated at 55 psi of hydrogen in the presence of 0.42 g of 5% Pd/C at room temperature for 24 hours. The catalyst was removed by filtration and the filtrate was evaporated under reduced pressure. The resulting residue was taken up in chloroform and was extracted with a saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was then subjected to thin layer chromatography using a 5% methanol:chloroform mixture as the eluent. After elution of a first fraction, there was obtained 19.6 mg of the title compound, NMR (CDCl3 250 MHz), d 1.20-1.33 (m, overlapping methyls, 9H), 2.45-3.36 (m, 15H), 4.11 (q, 2H, J=7.14 Hz), 4.23 (q, 2H, J=7.10 Hz), 4.89 (m, 1H), 5.44 (brs, 1H), 7.24 (d, 2H, J=7.54 Hz), 7.72 (d, 2H, J=7.54 Hz), 9.77 (brs, 1H), 11.26 (brs, 1H).
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]\[CH2:5]Cl.[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:7]([N:14]1[CH2:5][CH:4]=[CH:3][CH2:2]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClC/C=C\CCl
Reactant: NCc1ccccc1
Product: C1=CCN(Cc2ccccc2)C1

Procedure:
A mixture of 1,4-dichloro-cis-2-butene and benzylamine is heated at reflux to give 1-benzyl-3-pyrroline (2), which is converted to the epoxide (3) by first reacting (2) with chlorine in dilute hydrochloric acid and then with sodium hydroxide. The epoxide is opened to give the corresponding hydroxy amine (4) with either ammonia and water or sodium azide followed by reduction of the resulting azide. The resulting trans 1-benzyl-3-amino-4-hydroxypyrrolidine (4) is acetylated with acetic anhydride to give N-acetyl derivative (5) in which N-benzyl group is removed by hydrogenation in the presence of Pd/C under acidic conditions to give (6), and further alkylated with bromoethyl acetate to give N-ethoxycarbonyl methyl derivative (7). The basic hydrolysis of the ester (7) gives the target (8).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:22][C:23]1[S:24][C:25]([CH2:28]Cl)=[CH:26][CH:27]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[N:14]([CH2:28][C:25]3[S:24][C:23]([Cl:22])=[CH:27][CH:26]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3cc(F)ccc23)CC1
Reactant: ClCc1ccc(Cl)s1
Product: CCOC(=O)N1CCC(c2cn(Cc3ccc(Cl)s3)c3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.7 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) starting with 2.2 g (7.5 mmol) of 4-(6-fluoro-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester (example 24, part A) and 1.1 mL (8.8 mmol) of 2-chloro-5-chloromethyl-thiophene. The reaction mixture was stirred at room temperature for 18 hours. After standard work-up, 2.2 g (68% of yield) of 4-[1-(5-chloro-thiophen-2-ylmethyl)-6-fluoro-1H-indol-3-yl]-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C:15]([CH2:23][CH2:24][CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][C:27]=2[F:38])([C:18]([O:20]CC)=[O:19])[CH2:14][CH2:13]1.[OH-].[Na+]>O1CCOCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][N:12]1[CH2:13][CH2:14][C:15]([CH2:23][CH2:24][CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][C:27]=2[F:38])([C:18]([OH:20])=[O:19])[CH2:16][CH2:17]1
Reactant: CCOC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCN(CCSc2cc(F)ccc2F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc2ncc(F)c(CCCC3(C(=O)O)CCN(CCSc4cc(F)ccc4F)CC3)c2c1
Temperature: 70 °C
Reaction time: 17 h
Yield: 121.6 %

Procedure:
A mixture of 0.26 g of ethyl 1-[2-(2,5-difluorophenylthio)ethyl]-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate in 3 cm3 of dioxane, 3 cm3 of methanol and 1.4 cm3 of aqueous 5N sodium hydroxide solution was stirred at a temperature in the region of 70° C. for 17 hours. After cooling to about 20° C., the reaction mixture was concentrated to dryness under a pressure gradually reduced from 30 kPa to 2.5 kPa and at a temperature in the region of 45° C. The residue was taken up in 5 cm3 of a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume) and was then purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200μ; mass 10 g), eluting with a mixture of dichloromethane/methanol/aqueous ammonia (90/9/0.9 by volume) and then with a chloroform/methanol/aqueous ammonia mixture (77.5/19.5/3). The fractions containing the product were combined, concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. and dried in a desiccator (10 kPa). 0.3 g of 1-[2-(2,5-difluorophenylthio)ethyl]-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylic acid was obtained in the form of a white solid.
Reaction SMILES: [C:1]([C:4]1[C:5](I)=[N:6][N:7]2[CH2:12][CH:11]([C:13]([F:16])([F:15])[F:14])[N:10]([C:17]([O:19]C(C)(C)C)=[O:18])[CH2:9][C:8]=12)(=[O:3])[NH2:2].[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[F:32].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[C:1]([C:4]1[C:5]([C:28]2[CH:29]=[CH:30][C:31]([F:32])=[C:26]([Cl:25])[CH:27]=2)=[N:6][N:7]2[CH2:12][CH:11]([C:13]([F:15])([F:14])[F:16])[N:10]([C:17]([O:19][CH2:1][CH2:4][CH2:8][CH3:9])=[O:18])[CH2:9][C:8]=12)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)N1Cc2c(C(N)=O)c(I)nn2CC1C(F)(F)F
Reactant: OB(O)c1ccc(F)c(Cl)c1
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: CN(C)C=O
Solvent: O
Product: CCCCOC(=O)N1Cc2c(C(N)=O)c(-c3ccc(F)c(Cl)c3)nn2CC1C(F)(F)F
Temperature: 100 °C
Reaction time: 18 h
Yield: 142 %

Procedure:
To a solution of Intermediate 346F (0.35 g, 0.761 mmol) and (3-chloro-4-fluorophenyl)boronic acid (0.215 g, 0.837 mmol) in DMF (2 mL) was added a solution of Na2CO3 (0.242 g, 2.282 mmol) in water (1 mL) and the reaction mixture was purged with nitrogen for 5 min. Pd(PPh3)4 (0.044 g, 0.038 mmol) was then added and the reaction mixture was stirred at 100° C. for 18 h. The reaction mixture was cooled to RT and extracted with EtOAc (2×50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and the filtrate concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (12 g REDISEP® column, eluting with 5% MeOH in CHCl3). Fractions containing the product were combined and evaporated to afford Intermediate 346G as a white solid (0.25 g, 68%). MS(ES): m/z=464.5 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92-7.82 (m, 1H), 7.73-7.67 (m, 1H), 7.65-7.52 (m, 1H), 7.51-7.44 (m, 1H), 7.41-7.21 (m, 2H), 5.17-5.05 (m, 1H), 4.65-4.48 (m, 3H), 1.50 (s, 9H).
Reaction SMILES: [C:1]([S:20][CH:21]1[NH:24][C:23](=[O:25])[CH2:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28][O:29][CH2:30]Br>C1COCC1.CO.CCOCC>[CH3:28][O:29][CH2:30][N:24]1[CH:21]([S:20][C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:22][C:23]1=[O:25]
Reactant: O=C1CC(SC(c2ccccc2)(c2ccccc2)c2ccccc2)N1
Reactant: COCBr
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCN1C(=O)CC1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 110.4 %

Procedure:
A solution of 4-tritylthio-2-azetidinone (1.38 g, 4.0 mmoles) in THF (10 ml) was added to a well stirred suspension of sodium hydride (200 mg of commercial 50%, 4.1 mmoles, washed with pentane) in THF (10 ml) maintained at -15°. Methanol (12 drops) was added and the mixture was stirred at -15° for 0.5 h. Methoxymethyl bromide (0.58 g, 4.6 mmoles) was added and the mixture was stirred for 2 h, diluted with ether, washed with water and brine, dried and concentrated to leave an oil (1.72 g). Crystallization from pentane gave a white solid (1.41 g) m.p. 72-76 δ (ppm, CDCl3): 7.3 (15H, m, aromatics), 4.4 (3H, m, NCH2O and H-4), 3.22 (3H, s, CH3), 2.76 (2H, m, H-3).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:25][C:26]1[C:34]([OH:35])=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[C:29]([CH3:36])[NH:30]2>>[F:25][C:26]1[C:34]([O:35][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[C:29]([CH3:36])[NH:30]2
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCN(C)CC1
Yield: 69.5 %

Procedure:
Using an analogous procedure to that described in Example 237, 4-chloro-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (106 mg, 0.30 mmol), (prepared as described for the starting material in Example 176), was reacted with 4-fluoro-5-hydroxy-2methylindole (60 mg, 0.36 mmol), (prepared as described for the starting material in Example 237), to give 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (100 mg, 70%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=2)=[CH:2]1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][Br:13])=[CH:8][CH:7]=2)=[CH:2]1
Reactant: Cc1ccc(-c2ccsc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2ccsc2)cc1

Procedure:
To a solution of 4-(3-thienyl)toluene (3.56 g, 20.5 mmol) in carbon tetrachloride (100 ml) is added N-bromosuccinimide (3.64 g, 20.5 mol) and benzoyl peroxide (80 mg, 3.3 mmol). The reaction mixture is heated at reflux for 24 hrs. and concentrated in vacuo. The reaction mixture is recrystallized from ethanol to afford 4-(3-thienyl)benzyl bromide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:58]2[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=2)([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[O:10][CH2:11][CH2:12][CH:13]([OH:51])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C@H:24]2[CH2:48][CH2:47][C@@:46]3([CH3:49])[C:26](=[CH:27][CH2:28][C@@H:29]4[C@@H:45]3[CH2:44][CH2:43][C@@:42]3([CH3:50])[C@H:30]4[CH2:31][CH2:32][C@@H:33]3[C@H:34]([CH3:41])[CH2:35][CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:25]2)=[CH:5][CH:4]=1.[C:66]1(=[O:72])[O:71][C:69](=[O:70])[CH2:68][CH2:67]1.CCOC(C)=O>C(Cl)Cl>[CH3:65][O:64][C:61]1[CH:60]=[CH:59][C:58]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[O:10][CH2:11][CH2:12][CH:13]([O:51][C:66](=[O:72])[CH2:67][CH2:68][C:69]([OH:71])=[O:70])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C@H:24]2[CH2:48][CH2:47][C@@:46]3([CH3:49])[C:26](=[CH:27][CH2:28][C@@H:29]4[C@@H:45]3[CH2:44][CH2:43][C@@:42]3([CH3:50])[C@H:30]4[CH2:31][CH2:32][C@@H:33]3[C@H:34]([CH3:41])[CH2:35][CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:25]2)=[CH:63][CH:62]=1
Reactant: O=C1CCC(=O)O1
Reactant: COc1ccc(C(OCCC(O)CCCCCCCCCO[C@H]2CC[C@@]3(C)C(=CC[C@H]4[C@@H]5CC[C@H]([C@H](C)CCCC(C)C)[C@@]5(C)CC[C@@H]43)C2)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C(OCCC(CCCCCCCCCO[C@H]2CC[C@@]3(C)C(=CC[C@H]4[C@@H]5CC[C@H]([C@H](C)CCCC(C)C)[C@@]5(C)CC[C@@H]43)C2)OC(=O)CCC(=O)O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 17 h

Procedure:
In a 20 mL scintillation vial was 1-((bis(4-methoxyphenyl)(phenyl)methoxy))-12-(Cholest-5-en-3β-oxy)dodecan-3-ol (0.5 g, 0.562 mmol) and succinic anhydride (0.113 g, 1.124 mmol) in DCM (10 ml) to give a colorless solution. TEA (0.313 ml, 2.249 mmol) was added and the mixture set to stir for 17 hours. The reaction was judged complete by TLC (25% EtOAc/Hex, PMA visualization). The reaction mixture was washed with 5% NaHPO4 solution (3×15 mL) and brine (1×15 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to dryness for use without further purification. 1H NMR (300 MHz, CDCl3) δ0.70 (3H, s); 0.83-1.74 (49H, m); 1.77-2.12 (5H, m); 2.14-2.29 (1H, m); 2.33-2.44 (1H, m); 2.53-2.72 (4H, m); 3.00-3.09 (2H, m); 3.16 (1H, tt, J=11.2, 4.4 Hz); 3.48 (2H, t, J=6.8 Hz); 3.80 (6H, s); 4.85-5.00 (1H, m); 5.36 (1H, d, J=5.1 Hz); 6.78-6.90 (4H, m), 7.15-7.38 (7H, m); 7.40-7.49 (2H, m); 9.29 (1H, bs).