Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Li])([CH2:3]C)[CH3:2].CO[N:8]([CH3:14])[C:9](=O)[CH2:10][CH2:11][CH3:12].FC(F)(F)C(O)=O.[CH2:22]1[CH2:26][O:25][CH2:24][CH2:23]1>ClCCl>[CH3:24][O:25][C:26]1[CH:12]=[C:11]2[C:14](=[CH:23][CH:22]=1)[NH:8][C:9]([CH2:2][CH2:1][CH3:3])=[CH:10]2
Reactant: CCCC(=O)N(C)OC
Reactant: C1CCOC1
Reactant: [Li]C(C)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cc2cc(OC)ccc2[nH]1
Temperature: -40 °C
Reaction time: 48 h
Yield: 68 %

Procedure:
N-(t-Boc)-4-Methoxy-2-methylaniline (1.00 g, 4.2 mmol) was dissolved in THF (15 mL) under an atmosphere of Ar (g). The solution was cooled to −40° C. over 10 minutes and sec-butyllithium (1.4 M in cyclohexane, 6.66 mL) was added slowly to maintain an internal temperature of <−25° C. After reaching 1 equivalent of sec-butyllithium (3.33 mL) the reaction mixture turned a bright yellow signifying the total deprotonation of the amide nitrogen. The reaction mixture was then cooled to −50° C. and a solution of N-methoxy-N-methylbutanamide (580 mg, 4.4 mmol) in THF (3 mL) was added over 10 minutes in a dropwise fashion. The reaction mixture was warmed to −10° C. over 30 minutes. The mixture was partitioned between Et2O (50 mL) and 1 N HCl (50 mL). The aqueous layer was extracted an additional two times with Et2O (25 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to yield a brown solid. This above reaction was performed twice yielding crude brown solid (3 g), which was taken directly to the next step. Crude product (3 g) was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (3 mL) was added to the solution and the reaction mixture was stirred at room temperature for 48 hours. When the reaction reached completion, the reaction mixture was added to a separatory funnel and washed with NaHCO3 (30 mL) followed by brine (30 mL). The organic layer was dried over NaSO4 and concentrated in vacuo giving a crude black oil (3.03 g) which was purified with column chromatography to yield a yellow/brown solid (1.1 g, 68%): TLC Rf 0.32 in 10% EtOAc/hexanes. Melting point=64-65° C. 1H NMR (600 MHz, CDCl3) δ 7.74 (s, 1H), 7.19-7.17 (d, 1H, J=8.7 Hz), 7.01 (d, 1H, J=2.46 Hz), 6.78-6.76 (dd, 1H J1=8.7 Hz, J2=2.46 Hz) 6.18-6.17 (m, 1H), 3.84 (s, 3H), 2.72-2.70 (t, 2H, J=7.34 Hz), 1.77-1.71 (m, 2H), 1.01-0.99 (t, 3H, J=7.32 Hz); 13C NMR (150 MHz, CDCl3) δ 154.3, 140.9, 131.1, 129.5, 111.08, 110.96, 102.16, 99.7, 56.1, 30.6, 22.7, 14.1. Elemental analysis calculated for C12H15NO: C, 76.16; H, 7.99; N, 7.40. Found: C, 76.28; H, 7.97; N, 7.39.
Reaction SMILES: C1(C2(C3C=CC=CC=3)[O:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[O:17])=[CH:15][C:9]=3[O:8]2)C=CC=CC=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[OH:8][C:9]1[CH:15]=[C:14]([C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:17])[CH:13]=[CH:12][C:10]=1[OH:11]
Reactant: O=C(c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2)N1CCOCC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(O)c(O)c1)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 94.1 %

Procedure:
To a cooled (0° C.) solution of (2,2-diphenyl-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone (270 mg, 0.7 mmol) in trifluoroacetic acid (4 mL) was added triethylsilane (160 mg, 1.38 mmol, 1.96 eq.). The reaction mixture was stirred 20 min at 0° C. The cooling bath was removed and the reaction mixture was stirred for 4 h at R.T. The reaction mixture was evaporated. Purification by flash chromatography afforded the title compound (147 mg, 95%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2C=CN=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH3:17][N:18]1[CH2:23][CH2:22]C2N=C(N)[S:26][C:20]=2[CH2:19]1.BrC1C(=O)N(C)C=C(Br)C=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[S:26][C:20]3[CH2:19][N:18]([CH3:17])[CH2:23][CH2:22][C:13]=3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: CN1CCc2nc(N)sc2C1
Reactant: Cn1cc(Br)cc(Nc2ccncn2)c1=O
Agent: Cn1cc(Br)cc(Br)c1=O
Product: CN1CCc2nc(Nc3cc(Br)cn(C)c3=O)sc2C1
Yield: 44 %

Procedure:
Following the procedures described for compound 113a and starting with 115a (4.0 g, 23.5 mmol) and 3,5-dibromo-1-methylpyridin-2(1H)-one (3.0 g, 17.8 mmol) afforded 115b as a yellow solid (2.8 g, 44%). MS: [M+H]+ 357.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([S:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][CH2:6][CH2:7][OH:8].[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>N1C=CC=CC=1.C(Cl)Cl>[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35]([CH2:2][CH2:3][N:4]([S:9][C:10]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:5][CH2:6][CH2:7][O:8][S:35]([C:32]2[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=2)(=[O:37])=[O:36])(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCN(CCO)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)CCN(CCCOS(=O)(=O)c2ccc(C)cc2)SC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
N-(2-hydroxyethyl)-N-tritylsulfenyl-3-amino-1-propanol (5.0 g, 12.64 mmol) is dissolved in pyridine (100 mL) and cooled to 0° C. p-Toluensufonylchloride (2.65 g, 13.9 mmol) is dissolve in CH2Cl2 (50 mL) and added to the reaction mixture at 0° C. via dropping funnel. The reaction is monitored by TLC to completion. The reaction mixture is concentrated in vacuo and the resultant residue is dissolved in EtOAc and washed with H2O (3×50 mL) and brine (2×50 mL). The EtOAc is dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel column chromatography using EtOAc/hexanes as eluent. The appropriate fractions are pooled and concentrated in vacuo to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:49])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([O:35]CC3C=CC=CC=3)=[O:34])[N:28]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:49])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([OH:35])=[O:34])[N:28]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)n(-c3ccccc3)n2)CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)O)n(-c3ccccc3)n2)CC1
Reaction time: 16 h

Procedure:
To a solution of 13.2 g 4-{(S)-2-[(5-Benzyloxycarbonylmethoxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-4-tert-butoxycarbonyl-butyryl}-piperazine-1-carboxylic acid ethyl ester in 75 ml ethyl acetate were added under argon 1.1 g Pd/C (10%) and the suspension was stirred under an atmosphere of hydrogen (3 bar) for 16 h. The suspension was filtered over a plug of Celite® and washed with ethyl acetate. The crude product obtained after evaporation of the solvent was dried under vacuo at 40° C. for 24 h.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:16])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[NH4+].[NH4+].F[P-](F)(F)(F)(F)F.[N:30]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@@H:12]([CH3:16])[C:13]([NH2:30])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)OCc1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 121.5 %

Procedure:
A mixture of (2S)-2-[(benzyloxy)carbonyl]aminopropanoic acid (0.5 g, 0.002 mol), ammonium carbonate (0.43 g, 0.0045 mol), benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (1.2 g, 0.0027 mol), N,N-diisopropylethylamine (980 μL, 0.0056 mol) in methylene chloride (3 mL) was stirred at RT overnight. The mixture was quenched with saturated NaHCO3 solution, and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was flash chromatographed on a silica gel column to afford the desired product (0.54 g). Analytical LCMS: (M+H)+=223.1.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[CH:4]=1.[CH2:11]([CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)[CH2:12][CH2:13][CH2:14][CH3:15].Cl>C1COCC1>[OH:22][C:19]1([C:3]2[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[CH:4]=2)[CH2:20][CH2:21][CH:16]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:17][CH2:18]1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: CCCCCC1CCC(=O)CC1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCC1CCC(O)(c2cc(F)cc(F)c2)CC1
Reaction time: 0.5 h
Yield: 110 %

Procedure:
To a mixture of magnesium (600 mmol) and 1,300 ml of THF was added dropwise 1-bromo-3,5-difluorobenzene (500 mmol) at room temperature, and stirred at the same temperature for 30 min to prepare a Grignard reagent. To this solution was added dropwise a mixture of 4-pentylcyclohexanone (600 mmol) and 200 ml of THF, and stirred at the same temperature overnight. After 600 ml of 1N hydrochloric acid was added and stirred for 30 min, the reaction solution was extracted twice with diethyl ether and dried over anhydrous magnesium sulfate. The solvent was distilled off to give a (1-hydroxy-4-pentylcyclohexyl)-3,5-difluorobenzene (550 mmol). Purification was not particularly performed.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH2:13][OH:14])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[OH:14][CH2:13][C@@:10]1([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@]1(CO)CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@]1(CO)CCNC1
Yield: 95.4 %

Procedure:
A mixture of (R)-tert-butyl 1-benzyl-3-(hydroxymethyl)pyrrolidin-3-ylcarbamate (387 mg, 1.26 mmol), 10% Pd/C (134 mg, 0.126 mmol), ammonium formate (398 mg, 6.32 mmol) and MeOH (10 mL) was heated at reflux under nitrogen for 3 hours. After cooling, the reaction mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure. The residue was taken up in DCM and filtered through Celite again. Removal of the solvent gave (R)-tert-butyl 3-(hydroxymethyl)pyrrolidin-3-ylcarbamate (260 mg, 95%), which was used in the next Step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@H:13](OS(C)(=O)=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:21].[OH-].[Na+].[C:24]([OH:27])(=[O:26])[CH3:25]>C(OCC)(=O)C>[C:24]([OH:27])(=[O:26])[CH3:25].[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@@H:13]([NH2:21])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)O[C@H]1CCN(C(=O)OCc2ccccc2)C1
Reactant: N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: N[C@@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
In an autoclave were charged 2.44 g of (S)-1-(benzyloxycarbonyl)-3-(methanesulfonyloxy)pyrrolidine (7.38 mmol), and 15.7 g of 40% by weight aqueous ammonia (50 equivalent), which was heated to 80° C. whereby an internal pressure of 8 barr was observed. After allowing the reaction for 16 hrs, the reaction mixture was cooled to room temperature, followed by addition of a 30% by weight aqueous sodium hydroxide solution to adjust the pH to 13, and then ammonia was removed by distillation under reduced pressure. The residue was extracted with 15 mL of ethyl acetate three times, and the organic layers were combined. After washing with 3 mL of a saturated brine, drying over anhydrous magnesium sulfate, and concentration under reduced pressure gave a yellow oily material. When 10 mL of ethyl acetate, and 354 mg of acetic acid (0.8 equivalent) were added sequentially thereto, a crystal was precipitated. After stirring at 5° C. for 30 min, the crystal was filtrated under reduced pressure, which was washed with 10 mL of ethyl acetate, and thereafter vacuum drying was carried out to give a white crystal of 1.1684 g (yield: 56%, purity: 100% by weight, optical purity: 100% e.e.)
Reaction SMILES: [NH2:1][CH:2]1[C:12](=[O:13])[N:4]2[C:5]([C:9]([OH:11])=[O:10])=[CH:6][CH2:7][S:8][C@H:3]12.[Br:14]Br.[CH2:16]=[C:17]1[O:21][C:19](=[O:20])[CH2:18]1.O>C[Si](CC(N)=O)(C)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.C(OCC)(=O)C.C(Cl)Cl>[Br:14][CH2:21][C:17]([CH2:18][C:19]([NH:1][CH:2]1[C:12](=[O:13])[N:4]2[C:5]([C:9]([OH:11])=[O:10])=[CH:6][CH2:7][S:8][C@H:3]12)=[O:20])=[O:16]
Reactant: BrBr
Reactant: C=C1CC(=O)O1
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)CC(N)=O
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: O=C(CBr)CC(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reaction time: 1.5 h
Yield: 61.2 %

Procedure:
7-Amino-3-cephem-4-carboxylic acid (2.54 g.) was dissolved in a solution of trimethylsilylacetamide (11.7 g.) and bis(trimethylsilyl)acetamide (15 ml.) in dried ethyl acetate (50 ml.) A solution of bromine (2.43 g.) in dried methylene chloride (10 ml.) was added dropwise to a solution of diketene (1.28 g.) in dried methylene chloride (25 ml.) at -30° C. over 10 minutes and stirred at the same temperature for 1.5 hours. The solution was added to the above solution containing 7-amino-3-cephem-4-carboxylic acid at -15° C. over 10 minutes, and stirred at -15° to -10° C. for 1.5 hours. Water (50 ml.) was added to the resultant solution. The ethyl acetate layer was separated, and extracted with aqueous solution of sodium bicarbonate. The aqueous extract was adjusted to pH 2.0 with 10% hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 7-[2-(2-bromoacetyl)acetamido]-3-cephem-4-carboxylic acid (2.82 g.)
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH2:12][C:13]([OH:15])=[O:14])[CH2:9]1)=O)(C)(C)C.[F:16][C:17]([F:22])([F:21])[C:18]([OH:20])=[O:19]>ClCCl>[F:16][C:17]([F:22])([F:21])[C:18]([OH:20])=[O:19].[NH:8]1[CH2:11][CH:10]([CH2:12][C:13]([OH:15])=[O:14])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(CC(=O)O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC1CNC1
Temperature: 25 °C

Procedure:
2-(1-(tert-Butoxycarbonyl)azetidin-3-yl)acetic acid (0.308 g, 1.43 mmol) was dissolved in 5 mL dichloromethane and was stirred at room temperature. Trifluoroacetic acid (1.47 mL) was added dropwise to the reaction mixture at 0° C. The reaction mixture was allowed to stir at room temperature for 2 h. Trifluoroacetic acid was removed in vacuo to give 2-(azetidin-3-yl)acetic acid trifluoroacetic acid salt. 1H-NMR (400 MHz, CDCl3) δ ppm 4.18-4.13 (m, 2H), 3.93-3.88 (m, 2H), 3.25-3.19 (m, 1H), 2.71 (d, 2H, J=7.6 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@@H:4]([NH:15]C(OC(C)(C)C)=O)[CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([Cl:14])=[CH:12][CH:13]=1)=[O:8].[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[C:24]([OH:30])=[O:25].[CH3:1][O:2][C:3](=[O:23])[C@@H:4]([NH2:15])[CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([Cl:14])=[CH:12][CH:13]=1)=[O:8]
Reactant: COC(=O)[C@H](CNC(=O)c1ccc(Cl)s1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](N)CNC(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Intermediate 8 (13.3 g, 36.66 mmol) in 75 ml DCM was treated with 25 ml TFA and stirred overnight at RT. The solvents were evaporated and the residue was dissolved in DCM and evaporated again. Yield: 21 g (TFA-salt), oil, crude material
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]([Cl:23])([C:19]([F:22])([F:21])[F:20])[CH:8](O)[CH2:9][C:10]([CH3:17])([CH3:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13].O>N1C=C(C)C=C(C)C=1>[Cl:6][C:7]([Cl:23])([C:19]([F:20])([F:21])[F:22])[CH:8]=[CH:9][C:10]([CH3:16])([CH3:17])[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CC(C)(C)CC(O)C(Cl)(Cl)C(F)(F)F
Agent: Cc1cncc(C)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)CC(C)(C)C=CC(Cl)(Cl)C(F)(F)F
Temperature: 0 °C
Yield: 55.3 %

Procedure:
Phosphorus oxychloride (10 cm3) was added dropwise to a stirred solution of methyl 6,6-dichloro-3,3-dimethyl-5-hydroxy-7,7,7-trifluoro-heptanoate (5.49 g) in 3,5-lutidine (50 cm3) maintained at 0° C. The resultant mixture was heated at 100° C. for 30 minutes, and then cooled to the ambient temperature under a nitrogen atmosphere, and poured into a stirred mixture of ice and water (300 cm3). The mixture was extracted with ethyl acetate (2×150 cm3), diethyl ether (3×150 cm3) and finally with ethyl acetate (150 cm ). The volume of the combined extracts was reduced to about 400 cm3 by evaporation of some of the solvents under reduced pressure, and then washed with dilute (3.5M) hydrochloric acid. The aqueous washings were extracted with diethyl ether (3×50 cm3) and the extracts combined with the organic phase. After washing the combined organic phase with brine and drying over anhydrous magnesium sulphate, the solvents were removed by evapoation under reduced pressure and the residual oil purified by Kugelrohr distillation (128° C./1 mmHg) to give methyl 6,6-dichloro-3,3-dimethyl-7,7,7-trifluorohept-4-enoate as a pale yellow oil (2.86 g, 52% yield), together with a quantity of the allylically rearranged isomer methyl 4,6-dichloro-3,3-dimethyl-7,7,7-trifluorohept-5-enoate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1>CC(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:19]1[C:28]3[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=1)[CH2:13][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3c(c2)CCN3)cc1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4cc(OCc5ccccc5)ccc43)c2cc1OC
Yield: 90 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 90% yield from 5-benzyloxy-indoline (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 181°-182° C.; LC-MS: 415 (MH+); anal. RP18-HPLC RT: 4.78 min.).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([N+:28]([O-])=O)[CH:25]=[C:24]([Cl:31])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([OH:23])=[C:9]([CH:22]=1)[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:11]>CCO.CCOC(C)=O.[Pd]>[NH2:28][C:26]1[CH:25]=[C:24]([Cl:31])[C:3]([O:4][C:5]2[CH:6]=[CH:7][C:8]([OH:23])=[C:9]([CH:22]=2)[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:11])=[C:2]([Cl:1])[CH:27]=1
Reactant: CCCCCCCCCNC(=O)c1cc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)ccc1O
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCCCCCNC(=O)c1cc(Oc2c(Cl)cc(N)cc2Cl)ccc1O
Reaction time: 1.5 h
Yield: 72.7 %

Procedure:
To a solution of 5-(2,6-dichloro-4-nitro-phenoxy)-2-hydroxy-N-nonyl-benzamide (168 mg, 0.36 mmol) in a mixture of EtOH (3 ml) and EtOAc (3 ml) was added catalyst (10% Pd/C, 100 mg). The resulting mixture was hydrogenated at 55 psi for 1.5 h at RT. The mixture was filtered through Celite® and concentrated to give the title compound of Step E (115 mg) as a tan solid. The title product of Step E was used without further purification in the next step. MS (APCI+) Calc.: 438.1, Found: 439.3 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[F:26])=[C:14]([CH3:27])[N:13]([CH2:28][C:29]2[C:34](F)=[CH:33][CH:32]=[CH:31][C:30]=2[F:36])[C:12]1=[O:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:44][S-:45].[Na+]>CS(C)=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[F:26])=[C:14]([CH3:27])[N:13]([CH2:28][C:29]2[C:34]([S:45][CH3:44])=[CH:33][CH:32]=[CH:31][C:30]=2[F:36])[C:12]1=[O:37])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[S-]
Reactant: COc1cccc(-c2c(C)n(Cc3c(F)cccc3F)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c3ccccc3)c2=O)c1F
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3SC)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c3ccccc3)c2=O)c1F
Temperature: 100 °C
Yield: 78.6 %

Procedure:
To a solution of compound 5a (33 g, 56 mmol) in dry DMSO (100 mL) was added sodium thiomethoxide (4.0 g, 56 mmol) under nitrogen. The reaction mixture was heated to 100° C. under nitrogen for 1 hour. Another 0.28 eq. of sodium thiomethoxide (1.1 g, 16 mmol) was added, and the reaction mixture was heated to 100° C. under nitrogen for 1 hour. The reaction mixture was cooled and partitioned between ethyl ether and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried with sodium sulfate, filtered and concentrated. The crude product was purified with a flash chromatography on silica gel eluted with 50% ethyl acetate in hexane to yield compound 5b as a pale yellow solid (27 g, 44 mmol, 78%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[C:32]([N:34]1CCN(C2N=CC(Br)=CN=2)CC1)=O)(C)(C)C.C(C1C=CC(B(O)O)=CC=1)#N>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:32]#[N:34])=[CH:22][CH:21]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1
Agent: N#Cc1ccc(B(O)O)cc1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3ccc(C#N)cc3)cn2)CC1
Yield: 68 %

Procedure:
Prepared according to the method for the preparation of 4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-carboxylic acid tert-butyl ester, from 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1.00 g) and 4-cyanobenzeneboronic acid (0.47 g), to yield the title compound as a white solid (0.72 g, 68%).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([NH:22][C:23]5[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1.C=O.[CH2:33]([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1>[CH3:1][C:2]1([CH3:30])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([N:22]([CH3:33])[C:23]5[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1
Reactant: CCCC[Sn](Cl)(Cl)CCCC
Reactant: Cc1ccc(Nc2ccc3c(c2)N(c2nc4c(s2)C(=O)NC(C)(C)C4)CCO3)cn1
Agent: C=O
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(N(C)c2ccc3c(c2)N(c2nc4c(s2)C(=O)NC(C)(C)C4)CCO3)cn1
Yield: 1148 %

Procedure:
A stirred solution of Example 60 (0.017 g, 0.04 mmol), paraformaldehyde (0.04 g, 0.28 mmol), dibutyltin dichloride (0.0015 g, 0.004 mmol) and phenyl silane (0.01 g, 0.08 mmol) in THF (4 mL) was heated to 100° C. under microwave irradiation in a sealed tube for 1 h. The reaction mixture was concentrated in vacuo. Purification by preparative HPLC (Method 7) gave the title compound (0.020 g, 34%) as an off-white solid. δH (CDCl3) 8.20 (1H, d, J 2.8 Hz), 7.70 (1H, d, J 2.5 Hz), 7.16 (1H, d, J 8.5 Hz), 7.05-6.99 (1H, m), 6.93-6.87 (1H, m), 6.78 (1H, dd, J 8.7 and 2.5 Hz), 5.15 (1H, s), 4.36-4.29 (2H, m), 4.18-4.10 (2H, m), 3.20 (3H, s), 2.80 (2H, s), 2.50 (3H, s), 1.40 (6H, s). LCMS (ES+) 436 (M+H)+, RT 3.30 minutes (Method 2).