Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][O:10][C:9]([C:12]3[C:13]([F:22])=[C:14]([C:18]#[C:19][CH2:20]O)[CH:15]=[CH:16][CH:17]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([O:27][C:28]([NH:30][O:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:23]([O:27][C:28]([N:30]([CH2:20][C:19]#[C:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:9]2[O:10][CH2:11][C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[C:13]=1[F:22])[O:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)NOC(=O)OC(C)(C)C
Reactant: OCC#Cc1cccc(C2=N[C@H](c3ccccc3)CO2)c1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)ON(CC#Cc1cccc(C2=N[C@H](c3ccccc3)CO2)c1F)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
To a mixture of 3-[3-(4,5-dihydro-4(R)-phenyloxazol-2-yl)-2-fluorophenyl]-2-propyn-1-ol (1.41 g, 4.8 mmol), N,O-bis(tert-butoxycarbonyl)hydroxylamine (1.11 g, 4.8 mmol) and triphenylphosphine (1.63 g, 6.2 mmol) in dry tetrahydrofuran (350 ml) was added dropwise a solution of diethyl azodicarboxylate (1.08 g, 6.2 mmol) in dry tetrahydrofuran (15 ml). The reaction mixture was stirred for 2 hours and volatiles removed by evaporation. The residue was purified by column chromatography on silica gel eluting with ethyl acetate-hexane (=1:10) to afford N,O-di(tert-butoxycarbonyl)-[3-[3-(4,5-dihydro-4(R)-phenyloxazol-2-yl)-2-fluoro-phenyl]-2-propyn-1-yl]hydroxylamine (1.64 g, 67%) as pale yellow plates.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O.[F:14][C:15]1[CH:16]=[C:17]([N:23]2[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]2=[O:33])[CH:18]=[CH:19][C:20]=1[NH:21]N.C(O)C.Cl>O>[F:14][C:15]1[CH:16]=[C:17]([N:23]2[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]2=[O:33])[CH:18]=[CH:19][C:20]=1[N:21]1[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(NN)c(F)c2)C(=O)O1
Reactant: CN(C)/C=C/C(=O)c1cccnc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(-n3nccc3-c3cccnc3)c(F)c2)C(=O)O1
Yield: 42.5 %

Procedure:
(E)-3-(dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one (58 mg, 0.327 mmol) and (S)—N-((3-(3-fluoro-4-hydrazinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide (94 mg, 0.327 mmol) were combined with a solvent, ethanol (3 mL), and then the mixture was slowly heated to reflux, followed by addition of concentrated hydrochloric acid (40 μL). The reaction mixture was maintained under reflux until completion of the reaction as monitored by TLC. Then, the reaction mixture was poured into water and then was extracted with dichloromethane. The dichloromethane layer was rotary evaporated. The residue was purified with column chromatography to afford 55 mg light yellow solid, with a yield of 40.7%, melting point: 83.7-85.9° C., HPLC: 98.2%.
Reaction SMILES: [N:1]([C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH:5]([OH:10])[C:6]([O:8][CH3:9])=[O:7])=[N+:2]=[N-:3].C(=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[N:29]=[C:28](S(C)(=O)=O)[N:27]=1.O>CN(C=O)C>[N:1]([C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH:5]([O:10][C:28]1[N:29]=[C:30]([O:32][CH3:33])[CH:31]=[C:26]([O:25][CH3:24])[N:27]=1)[C:6]([O:8][CH3:9])=[O:7])=[N+:2]=[N-:3]
Reactant: COC(=O)C(O)C(C)(N=[N+]=[N-])c1ccccc1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(N=[N+]=[N-])c1ccccc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 67.5 %

Procedure:
5.9 g (25 mmol) of methyl 3-azido-3-phenyl-2-hydroxybutyrate (Ex. 1) are dissolved in 80 ml of DMF, treated with 1.7 g (12.5 mmol) of potassium carbonate and 5.5 g (25 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine, and stirred for 6 hours at 50° C. and 12 hours at room temperature. The mixture is then poured onto 400 ml of water, and the precipitate formed is filtered off with suction, washed with water and dried. 6.3 g of a white powder are obtained.
Reaction SMILES: [CH2:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[O:6][N:5]=1)[CH2:2][CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:36][C@H:37]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[C:57]([Cl:59])[CH:56]=[CH:55][C:54]=2[F:60])=[CH:49][CH:48]=1)[CH2:38][C@:39]([CH2:44][OH:45])([CH3:43])[C:40]([OH:42])=[O:41].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:59][C:57]1[CH:56]=[CH:55][C:54]([F:60])=[C:53]([C:50]2[CH:49]=[CH:48][C:47]([CH2:46][C@@H:37]([NH:36][C:9]([C:7]3[O:6][N:5]=[C:4]([CH2:1][CH2:2][CH3:3])[CH:8]=3)=[O:11])[CH2:38][C@:39]([CH2:44][OH:45])([CH3:43])[C:40]([OH:42])=[O:41])=[CH:52][CH:51]=2)[CH:58]=1
Reactant: CCCc1cc(C(=O)O)on1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2F)cc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(C(=O)N[C@H](Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@](C)(CO)C(=O)O)on1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 1.8 %

Procedure:
3-Propylisoxazole-5-carboxylic acid (9 mg, 55 μmol) and HATU (20.8 mg, 55 μmol) were combined in DMF (0.2 mL) and allowed to stand at room temperature for 10 minutes. (2S,4R)-4-Amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxymethyl-2-methylpentanoic acid (20 mg, 55 μmol) in DMF and DIPEA (28.6 μL, 164 μmol) were added, and the resulting mixture was stirred for 20 minutes at room temperature. The mixture was concentrated under reduced pressure and the residue was dissolved in AcOH purified by preparative HPLC to yield the title compound (0.5 mg). MS m/z [M+H]+ calc'd for C26H28ClFN2O5, 503.17. found 504.2.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:6]1(=[O:21])=[O:20].[C:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[O:20]=[S:6]1(=[O:21])[N:5]([CH2:4][CH2:3][CH2:2][N:32]2[CH2:31][CH2:30][N:29]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:34][CH2:33]2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S1(=O)N(CCCBr)c2ccccc2N1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(CCCN2c3ccccc3N(c3ccccc3)S2(=O)=O)CC1
Temperature: 90 °C
Yield: 96 %

Procedure:
A mixture of 1-(3-bromopropyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (prepared in an analogous manner as described in general procedure V), 1-Boc-piperazine (624 mg, 3.35 mmol, 6 equiv.), sodium carbonate (granular, 355 mg, 3.35 mmol, 6 equiv.), and ethanol (5 mL) in a sealed reaction vessel was heated at 90° C. for 8 h. After cooling, solid sodium carbonate was removed by decantation, and the supernatant was concentrated and re-dissolved in ethyl acetate (15 mL). The resulting solution was washed with water, dried (anhydrous sodium sulfate), and concentrated. The crude oil was pre-adsorbed onto Florisil and purified via Isco flash column chromatography (4-g redisep silica gel column, 5-60% ethyl acetate/hexane) to give 252 mg (96%) of tert-butyl 4-[3-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)propyl]piperazine-1-carboxylate as a viscous, brown liquid. MS (ESI) m/z 473.1 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]([CH3:17])[CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1.[F:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[C:20]=1[C:21](Cl)=[O:22]>O1CCOCC1.CO>[F:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[C:20]=1[C:21]([NH:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N:9]([CH3:17])[CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[C:2]=1[F:1])=[O:22]
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Reactant: CN1CCC(N(C)c2cccc(N)c2F)CC1
Solvent: CO
Solvent: C1COCCO1
Product: CN1CCC(N(C)c2cccc(NC(=O)c3c(F)cc(F)cc3F)c2F)CC1
Yield: 94 %

Procedure:
Heat a mixture of 2-fluoro-N-methyl-N-(1-methyl-piperidin-4-yl)-benzene-1,3-diamine (Preparation 22, 60 mg) and 2,4,6-trifluorobenzoyl chloride (59 mg) in 1,4-dioxane (5 mL) for 2 hr. Dilute the reaction mixture with methanol (5 mL) and load on a SCX column (10 g). After wash with methanol, elute the product with 2M NH3 in methanol, evaporate and purify on a silica gel column (4 g, solvent: dichloromethane-2M NH3 in methanol, gradient) to give 94 mg of the title compound: mass spectrum (electric spray) m/z=396 (M+1); 1H NMR (CDCl3): 7.96 (m, 1H), 7.84 (br s, 1H), 7.05 (m, 1H), 6.79 (m, 3H), 3.48 (d, 1H), 3.16 (m, 3H), 2.91 (br d, 2H), 2.74 (s, 3H), 2.27 (s, 3H), 1.97 (m, 2H), 1.84 (m, 2H), 1.72 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:14][CH:15]=[CH2:16])[C:10]([O:12][CH3:13])=[O:11].ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:14][CH:15]1[CH2:16][O:25]1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: C=CCC(C(=O)OC)c1ccc(F)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)C(CC1CO1)c1ccc(F)cc1Cl
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To an ice-cold solution of methyl 2-(2-chloro-4-fluorophenyl)pent-4-enoate (6.0 g, 24.7 mmol) in methylene chloride (50 mL) was added meta-chloroperbenzoic acid (6.7 g, 70% purity, 27.2 mmol). The cooling bath removed and the reaction stirred for 16 hours. The reaction was filtered, the filtrate washed repeatedly with 1 N sodium hydroxide, dried with sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel using n-heptane/ethyl acetate (v/v 1:9 to 2:8) as eluent. The title compound was obtained as a colourless liquid (5.1 g, 80%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[C:10]([NH:15][C:16](OC(C)(C)C)=[O:17])([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:14][CH:13]2[C:10]([NH:15][CH:16]=[O:17])([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC12CCC1CN(Cc1ccccc1)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=CNC12CCC1CN(Cc1ccccc1)C2
Reaction time: 3 h
Yield: 59.9 %

Procedure:
6.8 g of 3-benzyl-1-(t-butoxycarbonylamino)-3-azabicyclo[3.2.0]heptane was dissolved in 20 ml of methylene chloride, and 50 ml of trifluoroacetic acid was added thereto, followed by stirring for 3 hours. The reaction mixture was concentrated, mixed with an aqueous solution of sodium hydroxide under cooling with ice, and extracted with chloroform. After the extract was dried over anhydrous magnesium sulfate, the chloroform was distilled off. The resulting crude product was dissolved in 47 ml of formic acid, and 17 g of acetic anhydride was added dropwise thereto, under cooling with ice, over a period of 90 minutes. After the addition of ice water, the resulting mixture was neutralized by the addition of an aqueous solution of sodium hydroxide under cooling with ice, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (using a 30:1 mixture of chloroform and methanol as the eluent) to obtain 3.1 g of 3-benzyl-1-formylamino-3-azabicyclo[3.2.0]heptane.
Reaction SMILES: [CH3:1][C@H:2]([CH2:6][CH2:7][CH2:8][C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:3][CH2:4]Br.[Mg].[CH3:18][O:19][C:20]1[C:25]([CH3:26])=[C:24]([CH3:27])[C:23]([O:28][CH3:29])=[C:22]([CH3:30])[C:21]=1[CH2:31][CH2:32][C@:33]1([CH3:36])[O:35][CH2:34]1.[Cl-].[NH4+]>C(OCC)(=O)C>[CH3:18][O:19][C:20]1[C:25]([CH3:26])=[C:24]([CH3:27])[C:23]([O:28][CH3:29])=[C:22]([CH3:30])[C:21]=1[CH2:31][CH2:32][C@:33]([CH3:36])([OH:35])[CH2:34][CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:6][CH2:7][CH2:8][C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: COc1c(C)c(C)c(OC)c(CC[C@@]2(C)CO2)c1C
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COc1c(C)c(C)c(OC)c(CC[C@](C)(O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)c1C
Reaction time: 8 h

Procedure:
5.8 mmol of (3R,7R)-3,7,11-trimethyldodecyl bromide are heated at reflux for 1/4 hour in 20 ml of ethyl acetate with activated magnesium. Then, there are added at 0° C. 1 g of (S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-methyl-1,2-epoxybutane and 0.9 g of copper(I)-2-propylacetylide [or 1.2 g of copper(I) bromide/dimethyl sulphide complex]. The temperature of the reaction mixture is subsequently left to rise to room temperature and the mixture is stirred overnight. 10 ml of ammonium chloride are then added and the mixture is extracted with ethyl ether. The extract is dried and concentrated, and the residue is distilled in a bulb-tube (b.p.0.01 =140° C.). There are obtained 1.28 g (72%) [or 1.41 g (79%)] of (3R,7R,11R)-1-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-3,7,11,15-tetramethylhexadecan-3-ol as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1cc([N+](=O)[O-])ccc1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc([N+](=O)[O-])cc1CBr

Procedure:
A degassed solution of 2-methyl-4-nitrobenzonitrile (10 g, 61.7 mmol), N-bromosuccinimide (13.2 g (74.17 mmol, 1.2 eq.) and azobisisobutyronitrile (AlBN) (2.0 g, 12.18 mmol, 0.2 eq) in 300 ml CCl4 was heated at reflux for 3 days. After solvent was evaporated the residue was taken in ethyl acetate and washed 2× with aq. NaHCO3, aq. Na2S2O3, brine, dried over MgSO4, filtered, concentrated and purified chromatography using 15% ethyl acetate in hexane to provide 11.7 g of 2-bromomethyl-4-nitrobenzonitrile.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][OH:34])=[CH:29][CH:28]=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][OH:34])=[CH:29][CH:28]=3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: Nc1ccc(CO)cc1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(CO)cc3)nc12
Temperature: 110 °C
Yield: 91 %

Procedure:
To a 10 ml seal tube, 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.05 g, 0.000117 mol) and (4-aminophenyl)methanol (0.017 g, 0.00014 mol) was taken in toluene (2.0 ml). The reaction mixture was purged with argon for 15 min at RT after which CS2CO3 (0.189 g, 0.000586 mol) was added and the reaction mixture was further purged for 30 min with argon. BINAP (0.0015 g, 0.0000023 mol) and Pd(OAc)2 (0.0005 g, 0.0000023 mol) were added to reaction mixture and heated to 110° C. for 4 hr. After completion of the reaction, the reaction mixture was filtered through celite bed and washed with ethyl acetate. Filtrate was collected and concentrated to afford crude product which was purified using column purification by eluting the compound with 20-25% ethyl acetate in hexanes to yield 0.05 g of N-tert-butyl-2-(4-(hydroxymethyl)phenyl-amino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:16]([F:19])([F:18])[F:17])=[C:12]([CH2:14]O)[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:21].C(=O)(O)[O-].[Na+]>ClCCl.O>[Br:21][CH2:14][C:12]1[CH:13]=[C:8]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:9]=[CH:10][C:11]=1[C:16]([F:19])([F:18])[F:17]
Reactant: OCc1cc(Oc2ccccc2)ccc1C(F)(F)F
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Oc2ccccc2)cc1CBr
Temperature: -5 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
[5-(phenyloxy)-2-(trifluoromethyl)phenyl]methanol (0.493 g, 1.84 mmol) in dichloromethane (12 ml) under nitrogen was stirred and cooled to −5° C. A solution of phosphorus tribromide (173 μl, 1.84 mmol) in DCM (3.5 ml) was added dropwise over about 2 min. The solution was then allowed to warm to room temperature and left to stand overnight. The solution was cooled to 4° C. and stirred well as saturated aqueous sodium bicarbonate (11 ml) was added in portions over 2 min. The biphasic mixture was stirred for a further 20 min. The mixture was diluted with water and DCM. The phases were separated using a hydrophobic frit and the aqueous phase washed with DCM. The combined organic extracts were stored in a freezer over the weekend and the DCM solution decanted off from crystals of ice. The organic phase was further dried (MgSO4), filtered and the solvent removed in vacuo to leave crude 2-(bromomethyl)-4-(phenyloxy)-1-(trifluoromethyl)benzene as a colourless oil (0.425 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20]C(B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][C:1]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: CCCCC(=O)c1ccc(C)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: COCCOC
Solvent: O
Product: CCCCC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.9 %

Procedure:
To a solution of 1-(4-methylphenyl)-1-pentanone (1.00 g, 4.15 mmol) in DME (20 mL) and water (10 mL) was added 4-(trifluoromethyl)benzeneboronic acid (870 mg, 4.57 mmol) and Na2CO3 (1.10 g, 10.38 mmol). After 10 minutes under nitrogen, Pd(PPh3)4 (480 mg, 0.42 mmol) was added portion-wise, and the mixture heated to reflux and stirred under nitrogen for 2 hours. The reaction mixture was then allowed to cool to rt and the solvents removed under vacuum. The resulting residue was partitioned between water and EtOAc, the layers separated and the aqueous re-extracted with EtOAc (3×30 mL). The combined organic extract was separated and dried (MgSO4), and the solvent removed under vacuum. Purification by flash chromatography (silica), eluting with cyclohexane:EtOAc (19:1) afforded the title compound as a white solid (850 mg).
Reaction SMILES: [CH3:1][C:2]#[N:3].C([Li])CCC.C([O:11][C:12]([C@@H:14]1[CH2:16][C@@H:15]1[F:17])=O)C>C1COCC1>[F:17][C@H:15]1[CH2:16][C@H:14]1[C:12](=[O:11])[CH2:1][C:2]#[N:3]
Reactant: CCOC(=O)[C@@H]1C[C@@H]1F
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCC(=O)[C@@H]1C[C@@H]1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
To a solution of MeCN (7.28 mL, 139 mmol) in anhydrous THF (130 mL) at −78° C. under N2 was added n-butyllithium (2.4 mol/L) in hexanes (58 mL, 139 mmol) dropwise. The mixture was stirred at −78° C. for 30 min then cis-ethyl-2-fluorocyclo-propanecarboxylate (1.5 g; 87.0 mmol) was added dropwise with stirring while maintaining the temperature at −78° C. The resulting solution was stirred at 25° C. for 2 h, quenched by the addition of 50% satd. aq. NH4Cl solution and extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum to afford 7.7 g of crude cis-3-(2-fluorocyclopropyl)-3-oxopropanenitrile as a red oil. Crude cis-3-(2-fluoro-cyclopropyl)-3-oxopropanenitrile was dissolved in EtOH (130 mL) and hydrazine (8.45 mL, 261 mmol) was added. The reaction mixture was heated at reflux for 16 h then concentrated in vacuo. The resultant orange solid was triturated with DCM (ca. 50 mL). The precipitate was filtered, rinsed with DCM, and dried in vacuo to obtain 7.48 g (60.9%) of cis-5-(2-fluorocyclopropyl)-1H-pyrazol-3-amine as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 11.18 (br s, 1H), 5.16 (s, 1H), 4.81 (ddd, J=66.3, 9.5, 5.2 Hz, 1H), 4.46 (br s, 2H), 1.99-1.81 (m, 1H), 1.23-1.02 (m, 2H).
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[OH:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:33]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:26]=[C:25]([NH2:34])[C:24]=2[N:23]=[C:22]1[CH2:35][CH2:36][CH3:37].[OH-].[Na+]>ClCCl>[NH2:34][C:25]1[C:24]2[N:23]=[C:22]([CH2:35][CH2:36][CH3:37])[N:21]([CH2:20][CH2:19][CH2:18][CH2:17][N:16]([OH:15])[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[C:33]=2[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:26]=1
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CCCCNO
Reactant: CC(C)N=C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCCN(O)C(=O)NC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.4 %

Procedure:
Isopropyl isocyanate (0.67 mL, 6.85 mmol) and triethylamine (2.38 mL, 17.1 mmol) were added to a solution of 1-[4-(hydroxyamino)butyl]-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine hydrochloride (prepared as described in Parts A-D of Example 43, 2.00 g, 5.71 mmol) in dichloromethane (50 mL). The reaction mixture was stirred at room temperature for 2 hours, then 10% aqueous sodium hydroxide (2 equivalents) was added. After the mixture was stirred for 1 hour at room temperature, the layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, eluted with 3% methanol in dichloromethane). The appropriate fractions were combined and concentrated under reduced pressure. The resulting solid was slurried in 1:1 saturated aqueous sodium bicarbonate/water and was isolated by filtration, washed with water, and dried overnight in a vacuum oven at 80° C. to provide 0.327 g of N-[4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N-hydroxy-N′-isopropylurea as beige needles, mp 158-160° C.
Reaction SMILES: O[C:2]([CH:5]1[C:14](=[O:15])[N:8]2[C:9]([CH3:13])([CH3:12])[O:10][CH2:11][C@H:7]2[CH2:6]1)([CH3:4])[CH3:3].CS(Cl)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:12][C:9]1([CH3:13])[N:8]2[C:14](=[O:15])[C:5](=[C:2]([CH3:4])[CH3:3])[CH2:6][C@@H:7]2[CH2:11][O:10]1
Reactant: CC(C)(O)C1C[C@@H]2COC(C)(C)N2C1=O
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)=C1C[C@@H]2COC(C)(C)N2C1=O
Temperature: 55 °C

Procedure:
To a solution of (7aR)-6-(2-hydroxypropan-2-yl)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (5.06 g, 23.73 mmol) in DCM (50 mL) at room temperature was added methanesulfonyl chloride (2.75 mL, 35.6 mmol) followed by triethylamine (16.50 mL, 119 mmol) and then heated at 55° C. for 1 h. The resulting mixture was treated with additional methanesulfonyl chloride (2.75 mL, 35.6 mmol) and heated for another 1 h. The reaction mixture was allowed to cool to room temperature, quenched with water (50 mL) and extracted with DCM (2×100 mL). The combined extracts were washed with brine, dried over MgSO4, filtered and concentrated to provide crude (R)-3,3-dimethyl-6-(propan-2-ylidene)tetrahydropyrrolo[1,2-c]oxazol-5(3H)-one as a brown oil, which was used in the next step without purification. m/z (ESI, +ve) 196 (M+H).