Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5]([Cl:7])=[O:6].[NH2:14][CH:15]1[CH:20]2[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]2)[CH2:16]1>C(OCC)C>[ClH:7].[N:17]12[CH2:22][CH2:21][CH:20]([CH2:19][CH2:18]1)[CH:15]([NH:14][C:5](=[O:6])[C:4]1[C:3]([O:2][CH3:1])=[CH:11][CH:10]=[CH:9][C:8]=1[O:12][CH3:13])[CH2:16]2
Reactant: NC1CN2CCC1CC2
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: CCOCC
Product: COc1cccc(OC)c1C(=O)NC1CN2CCC1CC2
Product: Cl
Reaction time: 0.25 h
Yield: 59.6 %

Procedure:
In a closed system equipped with an oil bubbler, a solution of 2,6-dimethoxybenzoyl chloride (1.89 g, 0.0095 mole) in 20 ml diethyl ether was added dropwise to a stirred solution of 3-aminoquinuclidine (1.26 g, 0.010 mole) in 50 ml of diethyl ether. After the addition was completed, the reaction mixture was stirred for 15 min, and the precipitate that had formed was filtered under nitrogen. The wet (hygroscopic) solid was immediately recrystallized from methanol-isopropyl ether to give 1.85 g (60%) of the product. The material was vacuum dried for 4 hr at 98° C., m.p. 266°-268° C.
Reaction SMILES: CS(C)=O.[Br:5][C:6]1[CH:7]=[C:8]([C:12]#[C:13][C:14]2[CH:15]=[C:16]([CH:19]=[O:20])[NH:17][CH:18]=2)[CH:9]=[CH:10][CH:11]=1.C(OCC)(=[O:23])C.[OH2:27]>[Pd](Cl)Cl>[Br:5][C:6]1[CH:7]=[C:8]([C:12](=[O:23])[C:13]([C:14]2[CH:15]=[C:16]([CH:19]=[O:20])[NH:17][CH:18]=2)=[O:27])[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(C)=O
Reactant: O=Cc1cc(C#Cc2cccc(Br)c2)c[nH]1
Reactant: O
Agent: Cl[Pd]Cl
Solvent: CS(C)=O
Product: O=Cc1cc(C(=O)C(=O)c2cccc(Br)c2)c[nH]1
Temperature: 140 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To DMSO was added 4-[(3-bromophenyl)ethynyl]-1H-pyrrole-2-carbaldehyde (1.50 g; 5.47 mmol), and palladium(II) chloride (97 mg; 0.547 mmol). The resulting solution was stirred at 140° C. for one hour. The mixture was cooled to ambient temperature and diluted with water. The product was extracted into chloroform and dried over MgSO4. The resulting solid was chromatographed on silica gel using 7:3 hexane:ethyl acetate to give 1.21 g of the title compound as a greenish crystalline solid (72% yield), mp 202-203° C.; MS (ES) m/z 304.0, [M−H]−.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26](O)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:74][C:75]1[CH:76]=[N:77][CH:78]=[CH:79][CH:80]=1>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH:74][C:75]4[CH:76]=[N:77][CH:78]=[CH:79][CH:80]=4)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: Nc1cccnc1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1)Nc1cccnc1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (100 mg, 0.24 mmol), PyBOP® (125 mg, 0.24 mmol), DIEA (250 μL, 0.44 mmol) in CH2Cl2:DMF (4 mL:1 mL) stirred at RT for 10-15 minutes. To this solution of activated acid was added 3-amino pyridine (23 mg, 0.24 mmol) and the reaction mixture was stirred at 50° C. for 1.5 h. Concentrated in vacuo and the crude product was purified using prep HPLC (method 10-35_90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(pyridin-3-yl)acetamide. (11 mg, 0.023 mmol, 9%)
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]([CH3:17])[CH:15]=[N:14][C:13]=3[C:18]3[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][N:19]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4]1.[H-].[Na+].[CH3:28]I>CN(C=O)C>[CH3:28][O:1][CH2:2][C:3]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]([CH3:17])[CH:15]=[N:14][C:13]=3[C:18]3[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][N:19]=3)=[CH:8][CH:7]=2)[CH2:4][CH2:5]1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(C2(CO)CC2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC1(c2ccc(-c3c(-c4cc(C#N)ccn4)ncn3C)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(5-{4-[1-(hydroxymethyl)cyclopropyl]phenyl}-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile (30 mg, 0.09 mmol; Example 17, part A) in anhydrous DMF (2 mL) at 0° C. was added 60% NaH (6 mg, 0.136 mmol). After stirring for 10 minutes, MeI (10 μL, 0.136 mml) was added. The reaction mixture was warmed up to r.t. and stirred for 3 hr. It was then purified by ISCO flash column chromatography (MeOH/DCM=0-5%) to give the title product which was used for next step. [M+H] Calc'd for C21H20N4O, 345. Found, 345.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:9]=1[C:10](OCC)=[O:11].O>C1COCC1.C(O)C>[CH3:7][C:8]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:9]=1[CH2:10][OH:11]
Reactant: CCOC(=O)c1c(C)cccc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COc1cccc(C)c1CO
Yield: 97.9 %

Procedure:
To a solution of 1.0 M lithium aluminium hydride in anhydrous THF (3.6 ml, 3.6 mmol), under nitrogen, was added anhydrous THF (12 ml). Ethyl 2-methyl-6-(methyloxy)benzoate (1 g, 5.2 mmol, ABCR) in anhydrous THF (2 ml) was then added over 5 min with stirring. The solution was stirred for 15 min and then heated at gentle reflux for 100 min. The solution was allowed to cool. A 5% solution of water in ethanol was added dropwise. The solvent was removed in vacuo and acidified using 1 to 2M aqueous HCl. The mixture was extracted with chloroform and the organic solvent removed in vacuo to give the title compound as yellow solid (0.775 g); LCMS: (System 4) MH+=152, tRET=1.78 min.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].C1CNC([CH2:28][OH:29])C1.Cl.CC[N:33]([CH:37]([CH3:39])C)[CH:34]([CH3:36])C>CC(O)C>[Br:1][C:2]1[C:3]([N:33]2[CH2:34][CH2:36][C@H:39]([CH2:28][OH:29])[CH2:37]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: OCC1CCCN1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Agent: Cl
Solvent: CC(C)O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1

Procedure:
A mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 2.3, 500 mg, 1.264 mmol), (S)-beta-prolinol hydrochloride (226 mg, 1.643 mmol), DIPEA (662 μL, 3.79 mmol) and iPrOH (1.945 mL) in a sealed vial was subjected to MW irradiation at 140° C. for 60 min. The solvent was evaporated off under reduced pressure and the residue was treated with aq. 0.5 M HCl (20 mL) and extracted with EtOAc. The combined extracts were washed with 0.5 M HCl (10 ml) and water, dried over MgSO4 and the solvent was evaporated off under reduced pressure to give the product which was triturated with cyclohexane, filtered and dried to afford the title compound as a white solid. UPLC-MS (Condition 1) tR=2.76 min, m/z=460.0/462.0 [M+H]+, m/z=458.0/460.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.59-1.76 (m, 1H) 1.92-2.04 (m, 1H) 2.26-2.44 (m, 1H) 3.37-3.50 (m, 2H) 3.56 (dd, J=11.00, 7.34 Hz, 1H) 3.67-3.85 (m, 3H) 4.71 (br. s, 1H) 7.35 (d, J=8.56 Hz, 2H) 7.85 (d, 1H) 8.34 (d, J=1.96 Hz, 1H) 8.68 (d, J=1.96 Hz, 1H) 10.21 (s, 1H).
Reaction SMILES: C(OC([N:11]([CH2:13][C:14]1[CH:15]=[C:16]([NH:27][C:28]([O:30][CH2:31][C@@H:32]([C:34]2[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][C:35]=2[CH3:43])[CH3:33])=[O:29])[CH:17]=[C:18]([F:26])[C:19]=1[O:20][C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[CH3:12])=O)C1C=CC=CC=1.[NH2:44][C:45]1[CH:46]=[C:47]2[C:52](=[CH:53][CH:54]=1)[C:51]([N:55]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])=[N:50][CH:49]=[CH:48]2.O.[C:71]([OH:75])(=[O:74])[CH:72]=O>CC#N.CN(C=O)C>[C:66]([O:65][C:63]([N:55]([C:56]([O:58][C:59]([CH3:60])([CH3:61])[CH3:62])=[O:57])[C:51]1[C:52]2[C:47](=[CH:46][C:45]([NH:44][CH:72]([C:37]3[CH:38]=[CH:39][C:34]([C@@H:32]([CH3:33])[CH2:31][O:30][C:28](=[O:29])[NH:27][C:16]4[CH:15]=[C:14]([CH2:13][NH:11][CH3:12])[C:19]([O:20][C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])=[C:18]([F:26])[CH:17]=4)=[C:35]([CH3:43])[CH:36]=3)[C:71]([OH:75])=[O:74])=[CH:54][CH:53]=2)[CH:48]=[CH:49][N:50]=1)=[O:64])([CH3:69])([CH3:68])[CH3:67]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Reactant: O=CC(=O)O
Reactant: COC[C@H](C)Oc1c(F)cc(NC(=O)OC[C@H](C)c2ccc(B(O)O)cc2C)cc1CN(C)C(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: CNCc1cc(NC(=O)OC[C@H](C)c2ccc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2C)cc(F)c1O[C@@H](C)COC
Temperature: 85 °C
Reaction time: 3 h
Yield: 42.9 %

Procedure:
37D (309 mg, 0.518 mmol), Intermediate 1 (205 mg, 0.570 mmol), glyoxylic acid monohydrate (47.7 mg, 0.518 mmol) were dissolved in CH3CN (3 ml) and DMF (0.5 ml). The mixture was stirred at 85° C. 20 h, then concentrated and purified by prep HPLC. The desired fractions were combined, concentrated. The residue was dissolved in THF (8 mL). 10% Pd/C was added and the mixture was hydrogenated at 40 psi for 3 h. The mixture was filtered, concentrated and purified by prep HPLC to give 37E (185 mg, 0.222 mmol, 42.8% yield). MS (ESI) m/z: 834.4 (M+H)+.
Reaction SMILES: C([NH:5][C:6]1[CH:11]=[C:10]([C:12]2[C:13]([C:26]3[CH:27]=[C:28]([NH:32][C:33]([NH:35][C:36]4[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=4)=[O:34])[CH:29]=[CH:30][CH:31]=3)=[N:14][N:15](CC3C=CC(OC)=CC=3)[CH:16]=2)[CH:9]=[CH:8][N:7]=1)(C)(C)C.O.C([O-])(O)=O.[Na+]>FC(F)(F)C(O)=O>[NH2:5][C:6]1[CH:11]=[C:10]([C:12]2[C:13]([C:26]3[CH:27]=[C:28]([NH:32][C:33]([NH:35][C:36]4[CH:41]=[CH:40][C:39]([C:42]([F:44])([F:45])[F:43])=[CH:38][CH:37]=4)=[O:34])[CH:29]=[CH:30][CH:31]=3)=[N:14][NH:15][CH:16]=2)[CH:9]=[CH:8][N:7]=1
Reactant: COc1ccc(Cn2cc(-c3ccnc(NC(C)(C)C)c3)c(-c3cccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)c3)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(-c2c[nH]nc2-c2cccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)c2)ccn1
Temperature: 70 °C
Yield: 71.3 %

Procedure:
100 mg (0.16 mmol) of 1-(3-{4-[2-(tert-butylamino)pyridin-4-yl]-1-(4-methoxybenzyl)-1H-pyrazol-3-yl}phenyl)-3-[4-(trifluoromethyl)phenyl]urea were dissolved in 5 ml of trifluoroacetic acid and the mixture heated at 70° C. under stirring. After 16 hours the solution was poured into icy water, neutralized with aqueous NaHCO3 and extracted with dichloromethane. The organic layer was then dried over Na2SO4 and evaporated to dryness. The product was purified by chromatography on a silica gel column eluted with dichloromethane-methanol (gradient from 1% to 5%) obtaining 50 mg (71% yield) of the title compound.
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@H:32]([CH2:38][CH3:39])[CH:33]([OH:37])[CH:34]([CH3:36])[CH3:35]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][C@H:32]([CH2:38][CH3:39])[CH:33]([OH:37])[CH:34]([CH3:36])[CH3:35])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)([CH3:13])[CH3:12]
Reactant: CC[C@@H](N)C(O)C(C)C
Reactant: CC(C)n1cnc2c(NCc3ccccn3)nc(F)nc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCCCO
Product: CC[C@@H](Nc1nc(NCc2ccccn2)c2ncn(C(C)C)c2n1)C(O)C(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-2-ylmethyl-amine (30 mg, 1 eq, 0.10 mmol) in n-BuOH/DMSO (2.5 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.10 mL, 5.5 eq, 0.57 mmol) followed by (3RS,4R)-4-amino-2-methyl-hexan-3-ol (42 mg, 3.0 eq, 0.32 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSo4) and evaporated in vacuo. The residue was purified-by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 7.8 mg (19%). 50% de 4R,3S: 50% de 4R,3R). 1H-NMR (d-CDCl3, 250 MHz): δ 0.91-1.04 (m, 9H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 1.57 (d, 6H, J=6.79 Hz, —CH(CH3)2), 1.66-1.94 (m, 4H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 3.22-3.34 (m, 1H, —NHCH(CH2CH3) CH(CH (CH3)2)OH), 3.79-3.93 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 4.57-4.71 (m, 1H, —CH(CH3)2), 4.85-4.97 (m, 2H, —HNCH2-Pyr), 5.13-5.24 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 6.65-6.79 (m, 1H, —HNCH2-Pyr), 7.13-7.24 (m, 1H, Pyr-H), 7.32-7.42 (m, 1H, Pyr-H), 7.56 (s, 1H, —N═CH—N—), 7.58-7.73 (m, 1H, Pyr-H), 8.60 (d, 1H, J=4.42 Hz, Pyr-H). FABMS m/z (relative intensity): 398 ([M+H]+, 100), 324 (50). Accurate Mass (M+H): Actual: 398.2668, Measured: 398.2654.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([NH2:8])=[O:7])[C:4]=1[NH2:12].Br[C:14]1[S:15][C:16]([Br:20])=[C:17]([CH3:19])N=1>>[Br:20][C:16]1[S:15][C:14]2=[N:12][C:4]3[C:5]([C:6](=[O:7])[N:8]2[C:17]=1[CH3:19])=[CH:9][CH:10]=[CH:11][C:3]=3[O:2][CH3:1]
Reactant: Cc1nc(Br)sc1Br
Reactant: COc1cccc(C(N)=O)c1N
Product: COc1cccc2c(=O)n3c(C)c(Br)sc3nc12
Yield: 77.7 %

Procedure:
4.8 g of 3-methoxyanthranilamide and 7.5 g of 2,5-dibromo-4-methylthiazole were stirred for 12 hours at 140° C. After working up in the conventional manner there was obtained 7.3 g (77%) of the above compound; m.p. 198°-199° C.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)(=[O:4])[CH2:2][CH3:3].P([O-])([O-])(O)=O.[Na+].[Na+].[Br:19]Br>O.C(O)(=O)C>[C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Br:19])=[CH:8][N:7]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: BrBr
Reactant: CCC(=O)Nc1ccccn1
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCC(=O)Nc1ccc(Br)cn1
Reaction time: 4 h
Yield: 84.7 %

Procedure:
To 47.5g of an aqueous solution containing 0.2 mol of 2-propionamido pyridine (Ie), a solution containing 71 g (0.5 ml) of disodium hydrogenphosphate dissolved in 450 g of water was added. To this mixture, a solution containing 49.2 g (0.31 mol) of bromine dissolved in 50 g of acetic acid was added with stirring at 10°-15° C. for 4 hours. After having been stirred at room temperature for one hour and then at 60° C. for one hour, the mixture was cooled. The crystal precipitated thereby was filtered. After the crystal was washed with water and dried, 38.8 g (yield: 84.7%) of 2-propionamido-5-bromopyridine (IIe) was obtained as a dark white crystal.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].C1O[C:9]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[O:8]C1.[CH3:16][CH2:17][O:18]CC>ClCCl>[CH2:17]1[O:18][C:4]([N:12]2[CH2:13][CH2:14][C:9](=[O:8])[CH2:10][CH2:11]2)([NH:3][CH2:1][CH3:2])[O:5][CH2:16]1
Reactant: CCN=C=O
Reactant: C1CC2(CCN1)OCCO2
Reactant: CCOCC
Solvent: ClCCl
Product: CCNC1(N2CCC(=O)CC2)OCCO1
Temperature: 20 °C
Reaction time: 24 h

Procedure:
Ethyl isocyanate (0.85 ml, 0.76 g, 10.7 mmol) was added dropwise with stirring to 4-piperidone ethylene ketal (1.43 g, 10 mmol) in dry dichloromethane (30 ml). The resulting pale yellow solution was stirred at 20° C. for 24 h, then evaporated to yield a yellow solid. Trituration with ether gave the title compound as a white crystalline solid (1.85 g), m.p. 120°-122° C.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:37]1[N:41]=[C:40]([NH2:42])[S:39][N:38]=1)[C:6]([NH:8][CH:9]1[C:35](=[O:36])[N:11]2[C:12]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[C:13]([CH2:17][Cl:18])[CH2:14][S:15](=[O:16])[C@H:10]12)=[O:7])[CH3:2].[CH3:43][N:44]([CH3:51])[C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1>O1CCCC1>[Cl-:18].[CH2:1]([O:3][N:4]=[C:5]([C:37]1[N:41]=[C:40]([NH2:42])[S:39][N:38]=1)[C:6]([NH:8][CH:9]1[C:35](=[O:36])[N:11]2[C:12]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[C:13]([CH2:17][N+:47]3[CH:48]=[CH:49][CH:50]=[C:45]([N:44]([CH3:51])[CH3:43])[CH:46]=3)[CH2:14][S:15](=[O:16])[C@H:10]12)=[O:7])[CH3:2]
Reactant: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)c1nsc(N)n1
Reactant: CN(C)c1cccnc1
Solvent: C1CCOC1
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[n+]3cccc(N(C)C)c3)CS(=O)[C@H]12)c1nsc(N)n1
Product: [Cl-]
Reaction time: 2.5 h
Yield: 88.8 %

Procedure:
A mixture of diphenylmethyl 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate-1-oxide (syn isomer) (3 g) and 3-dimethylaminopyridine (0.7 g) in tetrahydrofuran (20 ml) was stirred for 2.5 hours at 48° to 50° C. The resulting precipitate was filtered, washed with tetrahydrofuran and dried to give diphenylmethyl 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(3-dimethylamino-1-pyridiniomethyl)-3-cephem-4-carboxylate-1-oxide chloride (syn isomer) (3.18 g), mp 120° to 130° C. (dec.).
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:14][C@@H:13]([CH:15]([O:18][CH3:19])[O:16][CH3:17])[N:12]1CC1C=CC=CC=1)=[O:10])C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH3:12].[CH3:17][O:16][CH:15]([O:18][CH3:19])[C@H:13]1[NH:12][C@@H:11]([C:9]([OH:10])=[O:8])[CH2:14]1
Reactant: COC(OC)[C@@H]1C[C@H](C(=O)OCc2ccccc2)N1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(OC)[C@@H]1C[C@H](C(=O)O)N1
Product: N
Yield: 97.9 %

Procedure:
12.5 mg (35 μmol) of cis-N-benzYl-4-(dimethoxymethyl)azetidine-2-carboxylic acid benzyl ester in 10 ml of methanol is hydrogenated in a Parr shaker over 53 mg of 20% Pd(OH)2/C (containing 31% water) under 4 atm of hydrogen for 3 h. Filtration through a double paper filter, repeated washing with methanol and evaporation gives a crude product which is filtered over silica gel with isopropanol/water/conc. ammonia (17:2:1) to yield 3.0 mg (49%) of cis-4(dimethoxymethyl)azetidine-2-carboxylic acid as a colorless glass. 1H NMR (D2O): δ4.73 (d, 1H, overlapping), 4.72 (t, 1H, overlapping), 3.53 (s, 3H), 3.50 (s, 3H), 2.80 (dt, 1H, J=12 (d), 9.5(t)), 2.50 (dt, 1H, J=12(d), 8(t)).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[S:22][C:23]([Cl:26])=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[Cl:26][C:23]1[S:22][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:25][CH:24]=1
Reactant: [O-]B([O-])Oc1ccc(Cl)s1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COC(=O)C1=Cc2cc(-c3ccc(Cl)s3)ccc2S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
In toluene/ethanol/water (10/1/1.2 ml) was dissolved methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (750 mg), and to the solution were added 5-chloro-2-thienyl borate (736 mg) and potassium carbonate (1.0 g). The mixture was stirred at room temperature for 30 minutes, and to the mixture was added tetrakistriphenylphosphinepalladium (210 mg). The mixture was stirred at 100° C. for 15 hours, cooled to room temperature, extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=3/1) to give methyl 7-(5-chloro-2-thienyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (350 mg).
Reaction SMILES: [Li].C[Si]([NH-])(C)C.Br[CH2:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[NH:34][CH:35]=2)=[CH:27][CH:26]=1>C1COCC1.CN(C=O)C>[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[N:32]=[C:33]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:34]([CH2:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)=[O:10])[CH:35]=2)=[CH:29][CH:30]=1
Reactant: O=C(CBr)N1CCN(c2ccccn2)CC1
Reactant: COc1ccc(-c2c[nH]c(-c3ccccc3)n2)cc1
Agent: C[Si](C)(C)[NH-]
Agent: [Li]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(-c2cn(CC(=O)N3CCN(c4ccccn4)CC3)c(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.8 %

Procedure:
250 μl 1 mol/L lithium his (trimethylsilyl) amide solution in THF was added to 29 mg 2-bromo-1-(4-pyridin-2-yl-piperazin-1-yl)-ethanone in 1 mL DMF. The mixture was stirred 10 min at RT and 28 mg 4-(4-methoxy-phenyl)-2-phenyl-1H-imidazole was added. The reaction was stirred 2 h at 60° C. The mixture was purified by HPLC to give 30 mg desired product.
Reaction SMILES: [C:1]([CH:5]1CCC(=O)CC1)(C)([CH3:3])[CH3:2].C(N(S(F)(F)[F:18])CC)C.B(F)(F)F.CCOCC.[F:30][C:31]1[CH:36]=[CH:35][C:34](OC)=[CH:33][CH:32]=1>C(Cl)Cl>[F:30][C:31]1([F:18])[CH2:36][CH2:35][CH:34]([C:1]([CH3:5])([CH3:3])[CH3:2])[CH2:33][CH2:32]1
Reactant: COc1ccc(F)cc1
Reactant: CC(C)(C)C1CCC(=O)CC1
Reactant: CCN(CC)S(F)(F)F
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 67 %

Procedure:
A solution of 4-t-butylcyclohexanone (308 mg, 2.0 mmol) in CH2Cl2 (10.0 mL) was added to diethylaminosulfur trifluoride (483 mg, 3.0 mmol ) at room temperature under N2. BF3.OEt2 (100 mL) was added and the mixture was stirred for 6 h at room temperature. The mixture was washed with saturated NaHCO3, dried (Na2SO4), filtered and evaporated in vacuo. Proton and Fluorine NMR with 4-fluoroanisole (2 mmol) as internal standard showed that a 67% yield of 1,1-difluoro-4-t-butylcyclohexane was obtained.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH:7]1[CH2:10][NH:9][CH2:8]1.C1(CC2C=CC=CC=2)C=CC=CC=1.[CH3:29][CH2:30][CH2:31][CH2:32][N:33]=[C:34]=[O:35]>C(OC(C)C)(C)C>[CH2:32]([NH:33][C:34]([N:9]1[CH2:10][CH:7]([O:6][C:5]2[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=2)[CH2:8]1)=[O:35])[CH2:31][CH2:30][CH3:29]
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Reactant: CCCCN=C=O
Solvent: CC(C)OC(C)C
Solvent: c1ccc(Cc2ccccc2)cc1
Product: CCCCNC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reaction time: 0.33 h

Procedure:
A solution of 18.9 (0.05 mole) of crude 3-[3-(trifluoromethyl)-phenoxy]azetidine (contains an equal molar amount of diphenylmethane) in 100 ml of isopropyl ether was stirred under nitrogen while 4.96 g (0.05 mole) of N-butyl isocyanate was slowly added. The clear reaction solution became warm to the touch, and after 20 minutes a white crystalline solid began to precipitate. After stirring for 16 hr, the solid was removed by filtration, washed with fresh isopropyl ether and air dried to yield 8 g of pale beige crystals, m.p. 108°-109° C.