Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]2[C:9]3[C:14]([NH:15][C:16]4[CH:25]=[CH:24][C:19]5[NH:20][C:21](=[O:23])[S:22][C:18]=5[CH:17]=4)=[N:13][CH:12]=[N:11][C:10]=3[S:26][C:5]=2[CH2:4]1.[OH:27][CH:28]([CH3:32])[C:29](O)=[O:30]>>[OH:27][CH:28]([CH3:32])[C:29]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]2[C:9]3[C:14]([NH:15][C:16]4[CH:25]=[CH:24][C:19]5[NH:20][C:21](=[O:23])[S:22][C:18]=5[CH:17]=4)=[N:13][CH:12]=[N:11][C:10]=3[S:26][C:5]=2[CH2:4]1)=[O:30]
Reactant: CC(O)C(=O)O
Reactant: NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Product: CC(O)C(=O)NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1

Procedure:
75 mg (196 μmol) (RS)-6-{[7-(aminomethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl]amino}-1,3-benzothiazol-2(3H)-one (prepared according to example 20) were transformed in analogy to example 23 using (RS)-2-hydroxypropanoic acid to give after working up and purification 6.0 mg (6%) of the title compound.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[C:11]([OH:13])=[O:12].C(Cl)Cl.[C:17]([S:25][CH2:26][CH:27]([CH3:31])[C:28](Cl)=[O:29])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(N(CC)CC)C>[C:17]([S:25][CH2:26][CH:27]([CH3:31])[C:28]([N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[C:11]([OH:13])=[O:12])=[O:29])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(CSC(=O)c1ccccc1)C(=O)Cl
Reactant: O=C(O)C1Cc2ccccc2N1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CSC(=O)c1ccccc1)C(=O)N1c2ccccc2CC1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the mixture of 5.0 g of indoline-2-carboxylic acid hydrochloride and 50 ml of methylene chloride are added 7.9 g of triethylamine, and after 5 minutes 6.1 g of 3-benzoylthio-2-methylpropanoyl chloride during 3 minutes. After stirring the mixture at room temperature for 2 hours, it is extracted thrice with 50 ml of saturated aqueous sodium bicarbonate. The combined aqueous solutions are adjusted to pH=1 with 4N hydrochloric acid and reextracted thrice with 50 ml of methylene chloride. The combined extracts are dried and evaporated, to yield the 1-(3-benzoylthio-2-methylpropanoyl)-indoline-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=[O:9])[N:3]=1.C[Si](C)(C)[C:12]([F:15])([F:14])[F:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([OH:9])[C:12]([F:15])([F:14])[F:13])[N:3]=1
Reactant: O=Cc1nccc(Cl)n1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1nccc(Cl)n1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Chloropyrimidine-2-carbaldehyde (283 mg, 1.99 mmol) was dissolved in tetrahydrofuran (11.4 mL) and cooled to 0° C. Trimethyl(trifluoromethyl)silane (0.37 mL, 2.38 mmol) was added followed by 1 M tetra-n-butylammonium fluoride in tetrahydrofuran (2.38 mL, 2.38 mmol). The ice bath was removed and the reaction was stirred for 1 hour. The reaction was then diluted with water and brine and extracted with ethyl acetate three times. The organic layers were combined and dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting mixture was purified via silica gel chromatography (0-5% methanol in ethyl acetate) to afford the title compound.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+](C)C.[OH:10][C:11]1[CH:20]=[CH:19][C:18]2[CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:16]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:15][CH2:14][C:13]=2[N:12]=1.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:6][O:10][C:11]1[CH:20]=[CH:19][C:18]2[CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:16]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:15][CH2:14][C:13]=2[N:12]=1
Reactant: C[O+](C)C
Reactant: CCOC(=O)C1c2ccc(O)nc2CCN1C(=O)OC(C)(C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)C1c2ccc(OC)nc2CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 27.7 %

Procedure:
Trimethyloxonium tetrafluoroborate (1.775 g, 12.00 mmol) was added to a mixture of 5-ethyl 6-tert-butyl 2-hydroxy-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate (1.289 g, 4.00 mmol) and acetonitrile (18 mL) at 0° C. The mixture was stirred at 0° C. for 2 hr, and the reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogencarbonate solution (100 mL), and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 2→19% ethyl acetate/hexane) to give 5-ethyl 6-tert-butyl 2-methoxy-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate (372 mg, 1.106 mmol, 28%) as a colorless oil.
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:18][C@@H:17]3[C@@H:12]([NH:13][CH2:14][CH2:15][CH2:16]3)[CH2:11]2)(=O)=O)=CC=1.Br.C(O)(=O)CC.C1(O)C=CC=CC=1>>[C@H:12]12[CH2:11][NH:10][CH2:18][C@H:17]1[CH2:16][CH2:15][CH2:14][NH:13]2
Reactant: Cc1ccc(S(=O)(=O)N2C[C@H]3CCCN[C@H]3C2)cc1
Agent: Br
Solvent: CCC(=O)O
Solvent: Oc1ccccc1
Product: C1CN[C@H]2CNC[C@H]2C1
Yield: 84.4 %

Procedure:
The title compound (9.12 g) is prepared from mixture system of (R,R)-6-(toluene-4-sulfonyl)-octahydro-pyrrolo[3,4-b]pyridine (24.0 g), hydrobromic acid (48%, 156 ml), propionic acid (72 ml) and phenol (14.6 g) following the same procedure described in example 9. After conventional work up and distillation 3.4 g of oil is obtained (yield: 78.0%).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl.O>[C:10]([C:4]1[C:3]([O:13][CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[C:2]([Br:1])[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)c1cc(Cl)c(C)c(Br)c1O
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c(C)c(Br)c1OCCNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 23 h
Yield: 59.8 %

Procedure:
A suspension of 1-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone (8.0 g, 30 mmol) in methylene chloride (304 mL) was heated with a heat gun to dissolve the solids and cooled to 0° C. To the mixture was added triphenylphosphine (11 g, 43 mmol) and tert-butyl (2-hydroxyethyl)carbamate (9.4 mL, 61 mmol). Diisopropyl azodicarboxylate (8.4 mL, 43 mmol) was added dropwise. The mixture was stirred for 23 hours at room temperature. The reaction mixture was poured into water and extracted with methylene chloride. The organic layer was separated, washed with brine, dried with sodium sulfate, filtered, and concentrated. The oil was dissolved in methylene chloride and was purified on silica using ethyl acetate in hexanes (0-25%) to give the desired compound (7.3 g, 59%). LCMS calculated for C16H21BrClNO4Na (M+Na)+: m/z=428.0, 430.0; found: 428.0, 430.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]Br)[CH:5]=[CH:4][C:3]=1[N:10](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.[P:25]([O:32]CC)([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]>>[NH2:10][C:3]1[CH:4]=[CH:5][C:6]([CH2:8][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:7][C:2]=1[Br:1]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ccc(CBr)cc1Br
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc(N)c(Br)c1)OCC
Temperature: 120 °C
Reaction time: 16 h

Procedure:
Di-tert-butyl [2-bromo-4-(bromomethyl)phenyl]imidodicarbonate (Compound 108B, 6.0 g, 13 mmol) was taken up in triethyl phosphite (5.0 mL, 29 mmol) and stirred at 120° C. for 16 h. The reaction mixture was transferred to a microwave vial and was irradiated in the microwave for 4 h at 190° C. The reaction mixture was concentrated in vacuo. The compound was purified on an Isco Combiflash eluting with 10 to 100% EtOAc in heptane. The product was partitioned between EtOAc and water and separated. The aqueous was extracted with EtOAc (3×) and the combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the title compound. 1H NMR (400 MHz, chloroform-d) δ 7.33 (t, J=2.27 Hz, 1H), 7.04 (ddd, J=2.27, 2.40, 8.21 Hz, 1H), 6.71 (dd, J=0.76, 8.08 Hz, 1H), 3.97-4.06 (m, 4H), 2.96-3.04 (m, 2H), 1.26 (t, J=7.07 Hz, 6H); MS (ES+): m/z: 322.00, 323.96 [MH+]. HPLC: tR=2.83 min (UPLC TOF MS: polar—3 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH2:23]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[CH2:24][CH2:25][CH3:26]>C(N(CC)CC)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:32]([C:31]2[CH:35]=[CH:36][C:28]([O:27][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:29][CH:30]=2)=[O:33])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOc1ccc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1
Temperature: 25 °C
Reaction time: 30 h
Yield: 41 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was suspended in triethylamine/methylene chloride (3 ml/2 ml), commercially available 4-butoxybenzoyl chloride (0.07 ml) was added, and the admixture was stirred at room temperature for 30 hours. The reaction mixture was then purified in the same manner as described in Example 62 to obtain 34 mg of the title compound (yield: 41%).
Reaction SMILES: FC(F)(F)C(O)=O.Cl[C:9]1[N:14]=[C:13]([F:15])[C:12]2[O:16][C:17]3[C:22]([C@@:23]4([C:27]5[CH:28]=[N:29][CH:30]=[CH:31][C:26]=5[C:25]([NH2:32])=[N:24]4)[C:11]=2[CH:10]=1)=[CH:21][C:20]([C:33]1[C:34]([F:39])=[N:35][CH:36]=[CH:37][CH:38]=1)=[CH:19][CH:18]=3.[O:40]1[CH2:45][CH2:44][CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH2:41]1.C(O)(C(F)(F)F)=O>>[O:40]1[CH2:45][CH2:44][CH:43]=[C:42]([C:9]2[N:14]=[C:13]([F:15])[C:12]3[O:16][C:17]4[C:22]([C@@:23]5([C:27]6[CH:28]=[N:29][CH:30]=[CH:31][C:26]=6[C:25]([NH2:32])=[N:24]5)[C:11]=3[CH:10]=2)=[CH:21][C:20]([C:33]2[C:34]([F:39])=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:19][CH:18]=4)[CH2:41]1
Reactant: CC1(C)OB(C2=CCCOC2)OC1(C)C
Reactant: NC1=N[C@]2(c3cc(-c4cccnc4F)ccc3Oc3c2cc(Cl)nc3F)c2cnccc21
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@]2(c3cc(-c4cccnc4F)ccc3Oc3c2cc(C2=CCCOC2)nc3F)c2cnccc21

Procedure:
The title compound was synthesized by procedures and steps analogous to those described in Example 14 above, but using (S)-3-Chloro-1-fluoro-7-(2-fluoropyridin-3-yl)spiro[chromeno[2,3-c]pyridine-5,3′-pyrrolo[3,4-c]pyridin]-1′-amine 2,2,2-trifluoroacetate (14d-2) and 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in step 5. MS m/z=496.0 [M+H]+. Calculated for: C28H19F2N5O2.O2HF3O2: 609.50 (TFA salt)
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CCN(C(C)C)C(C)C.Cl[C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1COCC1>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=1[NH:1][C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:5])[NH2:6]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Cc1cccc(C(N)=O)c1N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)Nc1c(C)cccc1C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.6 %

Procedure:
To a solution of 2-amino-3-methylbenzamide (1.50 g, 10.0 mmol) and DIEA (2.61 mL, 15 mmol) in THF (50 mL) at 0° C. was added ethyl chlorooxoacetate (1.23 mL, 11.0 mmol). The solution was allowed to warm to rt and stir for 16 h, then was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 20-100% EtOAc/hexanes to afford ethyl 2-(2-carbamoyl-6-methylphenylamino)-2-oxoacetate as a solid (490 mg, 20%). 1H NMR (300 MHz, DMSO-d6) δ 1.31 (t, J=7.1 Hz, 3H), 2.17 (s, 3H), 4.30 (q, J=7.1 Hz, 2H), 7.28 (t, 1H), 7.33-7.57 (m, 3H), 7.82 (s, 1H), 10.67 (s, 1H).
Reaction SMILES: [CH2:1]([C:4]1([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[OH:31]O.[OH-].[Na+]>C1COCC1>[F:30][C:27]1[CH:26]=[CH:25][C:24]([C:4]2([CH2:1][CH2:2][CH2:3][OH:31])[O:9][C:8](=[O:10])[N:7]([C@H:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)[CH2:6][CH2:5]2)=[CH:29][CH:28]=1
Reactant: C=CCC1(c2ccc(F)cc2)CCN([C@H]2CCCN(C(=O)OC(C)(C)C)C2)C(=O)O1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H](N2CCC(CCCO)(c3ccc(F)cc3)OC2=O)C1

Procedure:
The two diastereomers of (3S)-tert-butyl 3-(6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)piperidine-1-carboxylate were prepared from (3S)-tert-butyl 3-(6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)piperidine-1-carboxylate by treatment with (i) BH3 in THF and (ii) H2O2 and NaOH.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13](=[CH2:25])[CH2:14][N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][C:16]1=[O:24]>C(Cl)Cl>[CH3:25][C:13]1([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][C:16]2=[O:24])[CH2:12][O:9]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)Cn1c(=O)oc2ccccc21
Solvent: ClCCl
Product: CC1(Cn2c(=O)oc3ccccc32)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
m-Chloroperbenzoic acid (1.66 g, 9.65 mmol) was added to a mixture of 3-(2-methyl-2-propenyl)-3H-benzoxazol-2-one (1.66 g, 8.77 mmol) in methylene chloride (30 ml) while cooling in an ice-bath, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate was washed with a 20% sodium sulfite aqueous solution, saturated sodium bicarbonate aqueous solution and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was treated with methylene chloride/n-hexane, and the resulting precipitates were collected by filtration to afford 3-(2-methyl-2-oxiranylmethyl)-3H-benzoxazol-2-one (1.78 g, yield 99%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[NH:7][S:8][C:4]=2[CH:3]=1.[CH2:12]([N:16]=[C:17]=[O:18])[CH2:13][CH2:14][CH3:15]>>[CH2:12]([NH:16][C:17]([N:7]1[C:6](=[O:9])[C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=2[S:8]1)=[O:18])[CH2:13][CH2:14][CH3:15]
Reactant: O=c1[nH]sc2cc(Cl)ccc12
Reactant: CCCCN=C=O
Product: CCCCNC(=O)n1sc2cc(Cl)ccc2c1=O

Procedure:
Following the synthetic procedure of 6a as described in Example 1, compound 6w (90% yield) was synthesized from 6-chloro-benzo[d]isothiazol-3-one and n-butyl isocyanate as a white solid. IR(CHCl3) 3294, 1713, 1540 cm−1; 1H-NMR (DMSO-d6) δ0.89 (t, J=7.3 Hz, 3H), 1.26-1.37 (m, 2H), 1.47-1.55 (m, 2H), 3.28-3.34 (m, 2H), 7.50 (d, J=8.3 Hz, 1H), 7.91 (d, J=8.3 Hz, 1H), 8.14 (s, 1H), 8.76 (t, J=5.6 Hz, 1H); ESIMS m/e 284 and 286 (M++1, 35Cl and 37Cl).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[O:27]([CH2:34][CH2:35][CH2:36]Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[O:27]([CH2:34][CH2:35][CH2:36][N:1]1[CH2:2][CH2:3][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:5][CH2:6]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: c1ccc2c(c1)Cn1cccc1C(C1CCNCC1)O2
Reactant: BrCCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(OCCCN2CCC(C3Oc4ccccc4Cn4cccc43)CC2)cc1

Procedure:
To a solution of 11-(piperidin-4-yl)-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (5.07 g, 0.019 mole in 75 ml DMF), 10 g milled K2CO3 and 10 mg KI, was added a solution of 3-phenoxypropylbromide (4.78 g, 0.022 mole in 20 ml DMF).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]3[CH2:10][CH2:11][CH2:12][N:7]3[C:6]=2[CH:13]=1.N([O-])=O.[Na+].[ClH:18]>O>[Cl:18][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]3[CH2:10][CH2:11][CH2:12][N:7]3[C:6]=2[CH:13]=1
Reactant: Nc1ccc2nc3n(c2c1)CCC3
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Clc1ccc2nc3n(c2c1)CCC3

Procedure:
A suspension of 17.3 g of 7-amino-2,3-dihydro-1H-pyrrolo [1,2-a]benzimidazole prepared according to W. Reppe, Ann. 596, 209 (1955) in 200 cm3 of 5 N hydrochloric acid is diazotized with a solution of 7.2 g of sodium nitrite in 30 cm3 of water. The obtained solution is added to a solution of 8 g of cuprous chloride in 35 cm3 of concentrated hydrochloric acid at 50°-60°C. After cooling the precipitate is sucked off, washed with water and suspended in water. By adding to this suspension a 25 % aqueous solution of ammonia the heterocyclic base is set free and sucked off. After drying, recrystallization from benzene yields 4.1 g of 7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole. Melting point: 136°C.
Reaction SMILES: I[C:2]1[C:3]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)=[CH:13][CH:12]=2)=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[F:25][C:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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:25][C:26]1[CH:31]=[C:30]([C:2]2[C:3]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=4)=[CH:13][CH:12]=3)=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=2)[CH:29]=[CH:28][N:27]=1
Reactant: COc1ncc(I)c(Oc2ccc(Nc3ccc(C)cn3)cc2)n1
Reactant: OB(O)c1ccnc(F)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: O
Solvent: C1COCCO1
Product: COc1ncc(-c2ccnc(F)c2)c(Oc2ccc(Nc3ccc(C)cn3)cc2)n1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
N-(4-(5-Iodo-2-methoxypyrimidin-4-yloxy)phenyl)-5-methylpyridin-2-amine (0.061 g, 0.14 mmol), 2-fluoropyridine-4-boronic acid (0.030 g, 0.21 mmol), and tetrakis(triphenylphosphine)palladium (0.016 g, 0.014 mmol) were mixed in dioxane (0.5 mL) under an argon atmosphere. Sodium carbonate (0.21 mL, 0.42 mmol, 2.0 M in water) was added via syringe, and the reaction mixture was stirred at 80° C. for 20 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was separated, washed with sat. sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel chromatography to give N-(4-(5-(2-fluoropyridin-4-yl)-2-methoxypyrimidin-4-yloxy)phenyl)-5-methylpyridin-2-amine. MS (ESI, pos. ion) m/z: 404.2 (M+1). IC50 (uM) 0.016.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.[CH3:13][O:14][C:15](=[O:34])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24](Cl)[C:25]3[C:30]([CH3:31])=[C:29]([CH3:32])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1>>[CH3:13][O:14][C:15](=[O:34])[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:23]=[C:24]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:25]3[C:30]([CH3:31])=[C:29]([CH3:32])[S:28][C:26]=3[N:27]=2)=[CH:20][CH:21]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(C)c(C)sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCCc3ccc4c(c3)OCO4)c3c(C)c(C)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-methylenedioxyphenethylamine is reacted with 4-(4-chloro-5,6-dimethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-methylenedioxyphenethylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12](C=O)[CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].Cl.[NH2:21][OH:22].N1C=CC=CC=1>C(O)C>[CH2:1]([CH:3]([CH2:9][C:10]1[CH2:11][C:12](=[N:21][OH:22])[C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)c(C=O)c1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)C(CC)CC1=CC=C(OC)C(=NO)C1
Yield: 93.3 %

Procedure:
A mixture of ethyl 2-ethyl-3-(3-formyl-4-methoxyphenyl)propanoate (1.06 g, 4.01 mmol), hydroxylamine hydrochloride (293 mg, 4.22 mmol), pyridine (1 mL) and ethanol (20 mL) was refluxed for 6 hours. After cooling, the mixture was concentrated and the residue was dissolved in ethyl acetate, which was washed with 1 mol/L hydrochloric acid, saturated aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=6:1 v/v) to afford 1.00 g (89%) of the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:30])([C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)=[CH2:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:30])([C@H:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C=C(c1ccc(-c2ccnn2C)cc1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [Pd]
Solvent: CCO
Product: C[C@@H](c1ccc(-c2ccnn2C)cc1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 18 h

Procedure:
A solution of (2R)-2-(2,4-difluorophenyl)-3-(4-[1-methylpyrazol-5-yl]phenyl)-1-(1,2,4-triazol-1-yl)-3-buten-2-ol (2.0 g, 5 mmol-see Preparation 53) in ethanol (50 ml) was hydrogenated at 50 psi (333 KPa) pressure over 5% palladium on charcoal (0.2 g) for 18 hours at 50° C. A further batch of catalyst (0.2 g) was added, and the hydrogenation was continued for a further 18 hours. The mixture was filtered through "Arbocel" (Trade Mark) and the filtrate evaporated under reduced pressure.
Reaction SMILES: [OH:1][C:2]1[N:3]=[N:4][C:5]([SH:8])=[CH:6][CH:7]=1.CC(O[CH2:13][C:14]1[CH2:23][S:22][C@@H:17]2[C@H:18]([NH2:21])[C:19](=[O:20])[N:16]2[C:15]=1[C:24]([OH:26])=[O:25])=O.C(=O)(O)[O-].[Na+].P([O-])([O-])([O-])=O>>[NH2:21][CH:18]1[C:19](=[O:20])[N:16]2[C:15]([C:24]([OH:26])=[O:25])=[C:14]([CH2:13][S:8][C:5]3[N:4]=[N:3][C:2]([OH:1])=[CH:7][CH:6]=3)[CH2:23][S:22][C@H:17]12
Reactant: Oc1ccc(S)nn1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3ccc(O)nn3)CS[C@H]12

Procedure:
A mixture of 0.60 g. (0.0047 mole) of 3-hydroxy-6-mercaptopyridazine, 1.27 g. (0.0047 mole) of 7-aminocephalosporanic acid, 0.78 g. (0.0094 mole) of sodium bicarbonate in 25 ml. of 0.1 M phosphate buffer (pH 6.4) was heated at 60° C. for 5 hours. The reaction mixture was filtered to remove a trace of insoluble material and the filtrate was adjusted to pH 5 with acetic acid to give brown precipitates, which were collected by filtration, washed with water and acetone successively and dried in vacuo to give 7-amino-3-(6-hydroxypyridazin-3-ylthiomethyl)-3-cephem-4-carboxylic acid; 1.03 g. (71%). M.p. 290°-300° C. (decomp.).