Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CS(C)=O.O>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=2)[CH2:20][CH2:19]1
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 122 °C
Reaction time: 24 h
Yield: 53.6 %

Procedure:
To a suspension of 1-fluoro-3-nitrobenzene (3.77 mL, 35.4 mmol) and potassium carbonate (10 g, 71 mmol) in DMSO (30 mL) was added 1-methyl piperazine (59 mL, 53.2 mmol). The mixture was stirred at 122° C. for 24 hours. After cooing down, the mixture was diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried with sodium sulfate (Na2SO4), and concentrated in vacuo to afford an orange oil. Recrystallization from EtOAc/hexanes gave 4.2 g of 1-(4-methyl-piperazin-1-yl)-3-nitrobenzene, which was reduced via hydrogenation to give the title compound (beige solid, 3 g). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.04 (t, J=8.0 Hz, 1H), 6.38 (dd, J=2.3, 8.2 Hz, 1H), 6.26 (t, J=2.2 Hz, 1H), 6.22 (dd, J=2.3, 8.2 Hz, 1H), 3.60 (br, 2H), 3.18 (t, J=4.9 Hz, 4H), 2.55 (t, J=4.9 Hz, 4H), 2.34 (s, 3H).
Reaction SMILES: ClC(Cl)(Cl)C([N:5]=[C:6]=[O:7])=O.[CH3:10][O:11][N:12]=[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=1)[C:14]([OH:16])=[O:15]>O1CCOCC1>[CH3:10][O:11][N:12]=[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:6](=[O:7])[NH2:5])[CH:18]=1)[C:14]([OH:16])=[O:15]
Reactant: CON=C(C(=O)O)c1cccc(O)c1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CON=C(C(=O)O)c1cccc(OC(N)=O)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Trichloroacetyl isocyanate (70 ml) was dropwise added over 6 minutes at ambient temperature to a solution of 2-methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (40 g) in dry dioxane (200 ml), and the resulting mixture was stirred for 5 hours at ambient temperature. Dioxane was distilled off and to the residue were added ethyl acetate (200 ml) and by small portions water (200 ml) under ice-cooling. The mixture containing trichloroacetylcarbamoyl 2-methoxyimino-2-(3-trichloroacetylcarbamoyloxyphenyl)acetate was stirred for 5 hours at ambient temperature keeping the pH value of the mixture at 6.0 to 6.4 by adding an aqueous solution of sodium bicarbonate. The resulting mixture was wahsed twice with ethyl acetate. The aqueous layer was adjusted to pH 2 with a 10% hydrochloric acid and extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed twice with an aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and precipitating crystals were collected by filtration to give colorless crystals of 2-methoxyimino-2-(3-carbamoyloxyphenyl)acetic acid (syn isomer) (15 g), mp 163° C. (dec.). The same compound (5.4 g) was obtained from the mother liquor.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([N:14]=[C:15]([NH:17][C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[CH2:24][NH:23][CH2:22][CH2:21]5)[N:16]=3)[CH:11]=[CH:12][CH:13]=2)=[C:4]([O:28][CH3:29])[CH:3]=1.Cl[CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([N:14]=[C:15]([NH:17][C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[CH2:24][N:23]([CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:22][CH2:21]5)[N:16]=3)[CH:11]=[CH:12][CH:13]=2)=[C:4]([O:28][CH3:29])[CH:3]=1
Reactant: COc1cc(Cl)ccc1-c1cccn2nc(Nc3ccc4c(c3)CCNC4)nc12
Reactant: CN(C)C(=O)CCl
Product: COc1cc(Cl)ccc1-c1cccn2nc(Nc3ccc4c(c3)CCN(CC(=O)N(C)C)C4)nc12

Procedure:
2-{6-[8-(4-Chloro-2-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-3,4-dihydro-1H-isoquinolin-2-yl}-N,N-dimethyl-acetamide was prepared from [8-(4-chloro-2-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]-(1,2,3,4-tetrahydro-isoquinolin-6-yl)-amine (0.077 g, 0.190 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.029 mL, 0.284 mmol) in a manner analogous to Example 313 to give product (0.015 g, 16%). MP=103-106° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.53 (s, 1H), 8.78 (d, 1H), 7.58 (m, 2H), 7.42 (m, 2H), 7.25 (s, 1H), 7.15 (d, 1H), 7.05 (t, 1H), 6.92 (d, 1H), 3.78 (s, 3H), 3.54 (s, 2H), 3.28 (s, 2H), 3.05 (s, 3H), 2.85 (s, 3H), 2.78 (m, 2H), 2.70 (m, 2H): MS=491 (MH)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[O:21][CH3:20])=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: COc1ccccc1B(O)O
Product: COc1ccc2c(-c3ccccc3OC)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 2-methoxy-phenylboronic acid to give [6-methoxy-1-(2-methoxy-phenyl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 347(MH+).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[N:14]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNC1
Reactant: N#Cc1ccc(Br)c(C(F)(F)F)c1
Product: N#Cc1ccc(N2CCCC2)c(C(F)(F)F)c1

Procedure:
The title compound is prepared using an analogous method as described in Example 1.1, utilising 4-bromo-3-(trifluoromethyl)-benzonitrile and pyrrolidine (Fluka, Buchs, Switzerland), with a reaction temperature of 95° C.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].C(NC(C)C)(C)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][OH:28])=[CH:21][CH:20]=1.[Cl-].[NH4+]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:19]1([CH3:29])[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH2:27][O:28][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])=[CH:23][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(CCCO)cc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: Cc1ccc(CCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reaction time: 6 h
Yield: 66.1 %

Procedure:
2.46 g of tosyl chloride (13 mmol), 3.4 ml of diisopropylamine (19.4 mmol) and 158 mg of 4-(dimethylamino)pyridine (1.29 mmol) were added to reaction solution (6.46 mmol) dissolving 971 mg of 3-p-tolyl-propane-1-ol (40ac) prepared by above step 3 in methylene chloride at 0° C. under Ar atmosphere with stirring for 6 hrs, and the reaction mixture was stirred for 12 hrs at room temperature. After the reaction mixture was neutralized with ammonium chloride, the mixture was extracted with ethyl acetate, washed with saturated NaCl solution, dried over MgSO4, filtered, and concentrated in vacuo. The resultant was purified by Silica gel column chromatography with a solvent mixture mixed with methanol and chloroform (1:7) as an eluant to give 1.3 g of toluene-4-sulfonate-3-p-tolyl-propyl ester (40ad) (yield: 70%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=2)=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:29]=[O:30])C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:29]=[O:30])[N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc(F)cc2)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: C[Si](C)(C)CCOCn1cc(-c2ccc(F)cc2)nc1C=O

Procedure:
Reaction of 4-(4-fluoro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (688 mg, 2.35 mmol), 1.5 M n-BuLi (2.0 mL, 3.0 mmol), and DMF (0.55 mL, 7.1 mmol) gave the title compound as a brown oil that was used without further purification in the next step. 1H NMR (CDCl3) 0.00 (s, 9H), 0.95 (m, 2H), 3.61 (m, 2H), 5.82 (s, 2H), 7.12 (m, 2H), 7.28 (s, 1H), 7.59 (s, 1H), 7.80 (m, 2H), 9.88 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=2)[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[C:28](=O)([O:34]C(C)(C)C)[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>C(Cl)Cl>[C:30]([O:29][C:28](=[O:34])[NH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=2)[CH2:3][CH2:4][C:5](=[O:8])[CH2:6][CH2:7]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)c1cccc(C2(N)CCC(=O)CC2)c1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(c2cccc(C(C)(C)C)c2)CCC(=O)CC1
Reaction time: 19 h

Procedure:
4-Amino-4-(3-tert-butyl-phenyl)-cyclohexanone (441 mg, 1.8 mmol) was dissolved in dry methylene chloride (10 mL), diisopropylethylamine (0.31 mL, 1.8 mmol) and di-tert-butyl carbonate (400 mg, 1.83 mmol) were added in succession at room temperature. After 19 h, the reaction was concentrated under reduced pressure, and the desired product isolated by chromatography (Rf=0.35 in 20% EtOAc/hexanes). The resulting oil was taken to the next reaction: retention time=2.57 min, method [7]; mass spec (ESI) 369 (24), 368 (100), 272 (42), 211 (24).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([CH:15]=[CH:16][N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)Cl.[OH-].[Na+].CN([CH:28]=[O:29])C>>[CH:28]([C:15]1[N:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:10]2=[N:17][CH:16]=1)=[O:29]
Reactant: c1ccc(COc2cccn3ccnc23)cc1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnc2c(OCc3ccccc3)cccn12
Temperature: 10 °C

Procedure:
A mixture of 10 g of 8-(phenylmethoxy)imidazo[1,2-a]pyridine prepared in Example 13 and 31 ml of DMF is cooled to 10° C. 4.7 ml of POCl3 are added dropwise. The mixture is allowed to return to room temperature and then heated at 100° C. for 30 min. After cooling, 85 ml of H20 and 16 ml of NaOH (50%) are added. The mixture is heated at 90° C. for 1 h and then allowed to cool. The solid obtained is filtered off and then washed with water until the pH of the mother liquors is neutral. This gives 8.8 g of 3-formyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine.
Reaction SMILES: [C@H:1]1([O:12][CH2:13][C:14]2[O:18][C:17]([C:19]([OH:21])=[O:20])=[CH:16][CH:15]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[CH:22](Cl)(Cl)Cl.CO>CO.O>[CH3:22][O:20][C:19]([C:17]1[O:18][C:14]([CH2:13][O:12][C@H:1]2[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]2[OH:3])=[CH:15][CH:16]=1)=[O:21]
Reactant: O=C(O)c1ccc(CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)o1
Reactant: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)o1
Reaction time: 0.25 h
Yield: 84 %

Procedure:
To produce diazomethane, 1.0 g (10 mmol) N-methyl-N-nitrosourea was added portionwise with cooling to 20 ml diethyl ether to which 7 ml of 40% KOH had been added to form a lower layer, in such a way that the reaction temperature did not exceed +5° C. 30 min after the last addition the yellow organic phase was separated off and allowed to stand for 3 h over a little solid KOH. Enough of the ethereal solution of diazomethane thus obtained was added at room temperature with stirring during a period of 15 min to a solution of 500 mg (1.6 mmol) GMF carboxylic acid (formula 4, product of Example 4) in 18 ml methanol and 2 ml water for the yellow colour just to remain and no further evolution of gas to be observed. After a further 15 min stirring the reaction was complete (TLC monitoring with mobile solvent chloroform/methanol (2:1), Rf (educt)=0, Rf (product)= 0.41), whereupon the solvent was removed under vacuum and the crude product was purified by elution from a silica gel column (3×20 cm) with chloroform/methanol (2:1). Concentration of the fractions containing the product gave 440 mg (84%) of colourless syrup with [α]D20 =+113° (c=0.8, methanol), which gradually crystallised on scratching; m.p. 72° C.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH:15]=[CH2:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:25][C:26]1([CH3:38])[O:30][CH:29]([C:31]2[N:32]=[C:33]([CH:36]=[O:37])[S:34][CH:35]=2)[CH2:28][O:27]1.C(N(CC)CC)C>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH2:15][CH2:16][C:36]([C:33]3[S:34][CH:35]=[C:31]([CH:29]4[CH2:28][O:27][C:26]([CH3:38])([CH3:25])[O:30]4)[N:32]=3)=[O:37])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: CC1(C)OCC(c2csc(C=O)n2)O1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1(C)OCC(c2csc(C(=O)CCC(=O)C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)n2)O1
Yield: 60 %

Procedure:
A mixture of 4-[4-(cyclopropylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (0.50 g), 4-(2,2-dimethyl-1,3-dioxolan-4-yl)-1,3-thiazole-2-carbaldehyde (0.37 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (43 mg), triethylamine (0.09 mL) and ethanol (6 mL) was stirred with heating under reflux for 2 hr. The reaction mixture was concentrated, the residue was subjected to basic silica gel column chromatography, and the title compound (0.47% g, yield 60%) was obtained as a yellow oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 562 (MH+).
Reaction SMILES: [CH3:1][CH:2]([S:26]([NH2:29])(=[O:28])=[O:27])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][C:15](Br)=[CH:14][C:13]=3[N:12]=[C:11]([NH2:21])[C:10]=2[N:9]=[C:8]1[CH2:22][O:23][CH2:24][CH3:25].[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1>>[CH3:1][CH:2]([S:26]([NH2:29])(=[O:28])=[O:27])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][C:15]([C:32]4[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=4)=[CH:14][C:13]=3[N:12]=[C:11]([NH2:21])[C:10]=2[N:9]=[C:8]1[CH2:22][O:23][CH2:24][CH3:25]
Reactant: OB(O)c1cccnc1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCC(C)S(N)(=O)=O
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCCCC(C)S(N)(=O)=O
Yield: 27.8 %

Procedure:
Methyl 5-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentane-1-sulfonamide (0.47 g, 0.97 mmol) was coupled with pyridine-3-boronic acid (0.14 g, 1.2 mmol) according to the methods described in Part J of Example 1 and Part H of Example 370. The crude product was purified twice by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 70:30) and then recrystallized from methanol, isolated by filtration, and dried for 5 days under high vacuum at 100–140° C. to provide 0.13 g of methyl 5-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]pentane-1-sulfonamide as a white powder, mp 191–192° C.
Reaction SMILES: B(O)O.O[C:5](C(O)(C)C)([CH3:7])[CH3:6].C(B1OC(C)(C)C(C)(C)O1)C=C.[CH:24]([C:26]1[C@H:31]([C:32]([O:34][CH:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[N:30]2[C:48](=[O:60])[C@@H:49]([NH:50][C:51](=[O:59])[CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[C@H:29]2[S:28][CH:27]=1)=[O:25]>C1(C)C=CC=CC=1>[OH:25][CH:24]([C:26]1[C@H:31]([C:32]([O:34][CH:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:33])[N:30]2[C:48](=[O:60])[C@@H:49]([NH:50][C:51](=[O:59])[CH2:52][C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)[C@H:29]2[S:28][CH:27]=1)[CH2:7][CH:5]=[CH2:6]
Reactant: O=CC1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: CC(C)(O)C(C)(C)O
Agent: C=CCB1OC(C)(C)C(C)(C)O1
Agent: OBO
Solvent: Cc1ccccc1
Product: C=CCC(O)C1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
via a pinacol boronate. A mixture of 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (50 mg, 0.3 mmol), diphenylmethyl (4R, 6R, 7R)-3-formyl-7-phenylacetamidoceph-2-em-4-carboxylate (100 mg, 0.2 mmol), 0.4 nm molecular sieves (50 mg), and toluene (2 ml) was heated under reflux for 3 h and then cooled and purified by chromatography as in part a to give the title compound S-diastereomer, 20 mg (18%), and the R-diastereomer, 23 mg (20%).
Reaction SMILES: NC1C=CC(C2C=C(C)C=CC=2S(C2C=CC(C)=CC=2C2C=CC(N)=C([N+]([O-])=O)C=2)=O)=CC=1[N+]([O-])=O.[Br:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[C:49]([N+:50]([O-])=O)=[C:48]([NH2:53])[CH:47]=[CH:46][C:45]=2[S:54]([C:56]2[CH:61]=[CH:60][C:59]([NH2:62])=[C:58]([N+:63]([O-])=O)[C:57]=2[C:66]2[CH:71]=[CH:70][C:69]([Br:72])=[CH:68][CH:67]=2)=[O:55])=[CH:40][CH:39]=1>>[Br:37][C:38]1[CH:39]=[CH:40][C:41]([C:44]2[C:49]([NH2:50])=[C:48]([NH2:53])[CH:47]=[CH:46][C:45]=2[S:54]([C:56]2[CH:61]=[CH:60][C:59]([NH2:62])=[C:58]([NH2:63])[C:57]=2[C:66]2[CH:71]=[CH:70][C:69]([Br:72])=[CH:68][CH:67]=2)=[O:55])=[CH:42][CH:43]=1
Reactant: Nc1ccc(S(=O)c2ccc(N)c([N+](=O)[O-])c2-c2ccc(Br)cc2)c(-c2ccc(Br)cc2)c1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c([N+](=O)[O-])c2)c(-c2ccc(N)c([N+](=O)[O-])c2)c1
Product: Nc1ccc(S(=O)c2ccc(N)c(N)c2-c2ccc(Br)cc2)c(-c2ccc(Br)cc2)c1N

Procedure:
Following the procedure described in Example 2 but using as a starting material instead of (4-amino-3-nitrophenyl)-4-methylphenyl sulfoxide a corresponding amount of 4-bromophenyl-(4-amino-3-nitrophenyl) sulfoxide, the title compound is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[N:3]=1.Cl.C(OCC)C>C(O)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: Cc1ccc2c(OCCN3CCN(C(=O)OC(C)(C)C)CC3)cccc2n1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: Cc1ccc2c(OCCN3CCNCC3)cccc2n1
Temperature: 40 °C
Reaction time: 17 h
Yield: 90.8 %

Procedure:
tert-Butyl 4-[2-(2-methylquinolin-5-yloxy)ethyl]piperazine-1-carboxylate (1.04 g, 2.8 mmol) was dissolved in ethanol (60 mL) and treated with 1 M hydrochloric acid in diethyl ether (16 mL, 16 mmol) and stirred at 40° C. for 17 h. The reaction mixture was filtered and the white solid was collected and dried in vacuo. The hydrochloride salt precipitate was dissolved in water (25 mL) and potassium carbonate was added until the pH reached 10. The aqueous layer was washed with 5% methanol in dichloromethane (4×100 mL) then 10% methanol in dichloromethane (4×100 mL). The organic layers were combined, dried (Na2SO4) and concentrated in vacuo, affording the title compound as a brown oil (0.69 g, 91%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[CH:27]=[C:28]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH:33]2[CH3:38])[CH:29]=[CH:30][CH:31]=1.[Cl:39][C:40]1[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=1[CH3:45]>>[Cl:39][C:40]1[C:41]([C:50]([F:52])([F:51])[F:53])=[N:42][N:43]([CH2:46][C:47]([N:35]2[CH2:36][CH2:37][N:32]([C:28]3[CH:27]=[C:26]([CH3:25])[CH:31]=[CH:30][CH:29]=3)[CH:33]([CH3:38])[CH2:34]2)=[O:48])[C:44]=1[CH3:45]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: Cc1cccc(N2CCNCC2C)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1cccc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2C)c1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(3-Methylphenyl)-2-methyl-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.68 (br, 1H), 7.17 (br, 1H), 6.71 (br, 2H), 5.41 (m, 2H), 4.08 (m, 4H), 3.70 (m, 2H), 3.50 (br m, 2H), 2.30 (s, 3H), 2.18 (s, 3H), 1.01 (m, 3H) ppm; MS (ES) M+H expected=415.1, found=415.1.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[N:15]=[C:14]([NH2:16])[CH:13]=[C:12]([Cl:17])[N:11]=1>CO.O>[NH2:9][C:10]1[N:15]=[C:14]([NH2:16])[C:13]([Cl:1])=[C:12]([Cl:17])[N:11]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CO
Product: Nc1nc(N)c(Cl)c(Cl)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
50 g of N-chlorosuccinimide are added in portions at 23° C. to a solution of 45 g of 2,4-diamino-6-chloropyrimidine in methanol (1030 ml). On completion of addition, the reaction mixture is stirred at room temperature for 3 hours. The methanol is evaporated under reduced pressure and the crude product obtained is taken up under reflux in 850 ml of water for 1 hour. After filtering, the crude product is recrystallized two times from an EtOH:H2O (80:20) mixture to give 44.5 g of 2,4-diamino-5,6-dichloropyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH2:26]([CH:33]1[CH2:37][CH2:36][CH2:35][NH:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[CH2:26]([CH:33]1[CH2:37][CH2:36][CH2:35][N:34]1[C:4]([C:3]1[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])=[CH:10][C:2]=1[Cl:1])=[O:5])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: c1ccc(CC2CCCN2)cc1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCCC2Cc2ccccc2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-benzylpyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.79 minutes; C28H26C12N4O2 (521.45); mass spectrum: (M−H)−=520/522/524 (chlorine isotope).
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=S)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.O>C(OCCO)C>[N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[N:10]=[C:11]([NH:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NCc1cccnc1
Reactant: S=C1Nc2ccccc2Nc2ncccc21
Solvent: O
Solvent: CCOCCO
Product: c1cncc(CNC2=Nc3ccccc3Nc3ncccc32)c1
Yield: 52.8 %

Procedure:
A solution of 0.5 g (2.2 mmol) of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-thione [(European Published Patent Application EP-393,604); C.A. 114, 143455] in 10 mL 2-ethoxyethanol was treated with 0.24 mL (10.8 mmol) of 3-(aminomethyl)pyridine and heated at reflux for 2 days. The mixture was poured into H2O and extracted with EtOAc. The EtOAc was washed three times with H2O, then saturated NaHCO3 solution and saturated NaCl solution. Drying over MgSO4 and removal of the solvent under reduced pressure left the crude product. Chromatography on silica gel, eluting with a gradient of CH2Cl2 /hexane (90/10) to CH2Cl2 /MeOH (94/6) gave 0.35 g (53% yield) of the product as a yellow solid, mp 192-194° C. The structure was confirmed by NMR and mass spectroscopy. (m+H)+ =302.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH:10](=O)C1C=CC=CC=1.O>C1(C)C=CC=CC=1>[CH3:10][NH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1
Reactant: NC1CN2CCC1CC2
Reactant: O=Cc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CNC1CN2CCC1CC2
Temperature: 0 °C

Procedure:
A mixture of 50 g of 3-amino quinuclidine and 40 ml of benzaldehyde in 1000 ml of toluene is brought to reflux for 45 minutes, while eliminating the water formed. Then the solvent is evaporated, the residue is dissolved in 800 ml of methanol and 15 g of potassium borohydride are added within 3 hours while maintaining the temperature at 0° C. Then the solvent is evaporated, the residue is taken up in water, the mixture obtained is extracted with ethyl acetate (or with chloroform), dried on sodium (or magnesium) sulfate, filtered and the filtrate is evaporated. Thus 85 g (yield ≃100%) of the pure expected product are obtained (one spot in TLC) which is in liquid form.