Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]([C:9]([O:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[N:7]2[C:25](=[O:36])[C@@H:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C@H:6]2[S:5][CH:4]=1)=[O:2].[CH:37]([Mg]Cl)=[CH2:38].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>C(OCC)(=O)C.O.O1CCCC1>[OH:2][CH:1]([C:3]1[CH:8]([C:9]([O:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[N:7]2[C:25](=[O:36])[C@@H:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C@H:6]2[S:5][CH:4]=1)[CH:37]=[CH2:38]
Reactant: O=CC1=CS[C@@H]2[C@H](NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: C=C[Mg]Cl
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC(O)C1=CS[C@@H]2[C@H](NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
This example illustrates step 1 of the process of the invention. In this example 2.5 g. of benzhydryl 3-formyl-7β-(thiophen-2-yl-acetamido)-ceph-2-em-4-carboxylate in 50 ml. of anhydrous tetrahydrofuran is stirred under nitrogen at -70° C and 10 ml. of a 2.5 molar solution of vinyl magnesium chloride is added dropwise over five minutes. After 15 minutes, 50 ml. of pH 7 buffer solution of dibasic sodium phosphate and monobasic potassium phosphate is added to the well stirred mixture, which is then warmed to room temperature. The mixture is diluted with 200 ml. of water and layered with 200 ml. of ethyl acetate. The pH of the aqueous layer is adjusted to pH 4 by the addition of 20% aqueous hydrochloric acid. The ethyl acetate layer is separated and the aqueous layer extracted with 100 ml. ethyl acetate. The ethyl acetate extracts are combined and then washed twice with 50 ml. portions of brine, dried over sodium sulfate and evaporated under reduced pressure affording benzhydryl 3-(1-hydroxyprop-2-enyl)-7β-(thiophen-2-yl-acetamido)-ceph-2-em-4-carboxylate as a pale yellow oil (2.7 g.).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH:10]([CH3:14])[C:11]([OH:13])=[O:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:15]CCCC>C1COCC1>[CH3:15][N:8]([C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12]
Reactant: CC(CNC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCCC
Solvent: C1CCOC1
Product: C[C@H](CN(C)C(=O)OC(C)(C)C)C(=O)O
Reaction time: 8 h

Procedure:
To a solution of N-Boc-α-(R,S)-methyl-β-alanine (1.33 g, 6.5 mmol) in THF (80ml) was added pentane washed sodium hydride (1.2 g, 60% in oil dispersion) followed by methyl iodide (2 ml, exess). The reaction mixture was stirred overnight and then poured into an iced solution of citric acid (0.5N). The aqueous THF solution was extracted into ethyl acetate. Then the required acid was back extracted between ethyl acetate, sodium hydrogen carbonate and potassium hydrogen sulphate solutions. The organic extracts were dried (MgSO4) and evaporated to afford the title compound. (1.00 g, 71%), Anal: C10H19NO4.0.3H2O, Calc: C, 53.94; H, 8.87; N, 6.29. Found, C, 54.02; H, 8.56; N, 6.63.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1)(=O)=O.C([Li])CCC.[F:38][C:39]1[CH:40]=[C:41]([OH:46])[CH:42]=[CH:43][C:44]=1[F:45]>>[F:38][C:39]1[CH:40]=[C:41]([CH:42]=[CH:43][C:44]=1[F:45])[O:46][C:5]1[N:10]=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1
Reactant: Oc1ccc(F)c(F)c1
Reactant: CS(=O)(=O)c1nc(OC2CCCCC2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: [Li]CCCC
Product: Fc1ccc(Oc2nc(OC3CCCCC3)c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)n2)cc1F

Procedure:
2-(Methylsulfonyl)-4-(cyclohexyloxy)-5-(4-chlorophenyl)-6-(2,4-dichloro-phenyl)pyrimidine (Lower Rf product) (Example 52, Step A), (26 mg, 0.05 mmol) was reacted with 1 equivalent each of n-butyl lithium and 3,4-difluorophenol by the procedure described in Reference Examples 6 and 7. Workup and flash column chromatography on silica gel (eluted with 95/5 hexanes/ethyl acetate) afforded title compound. HPLC/MS: m/e=563 (M++1); Rt=5.25 min. 1H-NMR 500 MHz (CDCl3): 1.28-1.40 (m, 4H), 1.55 (m, 3H), 1.65 (m, 2H), 1.90 (m, 2H), 5.03 (m, J=4 Hz, 1H), 7.05 (m, 4H), 7.10 (m, 5H), 7.34 (d, J=2 Hz, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.C[O:9][C:10](=[O:35])[C@H:11]([CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)[NH:12][C:13](=[O:24])[CH:14]([CH2:19][S:20]C(=O)C)[CH2:15][CH2:16][CH2:17][NH2:18].[OH-].[Na+].[H][H]>CO>[NH2:18][CH2:17][CH2:16][CH2:15][CH:14]([CH2:19][SH:20])[C:13]([NH:12][C@H:11]([C:10]([OH:35])=[O:9])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:24]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C(CCCN)CSC(C)=O
Reactant: [H][H]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: NCCCC(CS)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
To a solution of N-(2-acetylthiomethyl-5-aminopentanoyl)-L-tryptophane methyl ester trifluoroacetate (3 g) in methanol (60 ml) N sodium hydroxide (60 ml) is added. After 4 hours the solution is applied to a column of Dowex 50 ion exchange resin in the hydrogen cycle. After washing with water, the N-(5-amino-2-mercaptomethylpentanoyl)-L-tryptophane is eluted with pyridine-acetic acid buffer at pH 6.5.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1>CN(C)C=O.ClCCl.O>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:1][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)[C:6]#[N:7]
Reactant: COc1cc(C#N)ccc1O
Reactant: COc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(COc2ccc(C#N)cc2OC)cc1
Reaction time: 0.25 h

Procedure:
3.73 g 4-Hydroxy-3-methoxybenzonitrile was dissolved in dimethylformamide and 3.8 g potassium carbonate was added before the mixture was stirred for 15 min. 5 g para-Methoxybenzylbromide was added and stirring was continued for 1 h. The mixture was diluted with dichloromethane and water. The phases were separated and the water phase extracted again with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated.
Reaction SMILES: Cl[C:2]1[S:28][C:5]2[NH:6][C:7](=[O:27])[C:8](C3C=CC=C(C(=O)C4C=CC(OC)=CC=4)C=3)=[C:9](O)[C:4]=2[C:3]=1C.Cl.N1C=CC=CC=1>>[S:28]1[C:5]2[NH:6][C:7](=[O:27])[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: COc1ccc(C(=O)c2cccc(-c3c(O)c4c(C)c(Cl)sc4[nH]c3=O)c2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=c1ccc2ccsc2[nH]1
Reaction time: 3 h

Procedure:
A mixture of 4.25 g of 2-chloro-3-methyl-4-hydroxy-5-(3-p-methoxybenzoylphenyl)-6,7-dihydrothieno [2,3-b]pyridin-6-one and 3.5 g of pyridine hydrochloride is stirred at 160° for 3 hours. 2-Chloro-3-methyl-4-hydroxy-5-3-p-hydroxybenzoylphenyl)-6,7-dihydrothieno [2,3-b]pyridin-6-one is obtained after the customary working-up.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([OH:32])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(O[N:41]1[N:49]=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.NN.C1COCC1>CN(C=O)C.C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([NH:41][NH2:49])=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)COc1ccc(Cl)cc1[C@@H]1c2ccccc2CCN1C(=O)OCc1ccccc1
Agent: F[B-](F)(F)F
Agent: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NNC(=O)COc1ccc(Cl)cc1[C@@H]1c2ccccc2CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (S)-1-(2-carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (165 mg, 0.36 mmol, 1.0 eq.) in DMF (0.9 mL), TBTU (138 mg, 0.43 mmol, 1.2 eq.) and DIPEA (0.19 mL, 1.08 mmol, 3.0 eq.) were added in sequence. The resulting reaction mixture was stirred at r.t. for 15 min. Then 1M hydrazine in anhydrous THF (1.99 mL, 1.99 mmol, 5.6 eq.) was added at 0° C. (exothermic). The resulting mixture was stirred at r.t. for 18 hours. The reaction mixture was diluted with DCM and then washed with sat. aq. NaHCO3 soln. The aq. phase was extracted once with DCM. The comb. org. phases were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, basic conditions) and evaporated to give the desired product as a brown foam.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19](Br)[CH:18]=3)([OH:16])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][N:25](C=O)C>[C-]#N.[Zn+2].[C-]#N>[CH2:1]([N:8]1[CH2:14][CH:13]2[C:15]([C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[C:24]#[N:25])([OH:16])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: OC1(c2cccc(Br)c2)C2CCC1CN(Cc1ccccc1)C2
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cccc(C2(O)C3CCC2CN(Cc2ccccc2)C3)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-Benzyl-8-(3-bromo-phenyl)-3-aza-bicyclo[3.2.1]octan-8-ol (2.17 g, 5.83 mmol) and zinc cyanide (1.03 g, 8.75 mmol) were combined in DMF (30 mL), degassed (evac/N2 purge 3×) then charged with tetrakistriphenylphosphine palladium (0) (3.37 g, 2.91 mmol). The resulting reaction mixture was heated to 85 □ C. in an oil bath for 5 h (or until complete by TLC). After cooling to room temperature, the reaction mixture was filtered through a Celite pad and rinsed with EtOAc. The filtrate was extracted with 1 N HCl (2×50 mL) then neutralized to pH 8 with 1 N NaOH and saturated aqueous NaHCO3 solution, causing an emulsion to form. The product was extracted with EtOAc (3×100 mL), washed with saturated aqueous NaCl solution (2×100 mL), dried over Na2SO4, filtered and concentrated. The resulting crude product was dissolved in ether (100 mL), washed with 50% saturated aqueous NaCl solution (4×100 mL), dried over Na2SO4, filtered and concentrated to a brown oil (1.86 g, 100%). (TLC 40% EtOAc/Hexanes Rf 0.42); 1H NMR (400 MHz, CDCl3) δ 7.76–7.72 (m, 2H), 7.55 (br d, J=7.9 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.36–7.20 (m, 5H), 3.59 (br s, 2H), 2.84 (d, J=10.8 Hz, 2H), 2.61 (br d, J=10.8 Hz, 2H), 2.36 (br, s, 2H), 1.83 (d, J=7.5 Hz, 2H), 1.35 (m, 2H); APCI MS m/z 319.2 (M+1)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([N:15]([CH2:22][C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[C:25]#[N:26])[CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Cl-].[NH4+].[N-:33]=[N+:34]=[N-:35].[Na+]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([N:15]([CH2:22][C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[C:25]3[NH:35][N:34]=[N:33][N:26]=3)[CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[S:13][CH:14]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(-c2csc(N(Cc3cccs3)Cc3ccccc3C#N)n2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: CC(C)c1ccc(-c2csc(N(Cc3cccs3)Cc3ccccc3-c3nnn[nH]3)n2)cc1
Yield: 4.1 %

Procedure:
[4-(4-Isopropyl-phenyl)-thiazol-2-yl]-[2-(1H-tetrazol-5-yl)-benzyl]-thiophen-2-ylmethyl-amine (6.0 mg) was prepared following general procedure H from the corresponding nitrile (130 mg, 0.31 mmol), ammonium chloride (3.1 mmol) and sodium azide (3.1 mmol). Purification (Silica gel, methanol/DCM 3:97) provided the product. LCMS m/z: 474 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:51]Br>C(#N)C>[CH3:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][Br:51]
Reactant: BrBr
Reactant: Cc1cccc(CO)c1[N+](=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Cc1cccc(CBr)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
A round bottomed flask was charged with 5.0 g (0.029 mol) of 3-methyl-2-nitrobenzyl alcohol and 100 mL of anhydrous acetonitrile. The reaction solution was cooled to 0° C. and treated, portionwise, with 13.2 g (0.031 mol) triphenylphosphine perbromide (Ph3P—Br2). The reaction was allowed to warm to rt overnight at which point the solvent was removed and the resulting solids triturated with 50:50 ether:hexanes. The wash solvent was filtered through a fine frit and then concentrated to give a quantitative yield (7.03 g) of the desired material as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.36–7.34 (m, 2H), 7.33–7.24 (m, 1H), 4.45 (s, 2H), 2.33 (s, 3H).
Reaction SMILES: [C:1]1([C:7]([C:9]2[S:13][C:12]([NH:14]C(=O)OC(C)(C)C)=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C>[NH2:14][C:12]1[S:13][C:9]([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:8])=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)c2ccccc2)s1
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)c2ccccc2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl [5-(phenylcarbonyl) thien-2-yl]carbamate (0.30 g, 0.99 mmol) is dissolved in 5 ml of trifluoroacetic acetic acid and the solution is stirred at room temperature for 2 hours. The trifluoroacetic acid is distilled off and the residue is partitioned between semisaturated sodium hydrogen carbonate solution and dichloromethane. The phases are separated and the aqueous phase is subjected to extraction with dichloromethane. The combined organic phases are dried over potassium carbonate and filtered and the solvent is distilled off.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[NH:10][C:9]3[CH2:12][CH2:13][NH:14][CH2:15][C:8]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1.[SiH](CC)(CC)CC>C(O)(C(F)(F)F)=O>[CH3:2][C:3]1[C:11]2[NH:10][C@@H:9]3[CH2:12][CH2:13][NH:14][CH2:15][C@@H:8]3[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cccc2c3c([nH]c12)CCNC3
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc2c1N[C@@H]1CCNC[C@H]21
Temperature: 0 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
6-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (36.6 g, 141.2 mmol) was suspended in TFA (200 mL). The mixture was cooled to 0° C. Et3SiH (32.86 g, 282.6 mmol) was added slowly. The reaction was stirred at rt for 18 h. Add hexane (2×300 mL), separate the acid layer, then basified with 50% NaOH until pH=14. Extract reaction with CHCl3 (3×300 mL). The combined organic layers were washed with brine, dried, and concentrated to afford a light brown amorphous solid cis-6-methyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (20.7 g, 110.1 mmol, 78%). 1H NMR (CDCl3, 300 MHz) δ 6.90 (1H, d, 7.3 Hz), 6.82 (1H, d, 7.4 Hz), 6.62 (1H, t, 7.3 Hz), 3.77–3.82 (1H, m), 2.65–3.08 (5H, m), 2.13 (3H, s), 1.72–1.92 (2H, m) ppm.
Reaction SMILES: C(OC([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[CH3:21])[CH:8]([O:22]C(OCC)=O)[CH2:7]1)=O)C.[ClH:28]>>[ClH:28].[ClH:28].[OH:22][CH:8]1[C:9]2=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]([CH3:21])=[C:18]2[CH2:19][CH2:20][NH:6][CH2:7]1
Reactant: CCOC(=O)OC1CN(C(=O)OCC)CCc2c1nc1ccccc1c2C
Agent: Cl
Product: Cc1c2c(nc3ccccc13)C(O)CNCC2
Yield: 68 %

Procedure:
1,2,4,5-Tetrahydro-5-hydroxy-11-methyl-3H-azepino[4,5-b]quinoline dihydrochloride was prepared from 5-(ethoxycarbonyloxy)-1,2,4,5-tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester by hydrolysis with 2 N hydrochloric acid for 36 hours at the boiling point. After distilling off the hydrochloric acid, the remaining water was removed by entrainment with benzene, and the raw salt was recrystallized from methanol.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]([CH:30]4[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]4)=[O:29])[CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].C(OCC)(=O)C.Cl.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]([CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[O:29])[CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NC2CCN(C(=O)C3CCN(C(=O)OC(C)(C)C)CC3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NC2CCN(C(=O)C3CCNCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
A solution of 4-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-ylmethyl)phenylamino]-1-[1-(tert-butoxycarbonyl)piperidin-4-ylcarbonyl]piperidine (0.311 g, 0.54 mmol) obtained in Step 1 in chloroform (5.0 mL) was added with a 4 mol/L hydrogen chloride-ethyl acetate solution (2.0 mL) followed by stirring at room temperature for 1 hour. The reaction mixture was added with a 2 mol/L aqueous sodium hydroxide solution to control the pH to 12 and extracted with chloroform three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were added with diisopropyl ether followed by stirring under reflux for 1 hour. The crystals were collected by filtration and dried under reduced pressure to obtain Compound 147 (0.153 g, 0.32 mmol, 60%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.Br[CH2:11][CH2:12][O:13][C:14](=[O:16])[CH3:15]>CN(C=O)C>[CH2:12]([O:13][C:14](=[O:16])[CH2:15][O:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)[CH3:11]
Reactant: Oc1ccncc1
Reactant: CC(=O)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccncc1
Reaction time: 0.17 h
Yield: 9.4 %

Procedure:
To a slurry of sodium hydride, 1.73 g (43.2 mmol) in 100 mL of DMF was added 3.4 g (36.0 mmol) of 4-hydroxypyridine. The mixture was stirred 10 minutes then added to a solution of 3.3 mL (30.0 mmol) of bromoethylacetate in 100 mL DMF. The reaction mixture was stirred 72 hours at rt. then concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and water and washed with saturated aqueous NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by radial chromatography using MeOH/chloroform as eluent and concentrated to dryness to yield 510 mg (9.4%) of the desired product as a tan oil. 1H—NMR is consistent with structure. MS (ion spray) 182.1 (M+).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([CH2:8][NH:9][C:10]2[C:15]([NH:16][C:17]([NH:19][CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]3)=S)=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1)[CH3:2]>[Hg]=O.C(O)C>[CH2:1]([C:3]1[O:7][C:6]([CH2:8][N:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[N:16]=[C:17]2[NH:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)N1CCC(NC(=S)Nc2cccnc2NCc2ccc(CC)o2)CC1
Agent: O=[Hg]
Solvent: CCO
Product: CCOC(=O)N1CCC(Nc2nc3cccnc3n2Cc2ccc(CC)o2)CC1
Reaction time: 1 h
Yield: 83.1 %

Procedure:
A mixture of 50 parts of ethyl 4-[[[[2-[[(5-ethyl-2-furanyl)methyl]amino]-3-pyridinyl]amino]thioxomethyl]amino]-1-piperidinecarboxylate, 32.4 parts of mercury(II) oxide and 480 parts of ethanol was stirred for 1 hours at reflux temperature. The reaction mixture was filtered over diatomaceous earth and the filtrate wax evaporated. The residue was stirred in 1,1'-oxybisethane. The crystallized product was filtered off and dried, yielding 38 parts (83.1%) of ethyl 4-[[3-[(5-ethyl-2-furanyl)methyl]-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidinecaroxylate; mp. 111.1° C. (int. 14). In a similar manner there was also prepared:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][N:12]=[N:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][F:23]>C(#N)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[N:13]([CH2:21][CH2:22][F:23])[N:12]=[N:11][N:10]=1
Reactant: FCCBr
Reactant: Clc1cccc(-c2nnn[nH]2)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FCCn1nnnc1-c1cccc(Cl)c1Cl
Reaction time: 0.25 h
Yield: 65.9 %

Procedure:
To 100 mL of acetonitrile was added 5 g of 5-(2,3-dichlorophenyl)-1H-tetrazole (Lancester Synthesis Inc., Windham, N.H.) followed by 2.5 g of potassium carbonate. After stirring for 15 min, 5 g of 1-bromo-2-fluoroethane was added dropwise. After the addition, the resulting mixture was then heated to reflux for 3 hours and then filtered. The solvent was then evaporated under reduced pressure leaving 4 g of 5-(2,3-dichlorophenyl)-1-(2-fluoroethyl)-1H-tetrazole as an oil.
Reaction SMILES: [NH3:1].[C:2]1([C:7]([C:9]2[CH:19]=[CH:18][C:12]([CH:13]([CH3:17])[C:14](Cl)=[O:15])=[CH:11][CH:10]=2)=[O:8])[S:6][CH:5]=[CH:4][CH:3]=1>CCOCC>[C:2]1([C:7]([C:9]2[CH:19]=[CH:18][C:12]([CH:13]([CH3:17])[C:14]([NH2:1])=[O:15])=[CH:11][CH:10]=2)=[O:8])[S:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C(=O)Cl)c1ccc(C(=O)c2cccs2)cc1
Reactant: N
Solvent: CCOCC
Product: CC(C(N)=O)c1ccc(C(=O)c2cccs2)cc1

Procedure:
Gaseous ammonia is introduced through a solution of 5.8 parts of p-(2-thenoyl)hydratropoyl chloride in 80 parts of ether: the product is precipitated as an oil. The solvent is decanted and the oil is stirred twice in petroleumether. The solvent is decanted each time. The oily residue is dissolved in 2-propanol and the solvent is evaporated. The residue is dissolved in ether and upon the addition of petroleumether, the product is precipitated. It is filtered off and purified by column-chromatography over silicagel, using a mixture of chloroform, methanol and acetone (8 : 1 : 1 by volume). The pure fractions are collected and the solvent is evaporated. The oily residue is triturated in ether. The solid product is filtered off and dried, yielding p-(2-thenoyl)hydratropamide; mp. 108° -124° C.
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:8]=1)[CH3:5])([OH:3])=O.[C:19](N1C=CN=C1)([N:21]1C=CN=C1)=O.CN>>[Cl:18][C:14]1[CH:13]=[C:12]([N:9]2[CH:10]=[N:11][C:7]([O:6][CH:4]([C:1]([NH:21][CH3:19])=[O:3])[CH3:5])=[N:8]2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(Oc1ncn(-c2cccc(Cl)c2)n1)C(=O)O
Agent: CN
Product: CNC(=O)C(C)Oc1ncn(-c2cccc(Cl)c2)n1
Yield: 73.1 %

Procedure:
The process was carried out as was Example 45, starting with 3 g of the compound of Example 25, 2.7 g of carbonyldiimidazole, and 3 ml of 40% aqueous methylamine. The product was recrystallized from toluene to obtain 2.3 g of the desired product, m.p. 120°-122°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:17]3[CH:18]=[C:19]([C:22]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([F:34])[CH:26]=4)=[O:23])[CH:20]=[CH:21][C:16]=3[O:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:35][C:36]1C=C(S(Cl)(=O)=O)C=C(C)C=1>>[CH2:35]([O:30][C:29](=[O:31])[C:28]1[CH:32]=[CH:33][C:25]([NH:24][C:22]([C:19]2[CH:20]=[CH:21][C:16]3[O:15][CH2:14][CH2:13][N:12]([S:9]([C:4]4[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=4)(=[O:11])=[O:10])[C:17]=3[CH:18]=2)=[O:23])=[CH:26][C:27]=1[F:34])[CH3:36]
Reactant: Cc1cc(C)cc(S(=O)(=O)Cl)c1
Reactant: Cc1cc(C)cc(S(=O)(=O)N2CCOc3ccc(C(=O)Nc4ccc(C(=O)O)c(F)c4)cc32)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(C)cc(C)c2)CCO3)cc1F

Procedure:
4-{[4-(3,5-Dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoic acid, MS (ISP): m/e=483.3 (M−H), was prepared as described for example 21, steps 1 to 8. Step 7 was performed using 3,5-dimethyl-benzenesulfonyl chloride and yielded 4-{[4-(3,5-dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 8.