Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][CH:8]=[CH:7][N:6]=2.O.[Se](=O)=[O:15].C([O-])(O)=O.[Na+]>O1CCOCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]=[O:15])=[CH:9][CH:8]=[CH:7][N:6]=2
Reactant: Cc1c(Cl)cnc2ncccc12
Reactant: O=[Se]=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: O=Cc1c(Cl)cnc2ncccc12
Temperature: 110 °C
Yield: 31.1 %

Procedure:
3-Chloro4-methyl-[1,8]naphthyridine (3.0 g, 16.7 mmol) from Step 3 was dissolved in 4:1 dioxane:water (30 mL) and selenium dioxide (5.9 g, 50.4 mmol) was added. The reaction mixture was heated (110° C.) for 2.5 h, cooled to RT, poured into satd. aq. NaHCO3 (30 mL) and water (10 mL). The mixture was subsequently treated with DCM (80 mL) and the solids filtered off through Celite and rinsing the filter cake with DCM. After separating the aqueous and organic layers, the aqueous phase was re-extracted with DCM (4×80 mL) and the combined organics were dried (Na2SO4) and concentrated. The crude product was chromatographed by SGC (MeCN eluant) to yield the title compound 3-chloro-[1,8]naphthyridine-4-carbaldehyde (1.0 g, 5.2 mmol). Note: owing to weak UV activity, it was found more efficacious to monitor column fractions with MS rather than UV, as in Step 3. MS (ESI+) for m/z 193 (M+H)+. 1H NMR(CDCl3)δ 10.79 (s, 1H), 9.28 (dd, 1H), 9.17 (s, 1H), 9.14 (dd, 1H), 7.63(dd. 1H).
Reaction SMILES: CC(CCCCCOC(C1C(C(OCCCCCC(C)C)=O)=CC=CC=1)=O)C.[CH2:29]=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(#N)C.[CH:40]#[N:41].CC#N>CCCCCCC.CCOCC.[Zn]>[C:31]1([CH:30]([CH3:29])[C:40]#[N:41])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C#N
Reactant: C=Cc1ccccc1
Agent: CC(C)CCCCCOC(=O)c1ccccc1C(=O)OCCCCCC(C)C
Agent: [Zn]
Solvent: CCCCCCC
Solvent: CC#N
Solvent: CCOCC
Product: CC(C#N)c1ccccc1
Reaction time: 5 h

Procedure:
A mixture of 1.5 g (+) Diop (2,3-0-Isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane, Aldrich Chemical Co.), 300 mg NiI2, 300 mg zinc dust, 2 ml commercial stabilized styrene, and 2 ml acetonitrile was stirred at 80° for 5 hr. then 250 μl HCN/CH3CN (11N) was added overnight by syringe pump. After addition of 2 ml styrene, 1 ml CH3CN and ca. 100 mg zinc dust another 400 μl HCN/CH3CN was added during eight hours. After addition of 4 ml styrene and 100 mg zinc addition of HCN/CH3CN at 50 μl/hr was continued overnight. The mixture was then diluted with 50 ml heptane and 25 ml ether. The mixture was filtered and the filtrate was concentrated to an oil which was diluted with an equal volume of toluene. The VPC analysis indicated that the two isomeric products PhCH(CN)CH3 and PhCH2CH2CN had been formed in approximately equal amounts. The PhCH(CN)CH3 was isolated by preparative VPC as described above to give 120 mg [α]25D +1.1° C5.5% in CD3CN. An e.e. of about 10% is estimated based on the reported [α]25D value of 10° for the pure isomer. The 1H nmr spectrum was as expected for PhCH(CN)CH3. The major product was apparently styrene polymer which hampered the isolation of the nitrile products.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:24]N1C(=O)CCC1=O.O.[OH-].[Na+]>C(O)(=O)C.C(Cl)Cl>[Br:24][C:12]1[C:13]2[C:18](=[CH:17][C:16]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=2)[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc2ccc(OS(C)(=O)=O)cc12
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(Br)c2ccc(OS(C)(=O)=O)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of the product from Step B, (2.05 g, 6.08 mmol) in acetic acid (50 mL) was added N-bromosuccinimide (1.14 g, 6.38 mmol) in one portion. The reaction mixture was stirred at ambient temperature for 2 hrs, then H2O (100 mL) and CH2Cl2 (100 mL) were added and the resulting mixture was cooled to 0° C. The aqueous layer was adjusted to pH of about 7 by addition of 10 N aqueous NaOH and the organic layer was extracted. The aqueous phase was extracted with a further portion of CH2Cl2 (100 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was triturated with 1:1 hexane-EtOAc to provide the titled product as a grey solid.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].ClOC(C)(C)C.[CH3:23][S:24][CH2:25][C:26](OCC)=[O:27].C(N(CC)CC)C>C(Cl)Cl>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]([C:3]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:2]=2[NH:1][C:26](=[O:27])[CH:25]3[S:24][CH3:23])=[O:5])=[CH:7][CH:8]=1
Reactant: CCOC(=O)CSC
Reactant: Nc1ccccc1C(=O)c1ccc(Cl)cc1
Agent: CC(C)(C)OCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSC1C(=O)Nc2c(C(=O)c3ccc(Cl)cc3)cccc21
Temperature: -65 °C
Reaction time: 0.25 h
Yield: 33 %

Procedure:
A solution of 23.1 g. (0.1 mole) of 2-amino-4'-chlorobenzophenone in 400 ml. of methylene chloride was cooled to -65°C. and treated dropwise with 12.4 g. (0.1 mole) of t-butyl hypochlorite. After 15 min., 13.4 g. of ethyl α-(methylthio)acetate (0.1 mole) was added dropwise maintaining -65°C. temperature. After 11/2 hr. 10.1 g. of triethylamine (0.1 mole) was added and the reaction mixture allowed to come to room temperature. The solution was then washed with water and stripped. The residue was taken into methanol and brought to reflux at which time lN hydrochloric acid was added and the resulting mixture refluxed overnight. The mixture was cooled, resulting precipitate filtered off and recrystallized from toluene, giving 10 g. of a cream colored solid. The product (33% yield) melted at 186°-188°C.
Reaction SMILES: [CH2:1]([C:8]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:27])[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[C:16]([N:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:19][CH2:20][CH3:21])[N:15]=[C:14](Cl)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36](=[O:39])([O-])[O-:37].[Na+].[Na+]>C(O)CCC.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl>[C:31]([O:30][C:29]([NH:28][C:8]([CH3:27])([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[C:16]([N:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:19][CH2:20][CH3:21])[N:15]=[C:14]([C:36]([O:37][CH2:8][CH2:1][CH2:2][CH3:3])=[O:39])[CH:13]=1)=[O:35])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCCN(c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(Cl)n1)S(C)(=O)=O
Reactant: O=C([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Na+]
Solvent: N#Cc1ccccc1
Solvent: CCCCO
Product: CCCCOC(=O)c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(N(CCC)S(C)(=O)=O)n1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A suspension of tert-butyl [1-benzyl-2-({2-chloro-6-[(methylsulfonyl)(propyl)amino]pyridin-4-yl}methoxy)-1-methylethyl]carbamate (115 mg, 0.22 mmol, intermediate VI), sodium carbonate (70 mg, 0.66 mmol), PdCl2(PhCN)2 (2 mg, 0.004 mmol), 4A sieves and 1-[2-(dicyclohexylphasphanyl)ferrocenyl]ethyldicyclohexylphosphane (11 mg, 0.017 mmol, STREM) in n-butanol (2 ml, degassed with Argon), was purged with CO and stirred at 100° C. for 16 h under 1 atm of CO. The reaction mixture was diluted with dichloromethane, washed with water and brine, dried over sodium sulfate, concentrated in vacuo, azeothroped with toluene, and purified by flash chromatography (silica, 0-35% EtOAc/hexanes) to provide butyl 4-({2-[(tert-butoxycarbonyl)amino]-2-methyl-3-phenylpropoxy}methyl)-6-[(methylsulfonyl)(propyl)amino]pyridine-2-carboxylate as a yellow oil which was dissolved in 1:1 THF:MeOH (1.6 mL) and treated with aq LiOH (0.38 mL, 0.38 mmol, 1N) for 2 h at rt. The reaction mixture was acidified to pH 3-4 with 1N HCl, extracted with dichloromethane, dried over sodium sulfate, concentrated in vacuo, azeothroped with toluene to give 4-({2-[(tert-butoxycarbonyl)amino]-2-methyl-3-phenylpropoxy}methyl)-6-[(methylsulfonyl)(propyl)amino]pyridine-2-carboxylic acid as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.71 (s, 1H), 7.34-7.13 (m, 5H), 4.67 (s, 2H), 4.49 (s, 1H), 3.93 (t, J=7.6 Hz, 2H), 3.72 (A of AB, d, J=9.2 Hz, 1H), 3.62 (B of AB, d, J=9.2 Hz, 1H), 3.17 (A of AB, d, J=13.6 Hz, 1H), 3.05 (s, 3H), 2.90 (13 of AB, d, J=13.6 Hz, 1H), 1.70-1.55 (m, 2H), 1.46 (s, 9H), 1.27 (s, 3H), 0.96 (t, J=7.6 Hz, 3H).
Reaction SMILES: Br[CH:2]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=2)[N:18]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=O.O1[C:29]2([CH2:34][CH2:33][CH:32]([C:35](=[S:37])[NH2:36])[CH2:31][CH2:30]2)[O:28]CC1.CC(C)=O.Cl>CN(C=O)C>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3]1[N:36]=[C:35]([CH:32]2[CH2:33][CH2:34][C:29](=[O:28])[CH2:30][CH2:31]2)[S:37][C:2]=1[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=2)[N:18]=1
Reactant: CC(C)c1nnc2ccc(C(Br)C(=O)c3ccc(F)cc3F)nn12
Reactant: NC(=S)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1nnc2ccc(-c3sc(C4CCC(=O)CC4)nc3-c3ccc(F)cc3F)nn12
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.5 %

Procedure:
The 2-bromo-1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.622 g, 1.57 mmol, Preparation #A.2) and 1,4-dioxaspiro[4.5]decane-8-carbothioamide (0.317 g, 1.57 mmol) were dissolved in DMF (5 mL) then stirred at ambient temperature for about 12 h. The mixture was concentrated under reduced pressure then acetone (25 mL) and concentrated hydrochloric acid (2 μL, 10 mmol) were added. The mixture was heated to about 60° C. for about 1.5 h then concentrated under reduced pressure, basified with 50% NaOH and diluted with water. The mixture was extracted with ethyl acetate then organic solution was dried over MgSO4, filtered and concentrated under reduced pressure. The material was purified by flash chromatography on silica gel using DCM/MeOH (95:5) as an eluent to give the title compound (0.495 g, 69%): LC/MS (Table 1, Method b) Rt=2.14 min; MS m/z: 454.2 (M+H)+.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54]C(OC(C)(C)C)=O)[S:52][CH:53]=4)=[N:28]\[O:29]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:64][S:65][C:66]2[N:67]=[N:68][N:69](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:70]=2)=[S:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.Cl.O>[NH2:54][C:51]1[S:52][CH:53]=[C:49](/[C:27](=[N:28]/[OH:29])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:63])[N:22]3[C:17]([C:15]([OH:14])=[S:16])=[C:18]([CH2:64][S:65][C:66]4[N:67]=[N:68][NH:69][CH:70]=4)[CH2:19][S:20][C@H:21]23)=[O:62])[N:50]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=S)OC(c4ccccc4)c4ccccc4)=C(CSc4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nn4)CS[C@H]23)cs1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Solvent: COc1ccccc1
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(O)=S)=C(CSc4c[nH]nn4)CS[C@H]23)cs1
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(1-trityl-1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester (29 g: 22.9 mMol.) in a mixture of anisole (50 ml) and nitromethane (200 ml) is added dropwise a solution of aluminum chloride (20.7 g: 156 mMol.) in anisole (50 ml) at -30° to -40° C., and the mixture is stirred for 1 hour at the same temperature. The reaction mixture is diluted with 1N-hydrochloric acid (200 ml) and water, and washed with ethyl acetate. The aqueous layer is concentrated to remove organic solvent under reduced pressure and passed through a column of styrene-divinylbenzene copolymer adsorbent. The product is eluted with aqueous methanol (4:1) to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid (8.07 g) as pale yellow powder. Yield: 68%.
Reaction SMILES: CO[C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[CH3:12][C:13]1[C:14]([CH2:18][S:19][CH2:20][CH2:21][NH2:22])=[N:15][O:16][N:17]=1.[CH3:23][NH2:24]>>[CH3:12][C:13]1[C:14]([CH2:18][S:19][CH2:20][CH2:21][NH:22][C:3]2[C:7]([NH:24][CH3:23])=[N:6][S:5](=[O:11])(=[O:10])[N:4]=2)=[N:15][O:16][N:17]=1
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: CN
Reactant: Cc1nonc1CSCCN
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1nonc1C

Procedure:
When a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide is successively treated with an equimolar amount of 2-[(4-methyl-1,2,5-oxadiazol-3-yl)methylthio]ethylamine [prepared in Step B] and excess methylamine by the general procedure of Example 2, the title compound is thereby produced.
Reaction SMILES: C(O[C:4]1[C:7](=[O:8])[C:6](=[O:9])[C:5]=1[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][N:19]2[CH2:23][C@H:22]3[C:24]4[CH:25]=[C:26]([C:32]#[N:33])[CH:27]=[CH:28][C:29]=4[O:30][CH2:31][C@@H:21]3[CH2:20]2)[CH2:13][CH2:12]1)C.[NH3:34].[ClH:35]>C(O)C.C(#N)C>[ClH:35].[NH2:34][C:4]1[C:7](=[O:8])[C:6](=[O:9])[C:5]=1[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][N:19]2[CH2:23][C@H:22]3[C:24]4[CH:25]=[C:26]([C:32]#[N:33])[CH:27]=[CH:28][C:29]=4[O:30][CH2:31][C@@H:21]3[CH2:20]2)[CH2:13][CH2:12]1
Reactant: N
Reactant: CCOc1c(N[C@H]2CC[C@H](CCN3C[C@H]4COc5ccc(C#N)cc5[C@@H]4C3)CC2)c(=O)c1=O
Agent: Cl
Solvent: CCO
Solvent: CC#N
Product: N#Cc1ccc2c(c1)[C@@H]1CN(CC[C@H]3CC[C@H](Nc4c(N)c(=O)c4=O)CC3)C[C@H]1CO2

Procedure:
A solution of 1.17 g of the compound obtained in Step A of Example 20 (2.61 mmol) in 13 ml of ethanol is treated with 13 ml of a saturated solution of ammonia in acetonitrile for 16 hours. The solid obtained is filtered off and then washed with ethyl acetate to finally yield, after converting to a salt in ethanol in the warm state using 1N ethereal HCl, the title product.
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[C:13]1([C:11]2[N:2]=[C:3]3[CH2:8][CH2:7][CH2:6][CH2:5][N:4]3[CH:10]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: N=C1CCCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(-c2cn3c(n2)CCCC3)cc1
Temperature: 25 °C
Yield: 71 %

Procedure:
Combine 2-iminopiperidine hydrochloride (4.9 g, 36.4 mmol, 3 equiv) and 2-bromoacetophenone (2.4 g, 12.1 mmol) with Na2CO3 (5.1 g, 48.4 mmol) in dry DMF (15 mL) and heat the mixture at 80° C. for 16 hours. Then, cool the mixture to room temperature, add water (200 mL), and extract with ether (3×100 mL). Wash the combined organic layers with water (2×50 mL), and re-extract the aqueous layer with ether (2×50 mL). Wash the combined organic layers with saturated aqueous sodium chloride (100 mL), dry (MgSO4), and concentrate in vacuo. Purify the residue by flash chromatography (SiO2; eluent: CH2Cl2 to CH2Cl2:MeOH 50:1) to obtain a brown solid, 1.7 g, 71% yield. MS(ES+): m/z=199.1 (M+H)+
Reaction SMILES: [NH:1]1[CH:5]([C:6]([O:8][CH3:9])=[O:7])[CH2:4][CH2:3][C:2]1=[O:10].C(N(CC)CC)C.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)(=O)C>[C:18]1([NH:24][C:25]([N:1]2[CH:5]([C:6]([O:8][CH3:9])=[O:7])[CH2:4][CH2:3][C:2]2=[O:10])=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)C1CCC(=O)N1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C1CCC(=O)N1C(=O)Nc1ccccc1
Reaction time: 8 h
Yield: 66.8 %

Procedure:
In this example, 14.3 g of methyl 2-pyrolidone-5-carboxylate and 10.1 g triethylamine are dissolved in 100 ml of ethyl acetate. Phenyl isocyanate (11.9 g) is added thereto, and the resulting solution is left standing at room temperature overnight. The reaction mixture is then filtered, and the filtrate is washed twice with 100 ml of 1N hydrochloric acid, and then three times with 100 ml water. Then, the filtrate is dried over anhydrous sodium sulfate, and then filtered. The filtrate is concentrated under reduced pressure, and the resulting viscous material is dissolved in 100 ml ether, admixed with 100 ml n-hexane, and recrystallized, whereby methyl 1-phenylcarbamoyl-2-pyrolidone-5-carboxylate (compound number 4; 17.5 g; mp 91°-92° C.) is obtained. Yield: 66.8%.
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=3)[N:11]([CH2:19][C:20]([OH:22])=[O:21])[C:10]=2[CH3:23])=[CH:6][CH:5]=1)(O)=[O:2].[CH2:26]([NH2:28])[CH3:27].[CH2:29]1COCC1>>[CH2:26]([NH:28][C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=3)[N:11]([CH2:19][C:20]([O:22][CH3:29])=[O:21])[C:10]=2[CH3:23])=[CH:24][CH:25]=1)=[O:2])[CH3:27]
Reactant: C1CCOC1
Reactant: Cc1c(Oc2ccc(C(=O)O)cc2)c2cc(F)ccc2n1CC(=O)O
Reactant: CCN
Product: CCNC(=O)c1ccc(Oc2c(C)n(CC(=O)OC)c3ccc(F)cc23)cc1

Procedure:
The sub-title compound was prepared by the method of Example 10, step a) using the product from Example 9 and ethylamine in THF.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[O:3]1.[Br:17]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(#N)C>[Br:17][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[B:4]1[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC#N
Product: CC1(C)OB(c2ccccc2CBr)OC1(C)C
Temperature: 25 °C

Procedure:
A mixture of 32.3 g (148 mmol) of 4,4,5,5-tetramethyl-2-(2-methylphenyl)-1,3,2-dioxaborolane, 25.0 g (141 mmol) of N-bromosuccinimide, and 0.32 g (2.62 mmol) of AIBN was refluxed in 1000 ml of acetonitrile for 2 h. The mixture was then cooled to room temperature and then evaporated to dryness. The residue was dissolved in 500 ml of hexane. The formed precipitate was filtered on glass frit (G3), and the filtrate was evaporated to dryness to give yellowish crystalline powder. Yield 28.9 g (66%). Anal. calc. for C13H18BBrO2: C, 52.57; H, 6.11. Found: C, 52.63; H, 6.29. 1H NMR (CDCl3): 7.81 (m, 1H, 6-H), 7.37-7.42 (m, 2H, 3, 5-H), 7.28 (m, 1H, 4-H), 4.91 (s, 2H, CH2Br), 1.37 (s, 1H, Bpin).
Reaction SMILES: C([S:14][C:15]1[N:16]=[N:17][N:18]([CH2:20][C:21]#[CH:22])[N:19]=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:20]([N:18]1[N:17]=[N:16][C:15]([SH:14])=[N:19]1)[C:21]#[CH:22]
Reactant: C#CCn1nnc(SC(c2ccccc2)c2ccccc2)n1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C#CCn1nnc(S)n1
Temperature: 50 °C
Reaction time: 1.7 h
Yield: 62.5 %

Procedure:
A mixture of 5-benzhydrylthio-2-(2-propynyl)-2H-tetrazole (1.05 g), anisole (1.79 g) and trifluoroacetic acid (9.7 ml) was stirred at 22° C. for 1.5 hours, at 35° C. for an hour, at 50° C. for 1.7 hours and then at room temperature for a further 14 hours. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. To the residue was added a saturated aqueous solution of sodium bicarbonate (10 ml) and the mixture was adjusted to pH 8.5 with 2N aqueous solution of sodium hydroxide. The aqueous layer was separated, washed with ethyl acetate (20 ml×2) and thereto was added ethyl acetate. The resulting mixture was adjusted to pH 2.5 with 10% hydrochloric acid. The ethyl acetate layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then evaporated to give an oil of 2-(2-propynyl)-2H-tetrazole-5-thiol (0.3 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:15](Cl)(=[O:17])[CH3:16]>C1COCC1>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:15](=[O:17])[CH3:16])[CH2:4][CH2:3]1
Reactant: CC(=O)Cl
Reactant: OC1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxypiperidine (5.00 g, 49.4 mmol) in anhydrous THF (30 mL) and triethylamine (10 mL, 75 mmol) was added acetyl chloride (3.52 mL, 49.4 mmol). After the addition, the mixture was stirred for another 2 hours at room temperature. The solid formed was filtered and the mother liquid was concentrated to yield 5.0 g of crude product, which was purified by column chromatography on silica gel (230-400 mesh), using 5% methanol in dichloromethane as eluent, to give 1-(4-hydroxy-piperidin-1-yl)-ethanone. Yield: 2.40 g (34%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C:4](=O)[CH2:5]Cl.[N+:9]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21](=[S:23])[NH2:22])=[CH:17]2)([O-:11])=[O:10]>>[CH3:1][O:2][C:3]([C:4]1[N:22]=[C:21]([C:18]2[NH:19][C:20]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N+:9]([O-:11])=[O:10])[S:23][CH:5]=1)=[O:8]
Reactant: NC(=S)c1cc2cccc([N+](=O)[O-])c2[nH]1
Reactant: COC(=O)C(=O)CCl
Product: COC(=O)c1csc(-c2cc3cccc([N+](=O)[O-])c3[nH]2)n1

Procedure:
3-Chloro-2-oxo-propionic acid methyl ester and 7-nitro-1H-indole-2-carbothioic acid amide prepared in Step A of Preparation 110 were reacted according to the same procedure as Preparation 110 to give the title compound.
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][N:4]1[C:13]([CH3:15])([CH3:14])[CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][C:5]1([CH3:17])[CH3:16].[C:19]([OH:28])(=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25].[C:29]([O:32][CH2:33][CH3:34])(=[O:31])[CH3:30]>C1(C)C(C)=CC=CC=1>[OH:1][CH:2]([CH2:3][N:4]1[C:5]([CH3:16])([CH3:17])[CH2:6][C:7]2([O:8][CH2:9][CH2:10][O:11]2)[CH2:12][C:13]1([CH3:14])[CH3:15])[CH2:18][O:25][C:24](=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][C:19]([O:28][CH2:18][CH:2]([OH:1])[CH2:3][N:4]1[C:5]([CH3:17])([CH3:16])[CH2:6][C:29]2([O:31][CH2:34][CH2:33][O:32]2)[CH2:30][C:13]1([CH3:14])[CH3:12])=[O:27]
Reactant: CCOC(C)=O
Reactant: O=C(O)CCCCC(=O)O
Reactant: CC1(C)CC2(CC(C)(C)N1CC1CO1)OCCO2
Solvent: Cc1ccccc1C
Product: CC1(C)CC2(CC(C)(C)N1CC(O)COC(=O)CCCCC(=O)OCC(O)CN1C(C)(C)CC3(CC1(C)C)OCCO3)OCCO2

Procedure:
A mixture of 10 g of 8-(2,3-epoxypropyl)-7,7,9,9-tetramethyl-1,4-dioxa-8-azaspiro[4.5]decane and 2.4 g of adipic acid in 60 ml of xylene was refluxed for 16 hours. After completion of the reaction, the residue obtained by evaporating the solvent under reduced pressure from the reaction mixture was purified by column chromatography through silica gel eluted with a 1:1 by volume mixture of ethyl acetate and benzene. The desired Compound No. 208 was obtained in the form of a pale yellow, viscous product. The compound had an Rf value of 0.53 on thin-layer chromatography on silica gel developed with ethyl acetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21]Br)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([CH2:26][NH2:27])[CH:24]=C.[CH3:28]N(C=O)C>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][N:27]([CH2:26][CH:23]=[CH2:24])[CH3:28])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(OCCCCBr)ccc21
Reactant: C=CCCN
Reactant: CN(C)C=O
Product: C=CCN(C)CCCCOc1ccc2c(c1)CCN2C(=O)OC(C)(C)C
Yield: 85 %

Procedure:
8.8 g (24 mmol) 5-(4-Bromo-butoxy)-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester in 10 ml DMF were treated with 7.11 g (100 mmol) N-allylmethylamine at 50° C. for 4 h. The solution was concentrated in vacuo and the residue was redissolved in ether and water. 2M NaOH was added and the inorganic phase was extracted with ether. The combined organic phases were washed with water, dried over Na2SO4 and evaporated. Column chromatography with a gradient of CH2Cl2/MeOH 19:1 to 9:1 yielded 7.4 g (85%) 5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester as colorless oil, MS: 361 (MH+).