Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14]([Li])CCC.S(OC)(OC)(=O)=O.[Cl-].[NH4+]>C1COCC1>[CH3:14][C:4]1[C:5]2[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=[CH:2][CH:3]=1
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)oc1ccccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Product: Cc1cccc2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.2 %

Procedure:
Dibenzofuran (26.94 g, 160 mmol) was dissolved in dry THF (500 ml) and cooled to -78° C. n-Butyl lithium (1.6M in hexane, 200 ml, 320 mmol) was added in portions over 30 mins. and the solution was allowed to warm to room temperature over 2.5 hours. The solution was recooled to -70° C. and a mixture of dimethyl sulphate (32 ml, 340 mmol) in dry THF (100 ml) was added dropwise. Once the addition was complete, the reaction was allowed to warm to room temperature, stirred for 18 hours and poured onto saturated ammonium chloride solution (400 ml). The phases were separated and the aqueous extracted twice with ether. The combined organic phases were dried (MgSO4) and evaporated in vacuo. Chromatography on silica (eluting with 40-60 petrol) gave the pure product as a clear oil (29.2 g, 100%) δH [2H6 ]-DMSO 8.1 (1H, d), 7.9 (1H, d), 7.7 (1H, d),7.5 (1H, t), 7.4 (1H, t), 7.25 (2H, m), 2.55 (3H, s).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[C:27]([N:30]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[CH3:31])(=[O:29])[CH3:28].[OH-].[Na+]>CN(C=O)C.CO>[C:27]([N:30]([C:32]1[CH:38]=[CH:37][C:35]([NH:36]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:34][CH:33]=1)[CH3:31])(=[O:29])[CH3:28]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CC(=O)N(C)c1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)N(C)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(N-acetyl-N-methyl-amino)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[CH3:14][N:15]([CH3:32])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]3[N:24]([N:28]=[C:29]([NH2:31])[N:30]=3)[CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1>>[CH3:14][N:15]([CH3:32])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]3[N:24]([N:28]=[C:29]([NH:31][CH:10]4[CH2:11][CH2:12][N:7]([C:5]5[S:4][N:3]=[C:2]([CH3:1])[N:6]=5)[CH2:8][CH2:9]4)[N:30]=3)[CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Reactant: CN(C)c1ccc(-c2cccn3nc(N)nc23)cc1
Product: Cc1nsc(N2CCC(Nc3nc4c(-c5ccc(N(C)C)cc5)cccn4n3)CC2)n1

Procedure:
Prepared in analogy to example 1h employing 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (see example 1c) and 8-(4-dimethylamino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (prepared in analogy to example 66a-c). The title compound was obtained as white foam. MS ISP (m/e): 435.3 (100) [(M+H)+].
Reaction SMILES: [N:1]1([CH2:6][C:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[O:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:26][C:27]1[N:28]=[C:29]([CH:32]=[CH:33][C:34]2[CH:39]=[CH:38][C:37]([S:40][C:41]([F:44])([F:43])[F:42])=[CH:36][CH:35]=2)[O:30][CH:31]=1.[I-].[K+]>CC(=O)CC>[F:44][C:41]([S:40][C:37]1[CH:38]=[CH:39][C:34](/[CH:33]=[CH:32]/[C:29]2[O:30][CH:31]=[C:27]([CH2:26][O:18][C:15]3[CH:16]=[CH:17][C:12]([C:9]4[O:10][CH:11]=[C:7]([CH2:6][N:1]5[CH:5]=[CH:4][N:3]=[CH:2]5)[N:8]=4)=[CH:13][CH:14]=3)[N:28]=2)=[CH:35][CH:36]=1)([F:42])[F:43]
Reactant: FC(F)(F)Sc1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: Oc1ccc(-c2nc(Cn3ccnc3)co2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCC(C)=O
Product: FC(F)(F)Sc1ccc(/C=C/c2nc(COc3ccc(-c4nc(Cn5ccnc5)co4)cc3)co2)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
A mixture of 0.121 g (0.50 mmol) 4-(4-imidazol-1-ylmethyl-oxazol-2-yl)-phenol and 0.10 g (0.30 mmol) cesium carbonate in 10 ml butanone was stirred at 60° C. for 30 min, then 0.160 g (0.50 mmol) 4-chloromethyl-2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-oxazole and 0.083 g (0.50 mmol) potassium iodide were added and stirring at 60° C. continued over night. After evaporation, 15 ml water was added and the mixture extracted with two portions of 15 ml ethyl acetate. The combined organic layers were washed with 1N sodium hydroxide and water, dried over sodium sulfate and evaporated to give 110 mg (42%) of the title compound as light brown crystals melting at 144-145° C. (from 2-propanol).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH3:11][CH:12]([CH3:30])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:22][CH:23]=1)=[O:17]>>[CH3:11][CH:12]([CH3:30])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=3)=[O:10])[CH2:26][CH2:25]2)=[CH:22][CH:23]=1)=[O:17]
Reactant: O=C(O)c1cccc(Cl)n1
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3cccc(Cl)n3)CC2)nn1

Procedure:
Following the procedure of Example 14, making variations only as required to use 6-chloropyridine-2-carboxylic acid in place of 4,4,4-trifluoro-2-methylbutyric acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white flaky solid (12% yield). 1H NMR (300 MHz, CDCl3) δ 8.05, 7.87, 7.82, 7.70, 7.43, 7.00, 3.80-4.00, 3.50, 1.70, 1.53, 0.95. MS (ES+) m/z 417 (M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[N:8])[N:6]=1.[I:9]N1C(=O)CCC1=O>C(#N)C>[I:9][C:4]1[NH:3][C:2]([CH3:1])=[N:6][C:5]=1[C:7]#[N:8]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1nc(C#N)c[nH]1
Solvent: CC#N
Product: Cc1nc(C#N)c(I)[nH]1
Temperature: 25 °C
Yield: 54.8 %

Procedure:
Into a 25-mL round-bottom flask, was placed a mixture of 2-methyl-1H-imidazole-4-carbonitrile (compound 16.3, 50 mg, 0.47 mmol), N-iodosuccinimide (116 mg, 0.52 mmol) in ACN (5 mL). The resulting solution was heated at reflux overnight, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/2) to yield 60 mg (55%) of the title compound as a light yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][CH:5]=[C:4]([OH:8])[CH:3]=1.[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>>[N:9]1([C:2]2[N:7]=[N:6][CH:5]=[C:4]([OH:8])[CH:3]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Oc1cnnc(Cl)c1
Reactant: C1CCNC1
Product: Oc1cnnc(N2CCCC2)c1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
In a 5 mL microwave vial, 6-chloro-4-pyridazinol (D46) (76 mg, 0.582 mmol) was dissolved in pyrrolidine (1 ml, 12.09 mmol). The reaction mixture was stirred for 30 min at 130° C. in a microwave. The reaction mixture was loaded onto the MDAP for purification (acidic conditions). The desired product recovered was triturated with DCM (1×3 mL) to afford the title compound (65 mg). LCMS (A): m/z (M+H)+ 166, C8H11N3O requires 165 (acidic).
Reaction SMILES: [N:1]1([C:16]([O:18][CH:19]2[CH:26]3[CH2:27][CH:22]4[CH2:23][CH:24]([CH2:28][CH:20]2[CH2:21]4)[CH2:25]3)=[O:17])[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][NH:8][CH2:7]2)[CH2:3][CH2:2]1.[CH:29]([S:32](Cl)(=[O:34])=[O:33])([CH3:31])[CH3:30]>>[CH:29]([S:32]([N:8]1[CH2:7][C:4]2([CH2:5][CH2:6][N:1]([C:16]([O:18][CH:19]3[CH:20]4[CH2:28][CH:24]5[CH2:23][CH:22]([CH2:27][CH:26]3[CH2:25]5)[CH2:21]4)=[O:17])[CH2:2][CH2:3]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)(=[O:34])=[O:33])([CH3:31])[CH3:30]
Reactant: O=C(OC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CNCc1ccccc12
Reactant: CC(C)S(=O)(=O)Cl
Product: CC(C)S(=O)(=O)N1Cc2ccccc2C2(CCN(C(=O)OC3C4CC5CC(C4)CC3C5)CC2)C1

Procedure:
The title compound was prepared from 2-adamantyl 2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate following a procedure analogous to that described in Example 34 using isopropylsulfonyl chloride in place of methanesulfonyl chloride. LC-MS Method 1 tR=2.31 min, m/z=487; 1H NMR (CDCl3) δ=7.36 (d, 1H), 7.26 (t, 1H), 7.20 (t, 1H), 7.05 (d, 1H), 4.88 (s, 1H), 4.56 (br s, 2H), 4.18 (d, 2H), 4.35 (m, 1H), 2.99 (m, 4H), 1.42 (d, 6H).
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:8]([C:9]([CH3:12])=[CH:10][CH:11]=1)=[N:7][C:6](=[O:13])[C:5]([CH3:15])([CH3:14])[CH:4]=2.[CH2:16](I)[CH:17]=[CH2:18].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.CCCCCC>[CH2:18]([O:1][C:2]1[C:3]2[C:8]([C:9]([CH3:12])=[CH:10][CH:11]=1)=[N:7][C:6](=[O:13])[C:5]([CH3:15])([CH3:14])[CH:4]=2)[CH:17]=[CH2:16]
Reactant: Cc1ccc(O)c2c1=NC(=O)C(C)(C)C=2
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: C=CCOc1ccc(C)c2c1=CC(C)(C)C(=O)N=2
Yield: 92.6 %

Procedure:
Using 5-hydroxy-3,3,8-trimethylcarbostyril (2.0 g, 9.77 mmol), allyl iodide (1.72 g, 10.2 mmol), and potassium carbonate (3 g, 21.7 mmol), the procedure of Reference Example 41 was followed (reaction, post-treatment, and recrystallization from chloroform-n-hexane). 2.2 g of the title compound was obtained as colorless flakes (92.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[SH:26][CH2:27][CH2:28][CH2:29][OH:30]>>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][S:26][CH2:27][CH2:28][CH2:29][OH:30])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCCl)ccc1Cl
Reactant: OCCCS
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCSCCCO)ccc1Cl

Procedure:
Prepared according to the method of Example 10 using 2-chloro-5-(2-chloroethoxy)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 11a, 0.34 g) and 3-mercaptopropan-1-ol (0.25 ml) to give the title compound (0.4 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:37](O)=[O:38])=[N:11][C:12]([N:19]([CH3:36])[S:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])(=[O:22])=[O:21])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:74][CH2:75][C:76]1[CH:86]=[CH:85][C:84]([F:87])=[CH:83][C:77]=1[C:78]([O:80][CH2:81][CH3:82])=[O:79]>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([C:37]([NH:74][CH2:75][C:76]2[CH:86]=[CH:85][C:84]([F:87])=[CH:83][C:77]=2[C:78]([O:80][CH2:81][CH3:82])=[O:79])=[O:38])=[N:11][C:12]([N:19]([CH3:36])[S:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])(=[O:21])=[O:22])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(F)ccc1CN
Reactant: CN(c1nc(C(=O)O)c(OCc2ccccc2)c2ncccc12)S(=O)(=O)CCCCCNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(F)ccc1CNC(=O)c1nc(N(C)S(=O)(=O)CCCCCNC(=O)OC(C)(C)C)c2cccnc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71 %

Procedure:
To a solution of 8-(benzyloxy)-5-(5-(tert-butoxycarbonylamino)-N-methylpentylsulfonamido)-1,6-naphthyridine-7-carboxylic acid (Example 2.4; 3.82 mmol) in dichloro methane (38 ml) were added HBTU (4.58 mmol) and DIPEA (15.8 mmol). The mixture was stirred for 5 min at rt. Ethyl 2-(aminomethyl)-5-fluorobenzoate hydrochloride (Example 4; 4.58 mmol) was added portionwise at rt. The mixture was stirred overnight at rt. The product was extracted with CH2Cl2, dried over MgSO4 and concentrated. The crude product was purified by SiO2 column chromatography (AcOEt:Hex, 1:1) to afford the target compound in 71% yield.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH2:18][CH2:19][CH3:20])[N:12]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[N:38]([CH2:39][O:40][CH3:41])[N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=1)[C:11]2=[O:42])(=O)C.C1COCC1.[OH-].[Na+].Cl>CO>[OH:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH2:18][CH2:19][CH3:20])[N:12]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[N:38]([CH2:39][O:40][CH3:41])[N:37]=[N:36][N:35]=3)=[CH:26][CH:27]=1)[C:11]2=[O:42]
Reactant: CCCc1nc2ccc(OCCOC(C)=O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2COC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1nc2ccc(OCCO)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2COC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6-(2-acetoxyethyloxy)-3-[[2'-(N-methoxymethyltetrazol-5-yl)biphenyl-4-yl]methyl]-2-propyl-4(3H)-quinazolinone (0.42 g) in a mixture of methanol (3 ml), THF (2 ml) and 1N aqueous sodium hydroxide (1.5 ml) was stirred at room temperature for 1 hour. After addition of 1N hydrochloric acid (1.5 ml), the reaction mixture was extracted with ethyl acetate and the extract was washed with water, dried and evaporated to dryness. The residue was purified by column chromatography on silica gel to give a white powder.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[CH2:8][CH2:9][N:10]1[C:14](=[O:15])[N:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:12]=[N:11]1.[CH3:35][C@H:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[NH2:37]>CN1CCCC1=O>[OH:34][C:31]1[CH:32]=[CH:33][C:28]([N:25]2[CH2:26][CH2:27][N:22]([C:19]3[CH:20]=[CH:21][C:16]([N:13]4[CH:12]=[N:11][N:10]([CH2:9][CH2:8][NH:37][C@@H:36]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH3:35])[C:14]4=[O:15])=[CH:17][CH:18]=3)[CH2:23][CH2:24]2)=[CH:29][CH:30]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=c1n(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)cnn1CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: C[C@@H](NCCn1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O)c1ccccc1
Temperature: 60 °C
Yield: 75.7 %

Procedure:
Reaction under N2 atmosphere. Na2CO3 (0.01 mol) was added to a mixture of 2-(2-bromoethyl)-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-3H -1,2,4-triazol-3-one (0.0054 mol) in 1-methyl-2-pyrrolidinone (25 ml). This mixture was stirred at 60° C. A solution of (+)-(R)-α-methylbenzenemethanamine (0.0065 mol) in 1-methyl-2-pyrrolidinone (25 ml) was added dropwise and the resulting reaction mixture was stirred overnight at 60° C. The reaction mixture was cooled, poured out into ice-water and the resulting precipitate was filtered off, washed with water, then dried. This fraction was recrystallized from 2-propanol, filtered off and dried, yielding 1.98 g (77%)of (R)-2,4-dihydro4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-[2-[(1-phenylethyl)amino]ethyl]-3H-1,2,4-Triazol-3-one (interm. 19).
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:11]([CH:13]=[N+]=[N-])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[ClH:23]>O1CCCC1>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:11]([CH2:13][Cl:23])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)C=[N+]=[N-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)CCl

Procedure:
Boc-TyrCHN2 (1.81 g, 5.92 mmol) was dissolved in 30 mL of tetrahydrofuran, and the resulting solution wwas treated with 3.45N ethanolic:HCl (1.72 mL, 5.92 mmol) for 5 minutes at 0°. Solvent was removed by evaporation on a rotary evaporator without temperature regulation. The remaining residue was dissolved in ethyl acetate, and the resulting solution was washed with 0.2N hydrochloric acid followed by saturated aqueous sodium chloride. The washed solution was dried over sodium sulfate, and then solvent was evaporated to yield crystalline Boc-TyrCH2Cl. Crystals were isolated and washed with cold ether to yield 0.45 g (m.p. 110°-112°) in a first crop, and 0.90 g (m.p. 110°-112°) in a second crop. NMR spectra in CDCl3 corresponded to that expected, except that methylene protons of --COCH2Cl appears as a doublet at δ4.1.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][CH3:8])=[N:5][N:6]=1.[C:9]([NH:12][C:13]1[CH:22]=[CH:21][C:16]([S:17](Cl)(=[O:19])=[O:18])=[CH:15][CH:14]=1)(=[O:11])[CH3:10].Cl>N1C=CC=CC=1>[CH2:7]([C:4]1[S:3][C:2]([NH:1][S:17]([C:16]2[CH:15]=[CH:14][C:13]([NH:12][C:9](=[O:11])[CH3:10])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[N:6][N:5]=1)[CH3:8]
Reactant: CCc1nnc(N)s1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCc1nnc(NS(=O)(=O)c2ccc(NC(C)=O)cc2)s1
Temperature: 95 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
2-Amino-5-ethyl-1,3,4-thiadiazole (250 mg, 1.93 mmol) was suspended in pyridine (0.5 mL). N-Acetylsulfanilyl chloride (361 mg, 1.54 mmol) was added slowly at 0° C. The reaction mixture was then heated to 95° C. and was stirred for 1 h. The reaction mixture was then added to aqueous 3N HCl and the mixture extracted with ethyl acetate. The organic extracts were washed with water (3×20 mL), brine (3×20 mL), dried over anhydrous Na2SO4, filtered, and volatiles evaporated. The residue was crystallized from MeOH to give the product (350 mg, 1.07 mmol, 70%) as a solid, mp 197-198° C.; 1H NMR (500 MHz, DMSO) δ 1.28 (3, t, J=7.0 Hz), 2.07 (3, s), 2.82 (2, q, J=7.0 Hz), 7.72 (4, s), 10.32 (1, s), 13.91 (1, s); 13C NMR (125 MHz, DMSO) δ 12.2, 23.7, 24.1, 48.6, 118.5, 126.9, 135.6, 142.7, 159.8, 167.3, 168.9; MS (LCQ, ESI+) Calculated for C12H15N4O3S2 327.1. found 327.1 (M+H)+; HRMS (FAB+, m/z) Calculated for C12H15N4O3S2 327.0586. found 327.0585 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[CH:21]=1)=[O:4].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:30])=[CH:10][N:9]2[CH:21]=1)=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)Nc1cn2cc(Sc3ccccc3)ccc2n1
Solvent: ClCCl
Product: COC(=O)Nc1cn2cc(S(=O)c3ccccc3)ccc2n1

Procedure:
Alternatively, 0.599 g. (0.002 mole) of the product of Example 3 is combined with 0.406 g. (0.002 moles) of metachloroperbenzoic acid (85%) in 300 ml. of methylene chloride and stirred at room temperature overnight. The solution is washed with saturated aqueous sodium bicarbonate and evaporated to dryness affording 0.75 g. of crude product which is recrystallized from methylene chloride affording 2-(methoxycarbonylamino) 6-(phenylsulfinyl) imidazo [1,2-a] pyridine m.p. 247°-248° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][CH3:12])=[CH:9][C:4]=2[N:3]=[CH:2]1.C(C1C2C(=CC=CC=2)C=CC=1CN)CC.Cl.[O:29]=[C:30]1[NH:39][C:38]2[N:37]=[CH:36][C:35](/[CH:40]=[CH:41]/[C:42]([OH:44])=O)=[CH:34][C:33]=2[CH2:32][CH2:31]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]([CH3:12])[C:42](=[O:44])/[CH:41]=[CH:40]/[C:35]3[CH:36]=[N:37][C:38]4[NH:39][C:30](=[O:29])[CH2:31][CH2:32][C:33]=4[CH:34]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CNCc1ccc2[nH]cnc2c1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCCc1c(CN)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: CN(Cc1ccc2[nH]cnc2c1)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Yield: 37 %

Procedure:
According to the procedure of Example 1 (a), except substituting ((1H-benzo[d]imidazol-5-yl)-N-methylmethanamine) for the methyl-(1-propyl-naphthalen-2-ylmethylamine, and substituting (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride. Purification by preparative HPLC (water/acetonitrile/0.05% TFA mixture) gave the title compound ((E)-N-((1H-benzo[d]imidazol-5-yl)methyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide) (143 mg, 37%) as a white solid and a mixture of amide rotomers: 1H NMR (400 MHz, DMSO-d6) δ 10.60 (m, 1H), 8.36 (m, 1H), 8.21 (s, 1H), 8.07 (s, 1H), 7.59-7.21 (m, 4H), 7.12-7.08 (m, 1H), 4.91-4.72 (m, 2H), 3.10-2.86 (m, 5H), 2.55-2.49 (m, 2H); ESI MS m/z 362 [C20H19N5O2+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([CH2:13]N2CCCCC2O)[C:10](=[O:12])[CH3:11])[CH2:4][CH2:3]1.C(O)(C(O)=O)=O>C(O)C>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9](=[CH2:13])[C:10](=[O:12])[CH3:11])[CH2:4][CH2:3]1
Reactant: CC(=O)C(CN1CCC(O)CC1)CN1CCCCC1O
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: C=C(CN1CCC(O)CC1)C(C)=O
Reaction time: 0.08 h

Procedure:
3-[(4-Hydroxypiperidino)methyl]-4-(hydroxypiperidino)butan-2-one (1 g.) was dissolved in 8 ml. of ethyl alcohol and added to a cooled solution of oxalic acid anhydrous (0.9 g.) in 5 ml. of ethyl alcohol. After standing at 0° C. for five minutes, the resultant precipitate was filtered. The filtrate was stripped of solvent under reduced pressure and the residual oil taken up in a small volume of water, saturated with potassium carbonate and then extracted with ether. The ether solution was dried over anhydrous sodium sulphate, filtered and the filtrate stripped of ether. The residual oil, approx. 0.1 g., was characterized including a proton nuclear magnetic resonance spectrum in deuterated dimethylsulfoxide. There were two vinylic protons, at 5.9 and 6.1 ppm downfield from the reference tetramethylsilane.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[C:12](=[O:27])[C:13]([N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)=[CH:14][C:15]1([CH3:21])[CH2:20][CH2:19][CH:18]=[CH:17][CH2:16]1.[BH4-].[Na+].Cl>CO.CC(C)=O.O>[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[CH:12]([OH:27])[C:13]([N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)=[CH:14][C:15]1([CH3:21])[CH2:20][CH2:19][CH:18]=[CH:17][CH2:16]1
Reactant: CC1(C=C(C(=O)c2ccc(Cl)cc2Cl)n2ccnc2)CC=CCC1
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: O
Solvent: CC(C)=O
Solvent: CO
Product: CC1(C=C(C(O)c2ccc(Cl)cc2Cl)n2ccnc2)CC=CCC1
Temperature: -20 °C
Yield: 85.9 %

Procedure:
3.05 g (0.025 mole) of calcium chloride were added to 18.1 g (0.05 mole) of 1-(2,4-dichlorophenyl)-2-(imidazol-1-yl)-3-(methylcyclohex-3-en-1-yl)-2-propen-1-one in 100 ml of methanol, and the mixture was cooled to -20° C. 1.9 g (0.05 mole) of sodium borohydride were added in portions, and, when the addition had ended, the mixture was warmed to -10° C. Thereafter, an acetone/water mixture was added dropwise and the reaction mixture was allowed to warm to room temperature. It was adjusted to a pH value of 5 with dilute hydrochloric acid and concentrated. The residue was taken up in a mixture of methylene chloride/water and the organic phase was separated off, dried over sodium sulphate, filtered and concentrated. 15.6 g (85.7% of theory) of 1-(2,4-dichlorophenyl)-2-(imidazol-1-yl)-3-(methyl-cyclohex-3-en-1-yl)-2-propen-1-ol were obtained as an amorphous powder.