Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:34])=[C:6]([C@:8]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])(=[O:24])=[O:23])([CH3:20])[CH2:9][O:10][C@@:11]([CH3:19])([C:15]([F:18])([F:17])[F:16])[C:12]([NH2:14])=O)[CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:34])=[C:6]([C@:8]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])(=[O:23])=[O:24])([CH3:20])[CH2:9][O:10][C@@:11]([C:12]#[N:14])([CH3:19])[C:15]([F:17])([F:18])[F:16])[CH:7]=1
Reactant: C[C@@](CO[C@](C)(C(N)=O)C(F)(F)F)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C[C@](C#N)(OC[C@](C)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ccc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-2-[(R)-2-(5-bromo-2-fluoro-pheyl)-2-(2-nitro-benzenesulfonylamino)-propoxy]-3,3,3-trifluoro-2-methyl-propionamide (20.83 g, 35.6 mmol) in CH2Cl2 (300 ml) was added under argon NEt3 (12.5 ml, 89 mmol) and at 0-5° C. trifluoroacetic anhydride (6.15 ml, 42.7 mmol). After stirring for 4 h at 25° C. the reaction mixture was added to a cold NaHCO3 solution and the product was extracted with CH2Cl2. Combined extracts were washed with cold 0.1 N aqueous HCl, water and saturated NaHCO3 solution, dried over MgSO4, filtered and concentrated to provide the title compound as a yellow oil, which was used as such for the next step: TLC (hexane-EtOAc 1:1): Rf=0.73; HPLC RtH5=1.364 min; ESIMS: 571, 573 [(M+NH4)+]; 1H NMR (360 MHz, CDCl3): δ 7.89 (d, 1H), 7.62 (ddd, 1H), 7.57 (ddd, 1H), 7.52 (m, 2H), 7.29 (m, 1H), 6.58 (dd, 1H), 6.19 (s, 1H), 4.17 (s, 2H), 1.81 (s, 3H), 1.72 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH:10]3[CH2:19][CH2:18][CH2:17][CH:16]4[C:11]3([CH2:12][CH2:13][N:14](C)[CH2:15]4)[C:7]=2[CH:6]=[CH:5][CH:4]=1.N#CBr.[OH-].[K+]>C(Cl)Cl.C(O)CO>[CH3:1][O:2][C:3]1[C:8]2[O:9][CH:10]3[CH2:19][CH2:18][CH2:17][CH:16]4[C:11]3([CH2:12][CH2:13][NH:14][CH2:15]4)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1OC1CCCC3CN(C)CCC231
Agent: N#CBr
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: OCCO
Product: COc1cccc2c1OC1CCCC3CNCCC231

Procedure:
Thus, 9-methoxy-3-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-benzo[4,5]furo[3,2-e]isoquinoline (Example 2d) is heated to reflux with cyanogen bromide in methylene chloride and the crude product is then heated with potassium hydroxide in ethylene glycol to 170° to give 9-methoxy-2,3,4,4a,5,6,7,7a-octahydro-1H-benzo[4,5]furo[3,2-e]isoquinoline (R1 =H; R2 =OMe; R3, R4, R5 =H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[CH2:6]2.[CH2:21]([C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1)[CH3:22].Cl>C(#N)C>[O:20]=[C:14]1[CH:13]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][NH:1][C:30]([NH:29][C:26]4[CH:27]=[CH:28][C:23]([CH2:21][CH3:22])=[CH:24][CH:25]=4)=[O:31])[CH:4]=3)[C:8]2=[O:12])[CH2:18][CH2:17][C:16](=[O:19])[NH:15]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: CCc1ccc(N=C=O)cc1
Agent: Cl
Solvent: CC#N
Product: CCc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
TEA (0.3 ml, 2.2 mmol) was added to a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.32 g, 0.85 mmol) and 1-ethyl-4-isocyanato-benzene (0.14 ml, 1 mmol) in acetonitrile (20 mL) under nitrogen. The mixture was stirred at ambient temperature for 1 h, during which time it remained a suspension. The reaction was then monitored and determined to be complete. A 3.5% aqueous HCl solution (10 mL) was added, and the mixture stirred for 10 minutes. The solid was isolated by filtration, and the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL), yielding the 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-(4-ethyl-phenyl)-urea as a white solid (230 mg, 64%). HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4 in H2O: tR=3.53 min (98%); mp. 263-265° C. 1H NMR (DMSO-d6) δ 1.94-2.06 (m, 1H, CHH), 2.38 (qd, J=4.2, 13.1 Hz, 1H, CHH), 2.60 (d, J=17.0 Hz, 1H, CHH), 2.84-3.00 (m, 1H, CHH), 4.26-4.50 (m, 4H, CH2+CH2), 5.03 (s, 2H, CH2), 5.11 (dd, J=5.0, 13.1 Hz, 1H, CHN), 6.64 (t, J=5.9 Hz, 1H, Ar), 6.90 (d, J=8.9 Hz, 2H, Ar), 7.26-7.48 (m, 8H, Ar), 7.51 (s, 1H, NH), 7.69 (d, J=7.9 Hz, 1H, Ar), 8.43 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 31.20, 42.79, 47.10, 51.56, 69.38, 114.92, 119.44, 121.85, 122.91, 126.88, 127.59, 127.68, 128.35, 130.25, 133.73, 137.26, 142.36, 145.00, 153.02, 155.41, 167.95, 170.99, 172.86; LCMS MH=421. Anal Calcd for: C23H24N4O4+0.15 CH3CN: C, 65.60; H, 5.78; N, 13.62. found: C, 65.42; H, 5.69; N, 13.24.
Reaction SMILES: Cl[C:2](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](=[O:5])[CH3:4].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.C(N(CC)CC)C>C(O)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:2](=[N:6][NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3](=[O:5])[CH3:4])=[CH:17][CH:16]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CC(=O)C(Cl)=NNc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)C(=NNc1ccccc1)Sc1ccc(Cl)cc1
Yield: 23.5 %

Procedure:
The reaction of 951 mg (4.85 mmol) of 1-chloro-1-[(phenyl) hydrazono]-2-propanone with 864 mg of 4-chlorothiophenol and 840 ul of triethylamine in 15 ml of ethanol as Example 11 yielded 347 mg of 1-[(4-chlorophenyl)thio]-1-[(phenyl)hydrazono]-2-propanone, mp 111°-113° C.
Reaction SMILES: Cl.[C:2]1([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[S:13][CH:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[N:26]([CH3:27])[N:25]=[CH:24][C:23]=1[CH2:28][C:29](O)=[O:30]>>[Cl:21][C:22]1[N:26]([CH3:27])[N:25]=[CH:24][C:23]=1[CH2:28][C:29]([N:18]1[CH2:19][CH2:20][CH:15]([C:12]2[S:13][CH:14]=[C:10]([CH2:9][CH2:8][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:11]=2)[CH2:16][CH2:17]1)=[O:30]
Reactant: c1ccc(CCc2csc(C3CCNCC3)n2)cc1
Reactant: Cn1ncc(CC(=O)O)c1Cl
Agent: Cl
Product: Cn1ncc(CC(=O)N2CCC(c3nc(CCc4ccccc4)cs3)CC2)c1Cl

Procedure:
4-[4-(2-Phenylethyl)-1,3-thiazol-2-yl]piperidine hydrochloride (II-1, 280 mg) is reacted analogously to Example I-63 with (5-chloro-1-methyl-1H-pyrazol-4-yl)acetic acid (174 mg). After chromatographic purification, this gives 2-(5-chloro-1-methyl-1H-pyrazol-4-yl)-1-{4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone (89 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]2[CH2:17][CH2:16][C:15](Cl)([Cl:18])[C@@H:14]2[C:20]2[CH:25]=[CH:24][C:23]([CH:26]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=2)=[CH:8][CH:9]=1)=[O:4].C(N=C(N(C)C)N(C)C)(C)(C)C.Cl>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]2[CH2:17][CH2:16][C:15]([Cl:18])=[C:14]2[C:20]2[CH:21]=[CH:22][C:23]([CH:26]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:24][CH:25]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: CCCCCC(OCc1ccc(OC)cc1)c1ccc([C@@H]2[C@@H](CCCc3ccc(C(=O)OC)s3)CCC2(Cl)Cl)cc1
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Agent: Cl
Solvent: ClCCCl
Product: CCCCCC(OCc1ccc(OC)cc1)c1ccc(C2=C(Cl)CC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Reaction time: 70 h

Procedure:
A solution of dichloride 4 (12 mg, 0.019 mmol) and 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG, 0.2 mL) in 1,2-dichloroethane (0.5 mL) was stirred at 60° C. After 70 h, 1 M HCl (28 mL) was added and the mixture was extracted with 20 mL CH2Cl2. The dichloromethane solution was washed further with 1 M HCl (3×25 mL) and then was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (0%→15% ethyl acetate/hexanes) gave the title compound, contaminated with 15% of the alkene regioisomer 6b as an inseparable mixture (10 mg, 93%).
Reaction SMILES: [Na][Na].[C:3]([NH:5][C:6](=[O:15])[CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]#[N:14])=[O:11])#[N:4].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)([O-:18])=[O:17]>CN(C)C=O>[C:13]([N:12]([CH2:23][C:22]1[CH:25]=[CH:26][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=1)[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]([N:5]([CH2:23][C:22]1[CH:25]=[CH:26][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=1)[C:3]#[N:4])=[O:15])#[N:14]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: N#CNC(=O)CCCC(=O)NC#N
Agent: [Na][Na]
Solvent: CN(C)C=O
Product: N#CN(Cc1ccc([N+](=O)[O-])cc1)C(=O)CCCC(=O)N(C#N)Cc1ccc([N+](=O)[O-])cc1

Procedure:
22.4 g (0.1 mol) of the disodium salt of glutaric acid bis-(N-cyanamide) and 51.85 g (0.2 mol+20% excess) of 4-nitrobenzyl bromide are reacted in 120 ml of dimethylformamide at 36°-40° C. for 1 hour and the mixture is worked up in a manner similar to that in Example 2. 44.3 g (98.4% of theory) of a yellowish crystalline crude product are obtained, and are recrystallised from 440 ml of ethyl acetate. 31.5 g (70.0% of theory) of a colourless, crystalline product of melting point 146.2°-148.2° C. are obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:52])[C@@H:7]([NH:31][C:32](=[O:51])[NH:33][C@@H:34]([CH2:42][CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:30])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](ON1C(=O)CCC1=O)=[O:21])([CH3:4])([CH3:3])[CH3:2].[NH2:53][C@@H:54]([CH2:58][CH2:59][CH2:60][CH2:61][N:62]([CH2:70][C:71]1[N:72]([CH3:76])[CH:73]=[CH:74][N:75]=1)[CH2:63][C:64]1[N:65]([CH3:69])[CH:66]=[CH:67][N:68]=1)[C:55]([OH:57])=[O:56].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:69][N:65]1[CH:66]=[CH:67][N:68]=[C:64]1[CH2:63][N:62]([CH2:70][C:71]1[N:72]([CH3:76])[CH:73]=[CH:74][N:75]=1)[CH2:61][CH2:60][CH2:59][CH2:58][C@@H:54]([C:55]([OH:57])=[O:56])[NH:53][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13](=[O:30])[NH:12][CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:52])[NH:31][C:32](=[O:51])[NH:33][C@H:34]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:42][CH2:43][C:44](=[O:45])[O:46][C:47]([CH3:49])([CH3:50])[CH3:48]
Reactant: Cn1ccnc1CN(CCCC[C@H](N)C(=O)O)Cc1nccn1C
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)CCCCCCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1ccnc1CN(CCCC[C@H](NC(=O)CCCCCCC(=O)NCCCC[C@H](NC(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)O)Cc1nccn1C
Yield: 17.6 %

Procedure:
A solution of (S)-di-tert-butyl 2-(3-((S)-1-tert-butoxy-6-(8-(2,5-dioxopyrrolidin-1-yloxy)-8-oxooctanamido)-1-oxohexan-2-yl)ureido)pentanedioate (0.356 g, 0.48 mmol), the compound of Compound 13 (0.16 g, 0.48 mmol) and DIPEA (1.0 mL) in DMF (5.0 mL) was stirred at room temperature for overnight. The solvent was evaporated to give a residue, which was purified by Biotage eluting with DCM/MeOH to give (7S,11S,26S)-26-(4-(bis((1-methyl-1H-imidazol-2-yl)methyl)amino)butyl)-7,11-bis(tert-butoxycarbonyl)-2,2-dimethyl-4,9,17,24-tetraoxo-3-oxa-8,10,16,25-tetraazaheptacosan-27-oic acid (81 mg, 18%). MS (ESI), 481 (M/2+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH2:14]([N:20]([CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl>N1C(C)=CC(C)=CC=1C>[CH:30]1([N:20]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([O:13][C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:24][CH:23]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CCCCCCN(C(=O)c1ccc(Br)cc1)C1CCCCC1
Reactant: COc1cc(O)cc(OC)c1OC
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Product: CCCCCCN(C(=O)c1ccc(Oc2cc(OC)c(OC)c(OC)c2)cc1)C1CCCCC1
Reaction time: 18 h

Procedure:
A slurry of cuprous oxide (300 mg, 2.1 mmol) in a solution of 3,4,5-trimethoxyphenol (736 mg, 4.0 mmol) and p-bromobenzoic acid N-n-hexyl-N-cyclohexyl amide (1.47 g, 4.0 mmol) in 2,4,6-collidine (20 ml) is refluxed with stirring under a nitrogen atmosphere for 18 hr. The reaction is cooled, poured onto dilute aqueous HCl and extracted three times with ethyl acetate. The combined organic layers are washed twice with saturated aqueous NaCl solution, twice with 5% NaOH solution, twice with saturated NaCl solution and dried (Na2SO4). The drying agent is filtered and the filtrate concentrated in vacuo to give the crude product. This material is chromatographed on silica gel using mixtures of ethyl acetate and hexane as the eluents to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][C:9]([OH:11])=O)[C:6](=[O:12])[C:5]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.Br.Br.[S:24]1[C:28]2[CH2:29][CH:30]([NH2:33])[CH2:31][CH2:32][C:27]=2[N:26]=[C:25]1[NH2:34]>>[NH2:34][C:25]1[S:24][C:28]2[CH2:29][CH:30]([NH:33][C:9](=[O:11])[CH2:8][N:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]([NH:13][CH2:14][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:6]3=[O:12])[CH2:31][CH2:32][C:27]=2[N:26]=1
Reactant: Cc1ccc(NCCc2ccccc2)c(=O)n1CC(=O)O
Reactant: Nc1nc2c(s1)CC(N)CC2
Agent: Br
Product: Cc1ccc(NCCc2ccccc2)c(=O)n1CC(=O)NC1CCc2nc(N)sc2C1

Procedure:
The title compound was prepared from 2-[6-methyl-2-oxo-3 -(phenethylamino)-1(2H)-pyridinyl]acetic acid and 4,5,6,7-tetrahydro-1,3-benzothiazol-2,6-diamine dihydrobromide using the procedure of EXAMPLE 1 (STEP 6), and was obtained as a yellow crystalline solid compound.
Reaction SMILES: CN(C)C=O.[OH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[H-].[Na+].[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1F)[CH:20]=[O:21]>O>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH:20]=[O:21]
Reactant: OCc1ccccn1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCc2ccccn2)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.6 %

Procedure:
To an N,N-dimethylformamide (40.0 mL) solution of 2-(hydroxymethyl)-pyridine (3.00 g, 27.5 mmol) was added sodium hydride (1.00 g, 25.0 mmol, 60% in oil) under nitrogen atmosphere at 0° C., which was stirred for 20 minutes at room temperature. 3,4-Difluorobenzaldehyde (4.69 g, 33.0 mmol) was then added at 0° C., and stirred for 20 minutes at room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:1→2:1) to obtain the title compound (2.90 g, 45.6%).
Reaction SMILES: [N:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][C:4]=1[C:12]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]2[C:13]=1[CH2:14][CH2:15][C:16](=[O:24])[NH:17]2)=[O:2].[ClH:25].O>CO.[C].[Pd]>[OH2:2].[ClH:25].[NH2:1][C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][C:4]=1[C:12]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]2[C:13]=1[CH2:14][CH2:15][C:16](=[O:24])[NH:17]2.[NH2:1][C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][C:4]=1[C:12]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]2[C:13]=1[CH2:14][CH2:15][C:16](=[O:24])[NH:17]2.[ClH:25]
Reactant: COc1ccc(-c2nc3ccccn3c2N=O)c2c1NC(=O)CC2
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccc(-c2nc3ccccn3c2N)c2c1NC(=O)CC2

Procedure:
To a suspension of 5-(3-nitrosoimidazo[1,2-a]-pyridine-2-yl)-8-methoxy-3,4-dihydrocarbostyril (20.85 g) in methanol (500 ml) was added 12 ml of concentrated hydrochloric acid to render the suspension acidic. 10% Palladium-carbon (2 g), was added to the suspension, and catalytic reduction was carried out at room temperature under atmospheric pressure. After completion of reaction, water was added to the reaction mixture to dissolve and the resulting mixture was heated. After removing the catalyst by filtration, the filtrate was concentrated to dryness. Acetone was added to the residue, and crystals which precipitated were collected by filtration and recrystallized from water to give 21.20 g of 5-(3-aminoimidazo[1,2-a]pyridine-2-yl)-8-methoxy-3,4-dihydrocarbostyril monohydrochloride hemihydrate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]3[CH2:20][CH2:21][CH2:22][O:23][C:12]=23)=[O:10])[CH2:3][CH2:2]1.[CH:24]1([CH2:30]Br)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH2:30][N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[N:13]4[CH2:20][CH2:21][CH2:22][O:23][C:12]=34)=[O:10])[CH2:3][CH2:2]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: BrCC1CCCCC1
Reactant: O=C(NCC1CCNCC1)c1c2n(c3ccccc13)CCCO2
Product: O=C(NCC1CCN(CC2CCCCC2)CC1)c1c2n(c3ccccc13)CCCO2
Reaction time: 8 h

Procedure:
N-(4-Piperidylmethyl) 3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide (E21) was alkylated with cyclohexylmethyl bromide using the method of Example 22 with a reaction time of 70 h at room temperature followed by 8 h at reflux temperature. The title compound (E23) was obtained as a white solid (31%) which was converted to its hydrochloride salt and crystallised from acetone/ether as a white solid mp 209-210° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:5]=1[N+:13]([O-:15])=[O:14].[BH4-].[Na+].O>CO>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:12])[CH3:11])=[CH:6][C:5]=1[N+:13]([O-:15])=[O:14]
Reactant: COC(=O)c1ccc(C(C)=O)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(C(C)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.5 %

Procedure:
To a solution of 4-acetyl-2-nitro-benzoic acid methyl ester (1 g, 4.48 mmol) in MeOH (5 mL) was added NaBH4. The reaction mixture was stirred at r.t. for 24 h (TLC control). To the reaction mixture was added water until the appearance of a white turbid solution and the reaction was stirred for 15 min at r.t. MeOH was removed under reduced pressure. The aqueous phase was extracted with EtOAc three times. The combined organic phases were dried (Na2SO4) and concentrated in vacuo to afford 4-(1-hydroxy-ethyl)-2-nitro-benzoic acid methyl ester (0.742 g, 73%) as a brown oil which was used in the next step without further purification. rt 4.74 min.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Br:8].[SH:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].ICCCCCCCCCCCCSCCC(OC)=O>CCCCCC.CCOCC>[Br:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: BrCCCCCCBr
Reactant: COC(=O)CCS
Agent: COC(=O)CCSCCCCCCCCCCCCI
Solvent: CCCCCC
Solvent: CCOCC
Product: COC(=O)CCSCCCCCCBr
Yield: 35.3 %

Procedure:
1,6-dibromo-hexane (1.6 g. 13 mmol) and methyl 3-mercapto-propionate (13 mmol) were caused to react according to the procedure for compound 1. The product 5 (1.3 g, 35% yield) was isolated as an oil by column chromatography (hexane/ether 1:1). TL (hexanelether 1:1) Rf=0.6. 1H-NMR δ1.4 (m, 12H, CH2), 2.52 (t, 2H, C(2)H2), 2.61 (t, 2H, C(5)H2), 2.8 (t, 2H, C(3)H2), 3.40 (t, 2H, C(10)H2), 3.7 (s, 3H, COO—CH3).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:13])[CH:10]=2)[C:5]1=O.O.[NH2:16][CH2:17][CH:18]([OH:20])[CH3:19]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:13][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5]1[N:16]([CH2:17][CH:18]([OH:20])[CH3:19])[CH:2]=[CH:3][C:4]=1[CH2:12]2
Reactant: CC(O)CN
Reactant: O=CCC1Cc2cc(F)ccc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(O)Cn1ccc2c1-c1ccc(F)cc1C2
Reaction time: 0.75 h
Yield: 69 %

Procedure:
A solution of 2.0 g of (RS)-2-(2-oxoethyl)-5-fluoro-1-indanone and 85 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.12 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 2:3). 1.66 g (69%) of (RS)-1-(6-fluoro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: C(NC(C1SC(N2CCN(CC3C=C(C=CC=3)C(OCC)=O)C2=O)=NC=1C)=O)C1C=CC=CC=1.[CH:35]1([CH2:38][N:39]2[CH2:43][CH2:42][N:41]([C:44]3[S:45][C:46]([C:49]([O:51]C)=[O:50])=[CH:47][N:48]=3)[C:40]2=[O:53])[CH2:37][CH2:36]1>>[CH:35]1([CH2:38][N:39]2[CH2:43][CH2:42][N:41]([C:44]3[S:45][C:46]([C:49]([OH:51])=[O:50])=[CH:47][N:48]=3)[C:40]2=[O:53])[CH2:37][CH2:36]1
Reactant: COC(=O)c1cnc(N2CCN(CC3CC3)C2=O)s1
Agent: CCOC(=O)c1cccc(CN2CCN(c3nc(C)c(C(=O)NCc4ccccc4)s3)C2=O)c1
Product: O=C(O)c1cnc(N2CCN(CC3CC3)C2=O)s1
Yield: 93 %

Procedure:
Following the procedure as described in Example 25, making variations as required to replace ethyl 3-((3-(5-(benzylcarbamoyl)-4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)benzoate with methyl 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in 93% yield: mp 250-252° C. (water); 1H NMR (300 MHz, DMSO-d6) δ 12.97 (s, 1H), 7.93 (s, 1H), 4.03-3.96 (m, 2H), 3.66-3.61 (m, 2H), 3.08 (d, J=7.1 Hz, 2H), 0.96-0.87 (m, 1H), 0.49-0.43 (m, 2H), 0.21-0.16 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 163.3, 162.8, 155.0, 145.2, 122.4, 48.2, 42.5, 42.4, 9.27, 3.62; MS (ES+) m/z 268.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[C:5]([CH2:7][C:8]([O:10]CC)=O)=O.[Cl-].[CH2:18]([O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH:29]([NH2+:31][NH2:32])[CH3:30])=[CH:25][CH:24]=1)=[O:22])[CH3:19]>CC(O)=O>[Cl:16][C:14]1[CH:13]=[C:4]([C:5]2[CH2:7][C:8](=[O:10])[N:31]([CH:29]([C:26]3[CH:27]=[CH:28][C:23]([C:21]([O:20][CH2:18][CH3:19])=[O:22])=[CH:24][CH:25]=3)[CH3:30])[N:32]=2)[CH:3]=[C:2]([Cl:1])[CH:15]=1
Reactant: CCOC(=O)CC(=O)c1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)c1ccc(C(C)[NH2+]N)cc1
Agent: [Cl-]
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(C(C)N2N=C(c3cc(Cl)cc(Cl)c3)CC2=O)cc1

Procedure:
A solution of ethyl (3,5-dichlorobenzoyl)acetate (3.0 g, 11.5 mmol) and {1-[4-(ethoxycarbonyl)phenyl]ethyl}hydrazinium chloride (2.55 g, 10.4 mmol) was refluxed in HOAc (80 ml) for 4 hr. The solvent was removed under reduced pressure, and the residue taken up with ethyl acetate, washed with sat. NaHCO3 2×, brine, and dried over Na2SO4. Flash column chromatography (SiO2, 0-5% ethyl acetate in DCM gradient) gave ethyl 4-{1-[3-(3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]ethyl}benzoate as a white solid. TLC (5% ethyl acetate-DCM) Rf 0.43. NMR (500 MHz, CDCl3) δ: 1.38 (t, J=7.1 Hz, 3H); 1.78 (d, J=7.0 Hz, 3H); 3.55 (d, J=22.6 Hz, 1H); 3.60 (d, J=22.6 Hz, 1H); 4.36 (q, J=7.1 Hz, 2H); 5.57 (q, J=7.0 Hz, 1H); 7.39 (t, J=1.9 Hz, 1H); 7.50 (d, J=8.4 Hz, 2H). 7.52 (d, J=1.9 Hz, 2H); 8.02 (d, J=8.4 Hz, 2H). MS C20H18Cl2N2O3 Cald: 404.07; Obsd (M+1): 405.20.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:31][O:32][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10](C(C1C=CC=CC=1)C1C=CC=CC=1)[C:9]3=[O:30].C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(C4C=C(C)C(OC)=CC=4OC3)C2=O)C=CC=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:31][O:32][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH:10][C:9]3=[O:30]
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc(Br)ccc12
Agent: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: O=C1Nc2ccccc2C12COc1cc(Br)ccc12

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 6-bromo-1′-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 6-bromospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (89%) as a colorless solid: MS (ES+) m/z 316.1 (M+1), 318.1 (M+1).