Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)[CH3:6])=[O:4].[CH2:22]([NH2:25])[CH2:23][NH2:24].C(N(CC)CC)C>C(O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:7]2[N:5]([CH3:6])[C:3](=[O:4])[CH2:2][N:24]3[CH2:23][CH2:22][NH:25][C:9]3([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]=2[CH:17]=1
Reactant: NCCN
Reactant: CN(C(=O)CCl)c1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1C(=O)CN2CCNC2(c2ccccc2)c2cc(Cl)ccc21

Procedure:
A solution of 6.4 g. (20 mmole) of 2-(2-chloro-N-methylacetamido)-5-chlorobenzophenone, 12.0 g. (0.2 mole) of ethylenediamine, 50 ml. of triethylamine and 250 ml. of ethanol was heated at reflux for 20 hours. The reaction mixture was concentrated to a residue which was partitioned between ether and water. The ether layer was washed with water, dried and concentrated to a small amount of liquid which was treated with a small amount of ethanol to give upon standing the above-titled product as colorless crystals, m.p. 164° -167°.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[N:15]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[O:28][C:29]4[CH:35]=[C:34]([C:36](Cl)=[O:37])[CH:33]=[CH:32][C:30]=4[N:31]=3)[CH:22]=1)[C:14]2=[O:39])=[O:10])C1C=CC=CC=1.[CH2:40]([NH2:46])[CH:41]1[O:45][CH2:44][CH2:43][CH2:42]1.N1CCOCC1.[N-]=C=O>C1COCC1>[O:45]1[CH2:44][CH2:43][CH2:42][CH:41]1[CH2:40][NH:46][C:36]([C:34]1[CH:33]=[CH:32][C:30]2[N:31]=[C:27]([C:23]3[CH:22]=[C:21]([N:15]4[C:14](=[O:39])[C:13]5[C:17](=[CH:18][CH:19]=[C:11]([C:9]([OH:8])=[O:10])[CH:12]=5)[C:16]4=[O:20])[CH:26]=[CH:25][CH:24]=3)[O:28][C:29]=2[CH:35]=1)=[O:37]
Reactant: O=C(Cl)c1ccc2nc(-c3cccc(N4C(=O)c5ccc(C(=O)OCc6ccccc6)cc5C4=O)c3)oc2c1
Reactant: NCC1CCCO1
Agent: [N-]=C=O
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)C(=O)N(c1cccc(-c3nc4ccc(C(=O)NCC5CCCO5)cc4o3)c1)C2=O
Reaction time: 8 h
Yield: 58.7 %

Procedure:
A solution of 2-[3-(6-chlorocarbonylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid benzyl ester (50 mg, 0.09 mmol) in THF (1 ml) was added to a solution of tetrahydrofurfurylamine (14 mg, 0.14 mmol) in THF (1 ml) containing polymer bound morpholine (2.5 mmol g−1, 72 mg). After shaking overnight, polymer bound isocyanate (2.0 mmol g−1, 90 mg) was added and the reaction shaken for 4 h. The reaction was filtered and the solvent removed under reduced pressure. The residue was suspended in dioxane and palladium on carbon was added (spatula tip). The reaction vessel was purged with hydrogen and stirred at room temperature overnight. The reaction was filtered through celite and the filtrate concentrated to give the title compound (27 mg, 59%). 1H NMR (DMSO) δ 8.74(t, 1H), 8.44(dd, 1H), 8.37(m, 2H), 8.31–8.27(m, 3H), 8.12(d, 1H), 7.97(dd, 1H), 7.90(d, 1H), 7.85–7.76(m, 1H), 4.00(m, 2H), 3.79(m, 1H), 3.65(m, 2H), 1.98–1.77(4H, m). MS 510.2 m/z (M−H)−.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[N:15]=[C:16]4[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][N:17]4[CH:24]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].Br[C:26]1OC(C2N=C3C(C)=CC(C#N)=CN3C=2)=CC=1.C(O)(=O)C.C(C1C=CC(C2OC(C3N=C4CCC(C(N)=N)CN4C=3)=CC=2)=CC=1)(=N)N>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[N:15]=[C:16]4[C:21]([CH3:26])=[CH:20][C:19]([C:22]#[N:23])=[CH:18][N:17]4[CH:24]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(-c2ccc(-c3cn4cc(C#N)ccc4n3)o2)cc1
Reactant: Cc1cc(C#N)cn2cc(-c3ccc(Br)o3)nc12
Agent: N=C(N)c1ccc(-c2ccc(-c3cn4c(n3)CCC(C(=N)N)C4)o2)cc1
Solvent: CC(=O)O
Product: Cc1cc(C#N)cn2cc(-c3ccc(-c4ccc(C#N)cc4)o3)nc12
Yield: 77 %

Procedure:
The same procedure described for 4a was used starting with 3b. Yield 77%, mp 276-277° C. 1H NMR (DMSO-d6); δ 2.54 (s, 3H), 7.12 (d, J=3.6 Hz, 1H), 7.38 (s, 1H), 7.39 (d, J=3.6 Hz, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.99 (d, J=8.4 Hz, 2H), 8.45 (s, 1H), 9.19 (s, 1H). 13C NMR; δ 151.1, 149.7, 144.9, 137.2, 133.6, 132.8, 132.0, 127.4, 123.8, 123.3, 118.8, 117.0, 111.4, 111.0, 110.3, 109.3, 97.1, 16.3. MS (m/z, rel.int.); 324 (M+, 100), 295 (7), 222 (8), 194 (15), 162 (15). High resolution mass calcd. for C20H12N4O: 324.10111. Observed: 324.10070.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17]#[N:18])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl.[CH2:20]([O:22]CC)[CH3:21]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17](=[NH:18])[O:22][CH2:20][CH3:21])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(/C=C/C#N)ccc1-n1cnc(C)c1
Reactant: CCOCC
Agent: Cl
Solvent: CCO
Product: CCOC(=N)/C=C/c1ccc(-n2cnc(C)c2)c(OC)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A suspension of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylonitrile (700 mg) in ethanol (6 mL) was saturated with hydrogen chloride gas under ice-cooling, and then the reaction solution was stirred at 0° C. overnight. Diethyl ether (10 mL) was added to the reaction solution. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate and a saturated sodium bicarbonate solution were added to the resulting residue, and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate-ethanol system) to obtain 127 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]2[CH:13]=[N:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[C:10]3[O:18]C(C)(C)[O:20][CH2:21][C:9]=23)=[CH:4][CH:3]=1>C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[C:9]([CH2:21][OH:20])=[C:10]([OH:18])[C:11]([C:14]([O:16][CH3:17])=[O:15])=[N:12][CH:13]=2)=[CH:24][CH:25]=1
Reactant: COC(=O)c1ncc(COc2ccc(F)cc2)c2c1OC(C)(C)OC2
Solvent: O=CO
Product: COC(=O)c1ncc(COc2ccc(F)cc2)c(CO)c1O

Procedure:
A solution of methyl 5-((4-fluorophenoxy)methyl)-2,2-dimethyl-4H-[1,3]dioxino[4,5-c]pyridine-8-carboxylate 28a (0.129 g, 0.37 mmol) in 3 mL of formic acid was stirred at 23° C. for 2 h and then it was concentrated. The crude residue was purified by chromatography (SiO2) with hexanes:ethyl acetate (3:7) as eluent to afford the title compound as a white solid: LC-MS (M+H)+ m/z 308; 1H NMR (DMSO-d6): 1.39 (s, 6H), 4.80 (s, 2H), 4.89 (s, 2H), 5.01 (s, 2H), 7.39-7.46 (m, 5H), 8.38 (s, 1H), 10.04 (s, 1H).
Reaction SMILES: ClCCl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][CH2:13][CH2:14][OH:15])=[CH:7][CH:6]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(N(CC)CC)C>[F:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][CH2:13][CH2:14][O:15][S:17]([CH3:16])(=[O:19])=[O:18])=[CH:9][CH:10]=1
Reactant: OCCC#Cc1ccc(F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC#Cc1ccc(F)cc1

Procedure:
To a mixture of 250 ml. of dichloromethane, 25 g. 4-(4-fluorophenyl)-3-butyn-1-ol and 16.7 g. of triethylamine cooled in an ice-salt bath to -10° C. is added dropwise, over 15 minutes, 18.9 g. of methanesulfonyl chloride. The mixture is cooled at -10° C. to -15° C. for 30 minutes and then washed with 300 ml. each of cold water, 10% hydrochloric acid, sodium carbonate solution and with saturated sodium chloride solution. The organic layer is dried with magnesium sulfate and concentrated in vacuo to give a pale yellow oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].CCN(C(C)C)C(C)C.[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH2:42][CH2:43][C:44](=[O:56])SC1C=CC(C(F)(F)F)=CC=1)[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C.O>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][NH:2][C:44](=[O:56])[CH2:43][CH2:42][C@H:31]([NH:30][C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:29])[C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)Sc1ccc(C(F)(F)F)cc1)C(=O)OCc1ccccc1
Reactant: NCC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CCC(=O)NCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 90.4 %

Procedure:
A solution of benzyl 2-aminoacetate hydrochloride (15.8 mg, 0.0784 mmol) and DIPEA (0.0136 ml, 0.0784 mmol) in DMF (0.0784 ml) was added to a solution of (S)-benzyl 2-((tert-butoxycarbonyl)amino)-5-((4-trifluorophenyl)thio)-5-oxopentanoate (Compound 5f-2) (30.0 mg, 0.0603 mmol) in DMF (0.541 ml) and water (0.200 ml), and the mixture was stirred at 50° C. for 45 minutes. The reaction mixture was then purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=70/30→20/80) to afford (S)-benzyl 5-((2-(benzyloxy)-2-oxoethyl)amino)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoate (Compound 5d-2) (26.4 mg, 90%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:23][CH:22]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:32])([F:33])[F:19])=[CH:26][CH:25]=3)[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3)n2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and (E)-3-(4-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13]N3CC(C)(C)NS3(=O)=O)[CH:11]=2)[NH:6][CH:5]=1.[C:23]([O:27][C:28]([N:30]1[CH2:34][C:33]([CH3:36])([CH3:35])[NH:32][S:31]1(=O)=O)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([NH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][N:32]3[S:31][N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[CH2:34][C:33]3([CH3:36])[CH3:35])[CH:11]=2)[NH:6][CH:5]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)S(=O)(=O)N1
Reactant: CC1(C)CN(Cc2ccc3[nH]cc(CCN)c3c2)S(=O)(=O)N1
Product: CC(C)(C)OC(=O)NCCc1c[nH]c2ccc(CN3SN(C(=O)OC(C)(C)C)CC3(C)C)cc12
Yield: 84 %

Procedure:
The title compound was prepared in 84% yield from Intermediate 3 and 2-tert-butyloxycarbonyl-4,4-dimethyl-1,2,5-thiadiazolidine-1,1-dioxide using a similar method to that described for Example 18 (step 2); white foam; δH (250 MHz, CDCl3) 8.04 (1H, br s, indole N--H), 7.58 (1H, s, Ar--H), 7.32 (2H, s, Ar--H), 7.02 (1H, d, J=2.2 Hz, Ar--H), 4.59 (1H, br s, --NH--), 4.36 (2H, s, Ar--CH2N--), 3.59 (2H, s, --CH2 --), 3.45 (2H, br q, J=6.3 Hz, --CH2NH--), 2.94 (2H, t, J=6.3 Hz, Ar--CH2 --), 1.55 (9H, s, t-Bu), 1.43 (9H, s, t-Bu), 1.30 (6H, s, --CMe2); m/z (FAB) 523 (M+ +1).
Reaction SMILES: [Br:1]P(Br)Br.O[CH:6]([C:8]1[CH:9]=[C:10]([C:25]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:26])[CH:11]=[C:12]2[C:17]=1[O:16][C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[CH:14][C:13]2=[O:24])[CH3:7]>ClCCCl.C(OCC)C>[Br:1][CH:6]([C:8]1[CH:9]=[C:10]([C:25]([N:27]2[CH2:28][CH2:29][CH2:30][CH2:31]2)=[O:26])[CH:11]=[C:12]2[C:17]=1[O:16][C:15]([N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)=[CH:14][C:13]2=[O:24])[CH3:7]
Reactant: BrP(Br)Br
Reactant: CC(O)c1cc(C(=O)N2CCCC2)cc2c(=O)cc(N3CCOCC3)oc12
Solvent: ClCCCl
Solvent: CCOCC
Product: CC(Br)c1cc(C(=O)N2CCCC2)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 129.4 %

Procedure:
A solution of tribromophosphine (0.491 mL, 5.22 mmol) in 1,2-dichloroethane (4 mL) at 10° C., was added dropwise to 8-(1-hydroxyethyl)-2-morpholino-6-(pyrrolidine-1-carbonyl)-4H-chromen-4-one (1.62 g, 4.35 mmol) suspended in 1,2-dichloroethane (18 mL) under nitrogen. The resulting suspension was stirred at 50° C. for 1 hour. The reaction mixture was allowed to cool to RT under stirring and diluted with diethyl ether (18 mL). The precipitate was collected by filtration, washed with diethyl ether and dried to a constant weight to afford 8-(1-bromoethyl)-2-morpholino-6-(pyrrolidine-1-carbonyl)-4H-chromen-4-one (2.45 g, 100%) hydrobromide as a white solid, which was used without further purification. NMR Spectrum (DMSOd6): 1.79-1.93 (m, 4H), 2.11 (d, 3H), 3.37-3.44 (m, 2H), 3.46-3.53 (m, 2H), 3.57-3.70 (m, 4H), 3.73-3.80 (m, 4H), 5.66 (s, 1H), 5.92 (q, 1H), 7.99-8.03 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]([CH3:13])([CH3:12])[CH2:8][C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.[Cl:27][C:28]1[CH:29]=[C:30]([C@@H:34]([NH:36][C:37](=[O:70])/[CH:38]=[CH:39]/[C@:40]23[CH2:66][CH2:65][C:64]([CH:67]([CH3:69])[CH3:68])=[C:41]2[C@@H:42]2[C@@:55]([CH3:58])([CH2:56][CH2:57]3)[C@@:54]3([CH3:59])[C@@H:45]([C@:46]4([CH3:63])[C@@H:51]([CH2:52][CH2:53]3)[C:50]([CH3:61])([CH3:60])[C@@H:49](O)[CH2:48][CH2:47]4)[CH2:44][CH2:43]2)[CH3:35])[CH:31]=[CH:32][CH:33]=1.O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:12][C:7]([CH3:13])([CH2:8][C:9]([O:11][C@H:49]1[CH2:48][CH2:47][C@@:46]2([CH3:63])[C@@H:51]([CH2:52][CH2:53][C@:54]3([CH3:59])[C@@H:45]2[CH2:44][CH2:43][C@H:42]2[C@@:55]3([CH3:58])[CH2:56][CH2:57][C@@:40]3(/[CH:39]=[CH:38]/[C:37]([NH:36][C@H:34]([C:30]4[CH:31]=[CH:32][CH:33]=[C:28]([Cl:27])[CH:29]=4)[CH3:35])=[O:70])[CH2:66][CH2:65][C:64]([CH:67]([CH3:69])[CH3:68])=[C:41]32)[C:50]1([CH3:60])[CH3:61])=[O:10])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:14]
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@@H](C)c2cccc(Cl)c2)CC1
Reactant: CC(C)(C)OC(=O)C(C)(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@@H](C)c2cccc(Cl)c2)CC1

Procedure:
To a solution of 4-tert-butoxy-3,3-dimethyl-4-oxobutanoic acid (1.174 g, 5.80 mmol), DMAP (0.709 g, 5.80 mmol) in DCM (20 mL) stirred at rt was added EDCl (1.854 g, 9.67 mmol). The reaction mixture was stirred at rt for 2 h. (E)-N—((S)-1-(3-Chlorophenyl)ethyl)-3-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)acrylamide (1.2 g, 1.934 mmol) was added to the reaction mixture. The resultant mixture was stirred at rt overnight. Water was added and the mixture was partitioned and washed with additional water. The organics were dried over sodium sulfate filtered through a short silica gel column and evaporated in vacuo to give the crude product as yellow foam. This material was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]([Cu])#[N:10]>CN(C=O)C>[Br:8][C:4]1[N:3]=[C:2]([C:9]#[N:10])[CH:7]=[CH:6][CH:5]=1
Reactant: N#C[Cu]
Reactant: Brc1cccc(Br)n1
Solvent: CN(C)C=O
Product: N#Cc1cccc(Br)n1
Temperature: 100 °C
Yield: 28 %

Procedure:
Take up 2,6-dibromopyridine (0.500 g, 2.11 mmol) and CuCN (0.189 g, 2.11 mmol) in DMF (5.3 mL). Heat at 100° C. for 22 hours. Cool to room temperature. Add water (50 mL) and extract with ethyl acetate (3× 100 mL). Wash the organic layer with brine (1× 75 mL), dry over Na2SO4, filter and concentrate. Purify by flash chromatography, eluting with 15-40% ethyl acetate in hexanes to give the title compound (0.108 g, 30.0%): GC/MS, MS ES+ 182 (M−H)+, time 8.78 min, % of total 100%; TLC [silica gel 60 F254, 30% ethyl acetate in hexanes] Rf=0.29.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]([CH3:16])([CH3:15])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7]>CO>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2([O:2][CH3:1])[C:5]([CH3:16])([CH3:15])[O:7]2)=[CH:9][CH:10]=1
Reactant: CC(C)(Cl)C(=O)c1ccc(Cl)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC1(c2ccc(Cl)cc2)OC1(C)C

Procedure:
57.0 g (1.056 mols) of sodium methylate are dissolved in 360 ml of methanol, and 208.4 g (0.96 mol) of 2-chloro-1-(4-chlorophenyl)-2-methylpropan-1-one are added dropwise to this solution at reflux temperature. The methanol is then removed by distillation. The residue is poured into ice water and the mixture is extracted with diethyl ether. The ether solution is washed with water, dried over Na2SO4 and concentrated. The resulting oil is purified by vacuum distillation.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.C(Cl)(=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[O:36]1[C:40]2[CH:41]=[CH:42][C:43]([CH2:45][N:46]3[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)=[CH:44][C:39]=2[O:38][CH2:37]1>>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[Cl:22])[CH2:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:24]([N:49]2[CH2:48][CH2:47][N:46]([CH2:45][C:43]3[CH:42]=[CH:41][C:40]4[O:36][CH2:37][O:38][C:39]=4[CH:44]=3)[CH2:51][CH2:50]2)=[O:26])[N:8]([C:6](=[O:7])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:12]1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)O
Reactant: O=C(Cl)c1ccccc1
Product: O=C([C@@H]1CC(=NOCc2ccc(Cl)c(Cl)c2)CN1C(=O)c1ccccc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, benzoyl chloride, and 1-(1,3-benzodioxol-5-ylmethyl)piperazine the title compound was obtained in 71% purity by LC/MS. MS(ESI+): m/z=609.8.
Reaction SMILES: [C:1]1([CH:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]2[CH2:13][CH2:12][CH:11]([N:14]=[CH:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C>[C:22]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C(=NC1CCN(C(c2ccccc2)c2ccccc2)CC1)c1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc(C(c2ccccc2)N2CCC(NCc3ccncc3)CC2)cc1
Temperature: 25 °C

Procedure:
A suspension of 3.55 parts of 1-(diphenylmethyl)-N-[(4-pyridyl)methylene]-4-piperidinamine in 150 parts by volume of ethanol, stirred at room temperature, is treated with 1 part of sodium borohydride. The resultant reaction mixture is stirred at room temperature for about three hours, then evaporated to dryness in vacuo. The residue is partitioned between 100 parts by volume of water and 100 parts by volume of chloroform and the layers separated. The aqueous layer is extracted with additional 100 parts by volume of chloroform and the chloroform layers combined. The combined chloroform fraction is washed with 150 parts by volume of water, dried over anhydrous sodium sulfate and evaporated to dryness to yield 1-(diphenylmethyl)-N-[(4-pyridyl)methyl]-4-piperidinamine which melts, after recrystallization from n-hexane, at about 138°-162° C. This compound is represented by the following structural formula. ##STR37##
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[CH:14]([C:16]1[C:17]([O:24][CH3:25])=[N:18][CH:19]=[C:20]([Cl:23])[C:21]=1[CH3:22])[OH:15]>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[C:14]([C:16]1[C:17]([O:24][CH3:25])=[N:18][CH:19]=[C:20]([Cl:23])[C:21]=1[CH3:22])=[O:15]
Reactant: COc1cc(C)c(C(O)c2c(OC)ncc(Cl)c2C)c(OC)c1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: COc1cc(C)c(C(=O)c2c(OC)ncc(Cl)c2C)c(OC)c1OC
Yield: 91.7 %

Procedure:
4 g of active manganese dioxide was added to a toluene 15 ml solution of 0.64 g (1.7 mmol) of (2,3,4-trimethoxy-6-methylphenyl)(5-chloro-2-methoxy-4-methyl-3-pyridyl)methanol, followed by stirring under reflux with heating for 1 hour. The reaction solution was subjected to filtration on the pad of celite, and the solvent was distilled off under reduced pressure to obtain 0.57 g (yield: 90%) of 3-(2,3,4-trimethoxy-6-methylbenzoyl)-5-chloro-2-methoxy-4-methylpyridine (melting point 94.5 to 95.5° C.)
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:12]=2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.[OH2:21].C(O)(=[O:24])C>>[CH2:1]([S:8]([C:9]1[S:10][C:11]2[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:12]=2[N:13]=1)(=[O:24])=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2nc(SCc3ccccc3)sc2c1
Reactant: O
Reactant: CC(=O)O
Agent: OO
Product: O=S(=O)(Cc1ccccc1)c1nc2ccc(O)cc2s1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 60.6 %

Procedure:
0.45 g (2 mmol) of 2-benzylmercapto-6-hydroxy-benzothiazole are dissolved in 15 ml of warm glacial acetic acid and at 50° C. 2.5 ml of 35% hydrogen peroxide is added. The mixture is stirred for 1 hour at 50° C. and 20 minutes at 100° C. It is then added to water, neutralised with soda and extracted with ethyl acetate. The extracts are dried and evaporated down. The evaporation residue is digested with a little ether and suction filtered. Yield: 60.6% of theory, Melting point: 188-189° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[S:18])[NH2:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:21].[Cl:22][CH2:23][C:24](=O)[CH2:25]Cl>O1CCOCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:18][CH:25]=[C:24]([CH2:23][Cl:22])[N:17]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:21]
Reactant: O=C(CCl)CCl
Reactant: CN1Cc2c(C(N)=S)ncn2-c2ccc(F)c(Cl)c2C1=O
Solvent: C1COCCO1
Product: CN1Cc2c(-c3nc(CCl)cs3)ncn2-c2ccc(F)c(Cl)c2C1=O
Yield: 35.1 %

Procedure:
A yellow suspension of 2.45 g (0.00754 mol) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-thiocarboxamide in 130 ml of dioxan was treated with 1.05 g (0.00829 mol) of 1,3-dichloro-2-propanone. The suspension was boiled at reflux for 20 hrs. and cooled. A further 1.05 g (0.00829 mol) of 1,3-dichloro-2-propanone and 60 ml of dioxan were added and the solution was boiled at reflux for a further 16 hrs. The solution was cooled and completely freed from the solvents. The residue was chromatographed over silica gel with cyclohexane/ethyl acetate 1:2 as the eluent and recrystallized from hot acetonitrile. There were obtained 1.05 g (35%) of 7-chloro-3-(4-chloromethyl-thiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 234°-235°.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:23])[O:9][CH:10]1[CH2:15][CH2:14][N:13](CC2C=CC=CC=2)[CH2:12][CH2:11]1.C(O)=O>CO.[Pd]>[C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:23])[O:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: O=C(Nc1ccccc1-c1ccccc1)OC1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: O=C(Nc1ccccc1-c1ccccc1)OC1CCNCC1
Reaction time: 18 h
Yield: 69.3 %

Procedure:
1-Benzyl-4-piperidyl N-(2-biphenylyl)carbamate (12.5 g, 32.3 mmol) was dissolved in anhydrous methanol (150 mL) and formic acid (25 mL, 660 mmol) and the solution was flushed with gaseous nitrogen for 15 min. 10% Palladium on carbon (3 g) was added and the reaction mixture was stirred under nitrogen atmosphere . After 18 h, the reaction mixture was filtered through Celite® and the filtrate was concentrated to give a yellow solid. The solid was partitioned between 0.1 N hydrochloric acid (300 mL) and diethyl ethr (300 mL). The aqueous layer was washed with diethyl ether and then basified with 1 N sodium hydroxide solution to pH 12. A white solid precipitated out which was extracted into ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate and evaporated to dryness to give 4-piperidyl N-(2-biphenylyl)carbamate as a colorless solid (6.63 g, 69%). MS=296.9 MH+.