Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:64][CH3:65])=[C:6]([C@@:8]2([F:63])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:21][O:22][CH:23]3[C@H:28]([O:29]CC4C=CC=CC=4)[C@@H:27]([O:37]CC4C=CC=CC=4)[C@@H:26]([O:45]CC4C=CC=CC=4)[C@@H:25]([CH2:53][O:54]CC4C=CC=CC=4)[O:24]3)[C:9]2=[O:62])[CH:7]=1.C(O)C>[Pt]=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:64][CH3:65])=[C:6]([C@@:8]2([F:63])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=3)[N:10]([CH2:21][O:22][CH:23]3[C@H:28]([OH:29])[C@@H:27]([OH:37])[C@H:26]([OH:45])[C@@H:25]([CH2:53][OH:54])[O:24]3)[C:9]2=[O:62])[CH:7]=1
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(COC2O[C@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c2cc(C(F)(F)F)ccc21
Agent: O=[Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(COC2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c2cc(C(F)(F)F)ccc21
Reaction time: 144 h

Procedure:
To a round bottom flask containing a solution of 3-(S)-(5-Chloro-2-methoxy-phenyl)-3-fluoro-6-trifluoromethyl-1-(3-(R),4-(S),5-(S)-tris-benzyloxy-6-(R)benzyloxymethyl-tetrahydro-pyran-2-yloxymethyl)-1,3-dihydro-indol-2-one; (3-(S)-VI) (0.768 g, 0.84 mmol) in 1:1 ethanol:ethyl acetate (6 mL) was added platinum oxide (0.095 g, 0.42 mmol). The reaction was allowed to run at room temperature under a hydrogen atmosphere for 6 days. Once complete, the reaction was filtered through a bed of celite and purified via reverse phase column chromatography (C18, 1:1 water:acetonitrile). The title compound was isolated as a white solid (0.279 g, 60%). 1H NMR (MeOH-D4, 400 MHz): δ 7.74 (m, 2H), 7.59 (d, 2H, J=8.8 Hz), 7.41 (m, 4H), 7.30 (dd, 2H, J=5.5 Hz, 2.3 Hz), 6.96 (m, 2H), 5.62 (d, 1H, J=10.8 Hz), 5.55 (d, 1H, J=11.3 Hz), 5.48 (d, 1H, J=10.8 Hz), 5.39 (d, 1H, J=11.2 Hz), 5.07 (d, 1H, J=3.8 Hz), 4.50 (d, 1H, J=7.8 Hz), 3.87 (dd, 1H, J=10 Hz, 1 Hz), 3.68 (m, 4H), 3.54 (d, 6H, J=2.6 Hz), 3.51 (d, 1H, J=4.6 Hz), 3.45 (d, 1H, J=3.8 Hz), 3.43 (d, 1H, J=3.8 Hz), 3.38 (m, 1H), 3.33 (m, 2H), 3.24 (m, 1H ); LRMS: 569 [M+NH4]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH3:12].[O:13]1CCOCC1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH:12]=[O:13]
Reactant: Cc1ccnc2ccc(Cl)cc12
Reactant: C1COCCO1
Product: O=Cc1ccnc2ccc(Cl)cc12
Yield: 61 %

Procedure:
A solution of 2 (16.04 g, 90.6 mmol) and SeO2 (13.0 g, 117.3 mmol) in 5% aq. 1,4-dioxane (200 mL) was refluxed for 2 h. The precipitated selenium was filtered off and the filtrate was evaporated to dryness in vacuo. The residue was taken into CH2Cl2, and filtered through a short plug of silica gel. The filtrate was concentrated to give a light brown solid. Further purification by crystallization (EtOAc/Hexanes) gave 1 (11.6 g, 61%) as a pale yellow solid Mp 152-153° C. (lit.2 153-154° C). 1H NMR (300 MHz, CDCl3): δ 10.43 (s, 1H), 9.20 (d, 4.4 Hz, 1H), 9.10 (d, 2.2 Hz, 1H), 8.16 (d, 9.1 Hz, 1H), 7.82 (d, 4.4 Hz, 1H), 7.77 (dd, 9.1, 2.2 Hz, 1H). MS m/z: 192 (M+1). Analysis calcd. for C10H6ClNO; C, 62.68; H, 3.16; N, 7.31; Cl, 18.50; found, C, 62.92; H, 3.33; N, 7.23; Cl, 18.60.2
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([OH:17])[CH:12]=3)[S:7][C:6]=2[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25][NH2:26])[CH3:22]>>[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25][NH:26][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([OH:17])[CH:12]=3)[S:7][C:6]=2[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1)[CH3:22]
Reactant: O=c1c2cc(O)ccc2sc2c([N+](=O)[O-])ccc(Cl)c12
Reactant: CCN(CC)CCN
Product: CCN(CC)CCNc1ccc([N+](=O)[O-])c2sc3ccc(O)cc3c(=O)c12

Procedure:
1-[[2-(Diethylamino)ethyl]amino]-7-hydroxy-4-nitro-9H-thioxanthen-9-one was prepared similarly from 10 g of 1-chloro-7-hydroxy-4-nitrothioxanthone and 8.3 g of N,N-diethylethylenediamine to provide 7.3 g as a tan solid which was used without further purification.
Reaction SMILES: [C:1]1([CH2:7][S:8][C:9]2[N:10]=[C:11](Cl)[C:12]3[S:17][C:16]([NH2:18])=[N:15][C:13]=3[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][C:21]1([CH2:26][OH:27])[CH2:25][CH2:24][CH2:23][CH2:22]1>>[NH2:18][C:16]1[S:17][C:12]2[C:11]([NH:20][C:21]3([CH2:26][OH:27])[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:10][C:9]([S:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:14][C:13]=2[N:15]=1
Reactant: Nc1nc2nc(SCc3ccccc3)nc(Cl)c2s1
Reactant: NC1(CO)CCCC1
Product: Nc1nc2nc(SCc3ccccc3)nc(NC3(CO)CCCC3)c2s1

Procedure:
Prepared according to the procedure in Example 1, from 5-phenylmethylthio-7-chloro-thiazolo[4,5-d]pyrimidin-2-ylamine and cycloleucinol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:10](=[O:26])[N:11]([O:22][CH2:23][O:24][CH3:25])[C:12]2([CH2:19][CH2:18][N:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[C:13]=1[OH:14].C(N(CC)CC)C.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:10](=[O:26])[N:11]([O:22][CH2:23][O:24][CH3:25])[C:12]2([CH2:15][CH2:16][N:17]([O:20][CH3:21])[CH2:18][CH2:19]2)[C:13]=1[O:14][C:37]([CH:34]1[CH2:36][CH2:35]1)=[O:38]
Reactant: COCON1C(=O)C(c2cc(C)ccc2C)=C(O)C12CCN(OC)CC2
Reactant: O=C(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCON1C(=O)C(c2cc(C)ccc2C)=C(OC(=O)C2CC2)C12CCN(OC)CC2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.5 %

Procedure:
To a solution of 3-(2,5-dimethyl-phenyl)-4-hydroxy-8-methoxy-1-methoxymethoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one (compound P2ii.2) (200 mg, 0.55 mmol), triethylamine (0.153 ml, 111 mg, 1.10 mmol) and a catalytic amount of 4-dimethylaminopyridine in tetrahydrofuran (6 ml) at 0° C. was added cyclopropanecarboxylic acid chloride (0.066 ml, 75 mg, 0.72 mmol) dropwise. The suspension was stirred at 0° C. for 10 minutes, and at room temperature for one hour. The reaction mixture was evaporated, diluted with ethyl acetate and filtered to remove salts. The filtrate was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/hexane 1:2) to afford 200 mg of an oily product. This material was triturated with diethyl ether, filtered and dried. Yield: 190 mg of cyclopropanecarboxylic acid 3-(2,5-dimethyl-phenyl)-8-methoxy-1-methoxymethoxy-2-oxo-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester (title compound P1ii.4) as a white solid, mp 114-116° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19](=[O:23])[N:20]([CH3:22])[CH3:21])=[N:11][C:10]=1[C:24](O)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.ClC(OCC(C)C)=O.Cl.[CH2:43]([O:50][C:51](=[O:54])[CH2:52][NH2:53])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)Cl>[CH2:43]([O:50][C:51](=[O:54])[CH2:52][NH:53][C:24]([C:10]1[N:11]=[C:12]([C:19](=[O:23])[N:20]([CH3:21])[CH3:22])[C:13]2[C:18]([C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:25])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CN(C)C(=O)c1nc(C(=O)O)c(OCc2ccccc2)c2ccccc12
Reactant: NCC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1nc(C(=O)NCC(=O)OCc2ccccc2)c(OCc2ccccc2)c2ccccc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 4-benzyloxy-1-dimethylcarbamoyl-isoquinoline-3-carboxylic acid (210 mg, 0.6 mmol), NEt3 (175 μl, 1.25 mmol), and CH2Cl2 (12 ml) cooled with an ice bath was added ClCO2iBu (83 μl, 0.63 mmol) with stirring. After stirring for 15 min glycine benzyl ester hydrochloride (127 mg, 0.63 mmol) was added and the mixture was stirred for another 15 min before the ice bath was removed. Stirring was then continued at ambient temperature for additional 1.5 h. Subsequently; the mixture was concentrated in vacuo. To the residue was added water (10 ml) and a few drops of aqueous 6N HCl. The mixture was extracted with EtOAc (15 ml). The organic phase was dried over MgSO4 and concentrated in vacuo to give a yellowish gum. Purification by flash column chromatography on silica gel using hexanes:EtOAc=7:3 as the eluent gave the title compound as a slightly yellowish gum (211 mg); MS-(+)-ion: M+1=498.1.
Reaction SMILES: [CH2:1]([S:8]([C:11]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[C:13]([NH2:20])[C:12]=1[CH2:21][CH2:22][NH2:23])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.O.[Ni]>[CH2:1]([S:8]([C:11]1[CH:16]=[C:15]([NH2:17])[CH:14]=[C:13]([NH2:20])[C:12]=1[CH2:21][CH2:22][NH2:23])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: NCCc1c(N)cc([N+](=O)[O-])cc1S(=O)(=O)Cc1ccccc1
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: NCCc1c(N)cc(N)cc1S(=O)(=O)Cc1ccccc1

Procedure:
20.0 g of 2-(2-aminoethyl)-amino-5-nitrophenyl benzyl sulphone are suspended in 100 ml of ethanol and 100 ml of water. In an autoclave 1 g of Raney nickel is added, 40 bar of hydrogen are injected, and the temperature is raised to 60° C. until after a further injection of hydrogen there is no further consumption. After the reduction has ended the resultant solution is clarified hot from Raney nickel, the nickel residue is washed with 40 ml of hot water, and the resulting solution is reacted as per Example 16.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]=[O:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH-:24].[Na+]>C1COCC1.C(OCC)C>[OH:24][CH2:3][CH2:2][CH2:1][N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]=[O:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1
Reactant: C=CCn1ccc2cc(C=O)ccc21
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1ccc2c(ccn2CCCO)c1

Procedure:
In a 10 mL round-bottom flask, 1-Allyl-1H-indole-5-carbaldehyde (169 mg, 0.91 mmol) is dissolved in 0.5 mL of anhydrous THF. To this solution is added 0.5 M of 9-BBN in THF (2 mL, 1.0 mmol). The reaction is allowed to stir at room temperature for 1 hr, whereupon a 1M solution of NaOH (2.5 mL) is added. The organic layer is diluted with 10 mL of diethyl ether and the aqueous layer is removed. The organic layer is washed 3×10 mL with 1M NaOH, followed by 2×10 mL water and 2×10 mL saturated NaCl solutions. The organic layer is then dried over Na2SO4 and the solvent is removed under reduced pressure to afford 1-(3-hydroxy-propyl)-1H-indole-5-carbaldehyde.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8](Cl)[C:7]([Cl:11])=[CH:6][C:3]=1[C:4]#[N:5].CCN(C(C)C)C(C)C.[CH:21]1([C:24]2[NH:28][N:27]=[C:26]([NH2:29])[CH:25]=2)[CH2:23][CH2:22]1>CCCCO>[Cl:1][C:2]1[N:9]=[C:8]([NH:29][C:26]2[CH:25]=[C:24]([CH:21]3[CH2:23][CH2:22]3)[NH:28][N:27]=2)[C:7]([Cl:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(Cl)c(Cl)nc1Cl
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)c(Nc2cc(C3CC3)[nH]n2)nc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
To a solution of 2,5,6-trichloronicotinonitrile (Method 44, 1.0 g, 4.8 mmol) and DIEA (0.81 g, 6.2 mmol) in n-BuOH (5 ml) was added 5-cyclopropyl-1H-pyrazol-3-amine (2.3 g, 19.3 mmol). The reaction was heated to 60° C. for 2 hours, at which point the reaction was cooled to room temperature and concentrated. The resulting residue was diluted with 10 ml ACN, and stored at 0° C. for 1 hour. The solids that formed were then filtered, washed with cold ACN, dried and collected to give the title compound (0.62 g, 43%). MS: Calcd.: 294. Found: [M+H]+ 295.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([S:12][C:13]2[CH:18]=[N:17][CH:16]=[CH:15][N:14]=2)=[CH:7][C:6]=1[CH3:19])=O.[NH2:20][C:21]([NH2:23])=[S:22]>CCO>[CH3:19][C:6]1[CH:7]=[C:8]([S:12][C:13]2[CH:18]=[N:17][CH:16]=[CH:15][N:14]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:20]=[C:21]([NH2:23])[S:22][CH:2]=1
Reactant: NC(N)=S
Reactant: Cc1cc(Sc2cnccn2)cc(C)c1C(=O)CBr
Solvent: CCO
Product: Cc1cc(Sc2cnccn2)cc(C)c1-c1csc(N)n1
Yield: 41.7 %

Procedure:
A mixture of 2-bromo-1-(2,6-dimethyl-4-(pyrazin-2-ylthio)phenyl)ethanone (11-4, 4.00 g, 11.9 mmol) and thiourea (902.9 mg, 11.9 mmol) in 95% EtOH (15 mL) was heated at reflux for 16 hr. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (10.0 mL). The resultant precipitate was filtered and recrystallized in toluene (30 mL). The solids were filtered and dried under vacuum to give 4-(2,6-dimethyl-4-(pyrazin-2-ylthio)phenyl)thiazol-2-amine (11-5, 1.56 g) as yellow solids in 42% yield: 1H NMR (500 MHz, CDCl3) δ 8.43 (s, 1 H), 8.36 (s, 1 H), 8.31 (s, 1 H), 7.47 (s, 2 H), 6.34 (s, 1 H), 2.24 (s, 6 H). ESI-MS: m/z 315.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[C:4]([C:14]([O:16]CC)=[O:15])[N:3]=1.FC(F)(F)C([O-])=O.[Cl:26][C:27]1[C:31]([Cl:32])=[C:30]([CH3:33])[NH:29][C:28]=1[C:34]([NH:36][CH:37]1[CH2:42][CH2:41][NH2+:40][CH2:39][CH2:38]1)=[O:35].C([O-])([O-])=O.[K+].[K+]>C(O)(C)(C)C>[Cl:26][C:27]1[C:31]([Cl:32])=[C:30]([CH3:33])[NH:29][C:28]=1[C:34]([NH:36][CH:37]1[CH2:42][CH2:41][N:40]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([O:12][CH3:13])=[C:4]([C:14]([OH:16])=[O:15])[N:3]=2)[CH2:39][CH2:38]1)=[O:35]
Reactant: CCOC(=O)c1nc(Cl)c2ccccc2c1OC
Reactant: Cc1[nH]c(C(=O)NC2CC[NH2+]CC2)c(Cl)c1Cl
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COc1c(C(=O)O)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)c2ccccc12
Temperature: 170 °C
Reaction time: 8 h
Yield: 1.8 %

Procedure:
In a sealed high pressure container with a Teflon lining was combined ethyl 1-chloro-4-methoxyisoquinoline-3-carboxylate (EP 650961 A1; 390 mg, 1.55 mmol), 4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidinium trifluoroacetate (Intermediate 86; 1.7 g, 4.4 mmol), and K2CO3 (2.2 g) in 20 ml tert-butanol. The container was heated at 170° C. with stirring for 8 hours. The solution was concentrated by rotary evaporation and reconstituted with EtOAc. The organic layer was washed 4× with H2O, and dried over MgSO4. Crude ethyl 1-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-4-methoxyisoquinoline-3-carboxylate was purified by reverse phase Si yielding 20 mg of the intermediate ester. The ethyl ester was then hydrolyzed as in Example 262 to yield 13.5 mg white solid final product.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[N:5]=[C:4]([C:18]([O:20]CC)=O)[CH:3]=1.Cl.[NH3:24]>>[OH:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[N:5]=[C:4]([C:18]([NH2:24])=[O:20])[CH:3]=1
Reactant: CCCOc1ccccc1-c1nc(O)cc(C(=O)OCC)n1
Reactant: N
Agent: Cl
Product: CCCOc1ccccc1-c1nc(O)cc(C(N)=O)n1
Reaction time: 72 h

Procedure:
A solution of ethyl 6-hydroxy-2-(2-propoxyphenyl)pyrimidine-4-carboxylate (0.44 g) in aqueous ammonia solution (20 ml) was stirred in a stoppered flask at ambient temperature for 4 hours and then allowed to stand for 3 days. The reaction mixture was acidified with concentrated hydrochloric acid to precipitate the title compound, 0.46 g, m.p. 232°-4° C. This was recrystallized from ethanol:methanol to yield the pure title compound, 0.32 g, m.p. 233.5°-234.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:27])[N:14]([CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[N:15]=[C:16]([CH:19]([CH3:21])[CH3:20])[C:17]=3[OH:18])=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C([O-])(O)=O.[Na+]>CN(C)C1C=CN=CC=1.CN(C=O)C>[OH:18][C:17]1[C:16]([CH:19]([CH3:21])[CH3:20])=[N:15][N:14]([CH2:22][CH2:23][CH:24]([CH3:25])[CH3:26])[C:13](=[O:27])[C:12]=1[C:7]1[NH:6][C:5]2[CH:28]=[CH:29][C:2]([NH:1][C:37](=[O:44])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:3][C:4]=2[S:9](=[O:10])(=[O:11])[N:8]=1
Reactant: CC(C)CCn1nc(C(C)C)c(O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c1=O
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CCn1nc(C(C)C)c(O)c(C2=NS(=O)(=O)c3cc(NC(=O)c4ccccc4)ccc3N2)c1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 52.1 %

Procedure:
To a solution of 5j (0.048 g, 0.11 mmol) and 4-dimethylaminopyridine (0.0014 g, 0.011 mmol) in DMF was added triethylamine (18 μL, 0.125 mmol) followed by benzoyl chloride (16 μL, 0.137 mmol). The reaction mixture was stirred 4 h at 80° C. and cooled to room temperature. The reaction mixture was treated with sat NaHCO3 (1 mL) and extracted two times with EtOAc (3 mL). The combined organic layer was washed with brine (1 mL), dried over MgSO4, and concentrated in vacuo. The crude mixture was purified by flash column chromatography using silica gel (0-40% EtOAc/hexanes) to give 5k (0.030 g, 50%) as a yellow solid. 1H NMR (400 MHz, D6-DMSO) δ 10.63 (br s), 8.45 (d, J=2.4 Hz, 1H), 8.09 (dd, J=8.8, 2 Hz, 1 H), 8.97 (d, J=7.2 Hz, 2 H), 7.67 (d, J=9.2 Hz, 1 H), 7.60 (d, J=7.2 Hz, 1 H), 7.54 (t, J=7.2 Hz, 2 H), 4.13 (d, J=6.8 Hz, 2 H), 3.25 (m, 1 H), 1.63 (m, 3 H), 1.22 (d, J=6.8 Hz, 6 H), 0.93 (d, J=6.4 Hz, 6 H). LC-MS(ESI+) m/e 524 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=1.C(O[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>>[Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][N:3]=1
Reactant: Nc1cnc(Br)nc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1cnc(Br)nc1)C(=O)OCC
Temperature: 135 °C

Procedure:
A mixture of 2-bromopyrimidin-5-amine (Krchnak, V.; Arnold, Z. Coll. Czech. Chem. Commun. 1975, 40, 1396-1402) (3.48 g) and diethyl ethoxymethylenemalonate (5.05 mL) is heated to 135° C. for 1 h. The mixture is allowed to cool affording a solid.
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]2[CH2:7][CH2:8][O:9][C:10]3[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:11]=3[C:12]=2[N:13]=1)=[N+:2]=[N-:3].[CH3:19][C:20]([CH3:24])([CH3:23])[C:21]#[CH:22]>>[Br:18][C:16]1[CH:15]=[CH:14][C:11]2[C:12]3[N:13]=[C:4]([N:1]4[C:21]([C:20]([CH3:24])([CH3:23])[CH3:19])=[CH:22][N:3]=[N:2]4)[S:5][C:6]=3[CH2:7][CH2:8][O:9][C:10]=2[CH:17]=1
Reactant: [N-]=[N+]=Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: C#CC(C)(C)C
Product: CC(C)(C)c1cnnn1-c1nc2c(s1)CCOc1cc(Br)ccc1-2

Procedure:
Following the procedure for 414, Step 3, 2-azido-8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 3,3-dimethyl-1-butyne to afford the title compound as a pale yellow solid. LCMS (Method A): RT=4.95 min, [M+H]+=405 and 407. 1H NMR (CDCl3): 8.16 (1 H, dd, J=8.1, 0.9 Hz), 7.55 (1 H, s), 7.28 (2 H, m), 4.42 (2 H, t, J=5.1 Hz), 3.37 (2 H, t, J=5.1 Hz), 1.54 (9 H, s).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14](=[O:19])[NH:15][CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:16]([NH:15][C:14]([C@H:11]1[CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:13][CH2:12]1)=[O:19])([CH3:18])[CH3:17]
Reactant: CC(C)NC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)[C@H]1CC[C@H](N)CC1

Procedure:
A mixture of trans (4-isopropylcarbamoyl-cyclohexyl)-carbamic acid tert-butyl ester (1.35 g, 4.75 mmoll) in DCM (25 ml) was treated with TFA (5 ml) at ambient temperature for 1 hour. The solvent was evaporated under vacuum and the residues diluted with water and extracted into ethyl acetate. The combined organic extracts were washed with 1M sodium hydroxide, water and brine, dried with magnesium sulfate and concentrated under vacuum affording 400 mg (46%) of trans 4-amino-cyclohexanecarboxylic acid isopropylamide as a white solid. LCMS (Method B, ESI): RT=0.43 min, m+H=185.21; 1H NMR (400 MHz, DMSO) δ: 7.50 (d; 1H); 3.81-3.75 (m; 1H); 2.55 (m, 1H); 1.94 (m; 1H); 1.79 (m; 2H); 1.69-1.58 (m; 2H); 1.35 (m; 2H); 1.01 (d; 6H) 0.99 (m; 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([Br:17])=[C:15]([Br:18])[N:14]=[C:13]2Br)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C([Mg]Br)C.O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([Br:17])=[C:15]([Br:18])[N:14]=[CH:13]2)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: Clc1cc2c(cc1Cn1c(Br)nc(Br)c1Br)OCO2
Agent: CC[Mg]Br
Solvent: ClCCl
Solvent: O
Product: Clc1cc2c(cc1Cn1cnc(Br)c1Br)OCO2
Temperature: 25 °C

Procedure:
The operation is carried out as in Stage 2 of Example 1 starting with 6 g of the product obtained in Stage 1 of Example 1 in 300 ml of a methylene chloride/sulphuric ether mixture (60/240), to which 4.6 ml of ethyl magnesium bromide is added dropwise, then the whole is maintained under agitation for 30 minutes at ambient temperature and then 100 ml of ice-cooled water is introduced into the reaction medium obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11]([CH3:22])=[N:10][N:9]=2)=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH:38](O)=[O:39]>ClCCl>[CH:38]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11]([CH3:22])=[N:10][N:9]=2)=[CH:4][CH:3]=1)=[O:39]
Reactant: CC1=NN=C(c2ccc(N)cc2)c2cc3c(cc2C1)OCO3
Reactant: O=CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC1=NN=C(c2ccc(NC=O)cc2)c2cc3c(cc2C1)OCO3
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
3.0 g (10.2 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine were dissolved in 160 ml of dichloromethane and first 2.75 g (13.3 mmol) of dicyclohexylcarbodiimide, then 0.51 ml (13.3 mmol) of 100% formic acid were added and the reaction mixture was stirred for 2 hours at room temperature. The precipitated N,N'-dicyclohexylurea was filtered, the filtrate was extracted with 2×30 ml of 10% aqueous sodium carbonate solution, then with 2×30 ml of distilled water, the organic layer was dried and evaporated at reduced pressure. The residue was dissolved in ethyl acetate, filtered and evaporated under reduced pressure. The resulting raw product was recrystallized from 20 ml of 50% ethanol to yield 2.93 g (89.3%) of the aimed product, m.p. 152°-154° C. (slight decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:28])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:10][CH2:9]2)[CH:7]=1.O.NN>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:28])=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:12][CH2:13]2)[CH:7]=1
Reactant: Cc1ccc(Cl)cc1N1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1ccc(Cl)cc1N1CCN(CCCN)CC1
Temperature: 25 °C

Procedure:
A solution of 2-(3-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)propyl)isoindoline-1,3-dione (397 mg, 1.0 mmol) and hydrazine monohydrate (52 mg, 1.04 mmol) in ethanol (5 mL) was heated at 70° C. for 12 h. After the reaction cooled to room temperature, the solid was filtered off, and filtrate is evaporated to give the title compound, used without further purification.