Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[OH-].[Li+]>CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: O=C([O-])c1cc(Br)cc2cc[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(Br)cc2cc[nH]c12
Yield: 99.4 %

Procedure:
5-bromo-1H-indole-7-carboxylate (5 g, 19.7 mmol) was dissolved in methanol (200 mL) and a solution of lithium hydroxide (0.99 g, 41 mmol) in water (10 mL) was added. The mixture was heated at reflux for 50 hours. The methanol was removed in vacuo and the residue diluted with aqueous hydrochloric acid (2 M). The resulting precipitate was filtered off and dried in a heated vacuum pistol to give the title compound as a beige solid (4.7 g).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)=[CH:4][C:3]=1[CH3:15].[F:16][C:17]1[CH:18]=[CH:19][C:20](B2OC(C)(C)C(C)(C)O2)=[C:21]2[C:25]=1[C@H:24]([O:26][C:27]1[CH:40]=[CH:39][C:30]3[C@H:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:32][O:33][C:29]=3[CH:28]=1)[CH2:23][CH2:22]2.BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:15][C:3]1[CH:4]=[C:5]([C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)[CH:6]=[C:7]([CH3:8])[C:2]=1[C:20]1[CH:19]=[CH:18][C:17]([F:16])=[C:25]2[C:21]=1[CH2:22][CH2:23][C@H:24]2[O:26][C:27]1[CH:40]=[CH:39][C:30]2[C@H:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:32][O:33][C:29]=2[CH:28]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(-c2nnnn2C)cc(C)c1Br
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6nnnn6C)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from 5-(4-bromo-3,5-dimethylphenyl)-1-methyl-1H-tetrazole and methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 11): tR=1.20 min; Mass spectrum (ESI+): m/z=529 [M+H]+.
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]2[C@H:15]([CH2:16][CH2:17]O)[O:14][CH2:13][CH2:12][C:11]=2[CH:19]=1.CS(Cl)(=O)=O.CS(OCC[C@H]1C2C=CC(C(N)=O)=CC=2CCO1)(=O)=O.S([O-])(=O)(=O)C.[CH2:51]1[C:61]2=[C:62]3[C:57](=[CH:58][CH:59]=[CH:60]2)[C:56]([N:63]2[CH2:68][CH2:67][NH:66][C@H:65]([CH3:69])[CH2:64]2)=[CH:55][CH:54]=[C:53]3[CH2:52]1>>[CH2:51]1[C:61]2=[C:62]3[C:57](=[CH:58][CH:59]=[CH:60]2)[C:56]([N:63]2[CH2:68][CH2:67][N:66]([CH2:17][CH2:16][C@H:15]4[C:10]5[CH:9]=[CH:8][C:7]([N:3]6[CH2:4][CH2:5][CH2:6][S:2]6(=[O:20])=[O:1])=[CH:19][C:11]=5[CH2:12][CH2:13][O:14]4)[C@H:65]([CH3:69])[CH2:64]2)=[CH:55][CH:54]=[C:53]3[CH2:52]1
Reactant: O=S1(=O)CCCN1c1ccc2c(c1)CCO[C@H]2CCO
Reactant: C[C@@H]1CN(c2ccc3c4c(cccc24)CC3)CCN1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)OCC[C@@H]1OCCc2cc(C(N)=O)ccc21
Agent: CS(=O)(=O)[O-]
Product: C[C@@H]1CN(c2ccc3c4c(cccc24)CC3)CCN1CC[C@@H]1OCCc2cc(N3CCCS3(=O)=O)ccc21

Procedure:
2-[(1S)-6-(1,1-Dioxido-2-isothiazolidinyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethanol was reacted with methanesulfonyl chloride, as described for the preparation of 2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl methanesulfonate. The resultant crude mesylate was then condensed with (3R)-1-(1,2-dihydro-5-acenaphthylenyl)-3-methylpiperazine, as described for Example 1b), to yield the title compound. M+H=532.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[C:13](=O)([O-])[O-].[Cs+].[Cs+].IC>C(#N)C.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Nc1ccccc1Br
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Solvent: ClCCl
Product: CN(c1ccccc1Br)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
196 b) To a suspension of N-(2-bromo-phenyl)-methanesulfonamide (5.01 g, 20.0 mmol) and cesium carbonate (7.2 g, 22 mmol) in acetonitrile (20 mL) was added iodomethane (1.4 mL, 22 mmol). The mixture was stirred at room temperature for 24 hours then diluted with dichloromethane (30 mL), filtered through a plug of diatomaceous earth and evaporated. N-(2-Bromo-phenyl)-N-methyl-methanesulfonamide was isolated as a pale orange solid (5.22 g, 98%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.65 (d, J=8.0 Hz, 1H), 7.50 (d, J=7.9 Hz, 1H), 7.37 (t, J=7.4 Hz, 1H), 7.23 (t, J=8.2 Hz, 1H), 3.29 (s, 3H), 3.06 (s, 3H). MS=286, 288 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[Cl:31][C:32]1[N:37]=[CH:36][N:35]=[C:34]([C:38](O)=[O:39])[CH:33]=1>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:38]([C:34]3[CH:33]=[C:32]([Cl:31])[N:37]=[CH:36][N:35]=3)=[O:39])=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=C(O)c1cc(Cl)ncn1
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Product: Nc1nccn2c([C@@H]3CCCN3C(=O)c3cc(Cl)ncn3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Yield: 6.2 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from the compound described in intermediate 2b and 6-chloropyrimidine-4-carboxylic acid, to afford the title compound (2.5 mg, 6.2%). Data: UPLC (C) Rt: 1.64 min; m/z 540.3 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18]2)=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][N:30]([CH3:35])[S:31](Cl)(=[O:33])=[O:32]>N1C=CC=CC=1>[CH2:1]([N:8]([C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18]2)=[O:16])=[CH:13][CH:14]=1)[S:31]([N:30]([CH3:35])[CH3:29])(=[O:33])=[O:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: O=C(c1ccc(NCc2ccccc2)cc1)N1CCOC(c2ccccc2)C1
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)N(Cc1ccccc1)c1ccc(C(=O)N2CCOC(c3ccccc3)C2)cc1
Yield: 34.8 %

Procedure:
A solution of (4-benzylamino-phenyl)-(2-phenyl-morpholin-4-yl)-methanone (80 mg, 0.21 mmol) and N,N-dimethylsulfamoyl chloride (0.3 ml, 2 mmol) in pyridine (5 ml) was heated to 70° C. for 16 hours. The reaction was cooled then filtered and the filtrate diluted with dichloromethane (20 ml). The resulting solution was washed with hydrochloric acid 2N (20 ml), the organics collected and dried over magnesium sulfate. The solvent was removed in vacuo and the residue purified by preparative thin layer chromatography eluting with 50% ethylacetate/hexanes to afford the title compound as a colourless oil (35 mg, 35% yield). HPLC retention time 6.1 min. Mass spectrum (ES+) m/z 480 (M+H).
Reaction SMILES: O1CCCC1.C([N-]C(C)C)(C)C.[Li+].C1CCCCC1.[CH3:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][CH:23]=1.Cl[C:32]([CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[O:33].Cl>C1COCC1>[OH:30]/[C:28](/[C:25]1[CH:26]=[CH:27][C:22]([S:21][CH3:20])=[CH:23][CH:24]=1)=[CH:29]\[C:32](=[O:33])[CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38]
Reactant: CSc1ccc(C(C)=O)cc1
Reactant: COC(=O)CCCC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: COC(=O)CCCC(=O)/C=C(\O)c1ccc(SC)cc1
Temperature: -72 °C
Reaction time: 0.5 h

Procedure:
Lithium diisopropylamide mono(tetrahydrofuran) in cyclohexane (1.5 M; 28 mL, 42 mmol) was added to a solution of 1-(4-methylthiophenyl)ethan-1-one (5.16 g, 31 mmol) in THF (120 mL) and stirred for 30 minutes at −72° C. A solution of methyl 4-(chloroformyl)butyrate (1.78 g, 10.8 mmol) was added to the above solution and stirred for 30 minutes and then warmed slowly from the −72° C. to −45° C. To the reaction mixture was added 3N HCl (50 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and evaporated. Trituration of the residue with diethyl ether/hexane gave a mixture of the title compound and starting material (˜30% yield) as a solid (2.42 g). The crude material was used in the next step without purification. A small quantity of pure sample was obtained at the beginning of the trituation. Mp. 92–93° C. 1H NMR (CDCl3) δ 15.1 (br, 1H), 7.79 (d, J=8.6 Hz, 2H), 7.27 (d, J=8.6 Hz, 2H), 6.13 (s, 1H), 3.69 (s, 3H), 2.52 (s, 3H), 2.48 (t, J=7.4 Hz, 2H), 2.42 (t, J=7.4 Hz, 2H), 2.02 (m, 2H). 13C NMR (CDCl3) δ 194.8, 183.0, 173.4, 144.9, 131.0, 127.3, 125.2, 95.6, 51.5, 37.9, 33.1, 20.8, 14.8.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1>CN(C=O)C>[CH3:1][N:2]([CH2:9][C:8]1[CH:11]=[CH:12][C:5]([Br:4])=[CH:6][CH:7]=1)[CH3:3]
Reactant: BrCc1ccc(Br)cc1
Reactant: CNC
Solvent: CN(C)C=O
Product: CN(C)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2M Ethanolic dimethylamine solution (30 ml) was added to a solution of 4-bromobenzyl bromide (5 g) in DMF (20 ml). The mixture was stirred at ambient temperature for 18 h and was then partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried, evaporated and purified by column chromatography, eluting with a gradient of 0 to 5% methanol in DCM to yield the product as a clear oil. MS (M+H)+ 214. 1H NMR (CDCl3) 2.21 (s, 6H), 3.35 (s, 2H), 7.18 (d, 2H), 7.43 (d, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:49])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:30][C:31]2[CH:32]=[C:33]([C:39]3[CH:44]=[CH:43][N:42]=[C:41]([C:45]([O:47]C)=O)[CH:40]=3)[CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:16]([C:18]2[S:22][C:21]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=3[C:19]=2[Cl:29])=[O:17])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:50][NH2:51]>CO>[Cl:29][C:19]1[C:20]2[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:21]=2[S:22][C:18]=1[C:16]([N:15]([CH2:30][C:31]1[CH:32]=[C:33]([C:39]2[CH:44]=[CH:43][N:42]=[C:41]([C:45](=[O:47])[NH:51][CH3:50])[CH:40]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH:12]1[CH2:11][CH2:10][CH:9]([N:8]([CH3:49])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:14][CH2:13]1)=[O:17]
Reactant: COC(=O)c1cc(-c2ccc(OC)c(CN(C(=O)c3sc4c(F)ccc(F)c4c3Cl)C3CCC(N(C)C(=O)OC(C)(C)C)CC3)c2)ccn1
Reactant: CN
Solvent: CO
Product: CNC(=O)c1cc(-c2ccc(OC)c(CN(C(=O)c3sc4c(F)ccc(F)c4c3Cl)C3CCC(N(C)C(=O)OC(C)(C)C)CC3)c2)ccn1
Reaction time: 1 h

Procedure:
A stirred solution of methyl ester 148 (30 mg, 0.05 mmol) in MeOH (2 mL) is treated with methylamine (1 mL, 40% solution in water) at RT. After 1 h, the reaction mixture is reduced in vacuo and the residue purified by column chromatography (75% EtOAc in heptane) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([C:26](OC)=[O:27])=[CH:25][C:4]=2[N:3]=1>C1COCC1>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH2:26][OH:27])=[CH:25][C:4]=2[N:3]=1
Reactant: COC(=O)c1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OC)cc3)cc12
Solvent: C1CCOC1
Product: COc1ccc(CCc2cnc3c(N)nc4cc(CO)ccc4c3c2)cc1
Temperature: 25 °C

Procedure:
To a solution of methyl 5-amino-2-(4-methoxyphenethyl)benzo[f][1,7]naphthyridine-8-carboxylate (from the previous step) (1.0 eq.) in THF (0.03M) was added Super-H (10 eq.) at 0° C. The solution was allowed to warm to ambient temperature over 30 minutes. The reaction was quenched by water until no bubbling. The layers were separated and aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4 and concentrated en vaccuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-100% EtOAc/Hexanes to give (5-amino-2-(4-methoxyphenethyl)benzo[f][1,7]naphthyridin-8-yl)methanol as an off white solid (31%): 1H NMR (acetone-d6): δ 8.79 (d, 1H), 8.70 (d, 1H), 8.35 (d, 1H), 7.61 (d, 1H), 7.33 (dd, 1H), 7.13 (d, 2H), 6.83 (d, 2H), 6.62 (br s, 2H), 4.47 (s, 2H), 4.40 (br s, 1H), 3.75 (s, 3H), 3.22 (t, 2H), 3.06 (t, 2H). LRMS [M+H]=360.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:14][CH3:15])=[N:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[C:16]1([CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:14][CH3:15])=[N:10][N:11]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][CH2:23][CH2:22][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CCc1n[nH]c2cc(C(=O)OC)ccc12
Reactant: BrCCCCCCOCCCCc1ccccc1
Product: CCc1nn(CCCCCCOCCCCc2ccccc2)c2cc(C(=O)OC)ccc12
Yield: 55.6 %

Procedure:
This compound was prepared according to the method of Preparation 3, using 137 mg (0.671 mmol, 1.0 equiv) 3-ethyl-1H-indazole-6-carboxylic acid methyl ester and 273 mg (0.872 mmol, 1.3 equiv) 6-(4-phenyl-butoxy)-hexyl bromide as starting materials to give 163 mg (56%) of a yellow oil: HRMS calcd for C27H36N2O3+H: 437.2804. Found 437.2833.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.N(OC(C)(C)C)=O.[ClH:25].CO>C(#N)C.[Cu](Cl)Cl>[Cl:25][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1
Reactant: Cl
Reactant: N#Cc1ccc(-c2cc(N)cc(CO)c2)cc1
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CO
Solvent: CC#N
Product: N#Cc1ccc(-c2cc(Cl)cc(CO)c2)cc1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
A solution of 3′-amino-5′-(hydroxymethyl)biphenyl-4-carbonitrile (120 mg, 0.54 mmol) in dry acetonitrile (1 mL) was added dropwise to a solution of copper (II) chloride (86 mg, 0.64 mmol) and tert-butyl nitrite (91 μL, 0.78 mmol) in acetonitrile (2 mL) at 65° C. After stirring for 30 min at 65° C., the reaction mixture was cooled to room temperature, poured into a 1 N hydrochloric acid solution, and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (20% ethyl acetate/hexanes) afforded 46 mg (35%). LC/MS: tR=2.54 min, 244.03 (MH)+. (Phenomenex C18 4.6×50 mm, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA, Gradient time=4 min., Flow rate=4 mL/min.).
Reaction SMILES: SC([OH:4])C.C1C(CN2C(=O)C=CC2=O)CCC(C(ON2C(=O)CCC2=O)=O)C1.C([O-])(=O)CCCCC.C1C(SSC2C=CC([N+]([O-])=O)=C(C(O)=O)C=2)=CC(C(O)=O)=C([N+]([O-])=O)C=1.[C:63]([CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][NH:71][C:72]([CH:74]1[CH2:79][CH2:78][CH:77]([CH2:80][N:81]2[C:85](=[O:86])[CH2:84][CH:83]([CH2:87][CH2:88]C(O)=O)[C:82]2=[S:92])[CH2:76][CH2:75]1)=[O:73])([OH:65])=[O:64]>>[C:63]([CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][NH:71][C:72]([CH:74]1[CH2:79][CH2:78][CH:77]([CH2:80][N:81]2[C:85](=[O:86])[CH2:84][CH:83]([CH2:87][CH2:88][OH:4])[C:82]2=[S:92])[CH2:76][CH2:75]1)=[O:73])([OH:65])=[O:64]
Reactant: O=C(O)CCCCCNC(=O)C1CCC(CN2C(=O)CC(CCC(=O)O)C2=S)CC1
Reactant: CC(O)S
Agent: CCCCCC(=O)[O-]
Agent: O=C(O)c1cc(SSc2ccc([N+](=O)[O-])c(C(=O)O)c2)ccc1[N+](=O)[O-]
Agent: O=C(ON1C(=O)CCC1=O)C1CCC(CN2C(=O)C=CC2=O)CC1
Product: O=C(O)CCCCCNC(=O)C1CCC(CN2C(=O)CC(CCO)C2=S)CC1
Reaction time: 12 h

Procedure:
Mercaptoethanol (0.0045 ml of 1.43M solution in dimethylformamide, 6.4×10-6 mol) was added to SMCC-caproate (0.016 ml, 6.4×10-6 mol) in pyridine (see Example 6). The solution was gassed with argon and the tube sealed. After 12 hr at room temperature, no thiol remained (as determined by reaction with DTNB) and the solvents were removed in vacuo. The residue was dissolved in 0.03 ml of 0.2M potassium phosphate, pH 7, to make a 213 mM solution of the desired compound (see FIG. 1D).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[N:9]2[C:10]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:11]=3[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])=[N:13][CH2:14][C:8]2=[N:7][N:6]=1.[CH3:28][NH:29][CH3:30]>CN(C)C=O>[CH3:28][N:29]([CH3:30])[C:3](=[O:2])[CH2:4][C:5]1[N:9]2[C:10]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:11]=3[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])=[N:13][CH2:14][C:8]2=[N:7][N:6]=1
Reactant: COC(=O)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: CNC
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Preparation 3, 8-chloro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-acetic acid methyl ester is reacted with dimethylamine in dimethylformamide to give N,N-dimethyl-8-chloro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-acetamide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1>O1CCCC1>[N:9]1([C:2]2[N:7]=[C:6]([N:9]3[CH:13]=[CH:12][N:11]=[CH:10]3)[CH:5]=[CH:4][N:3]=2)[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: Clc1ccnc(Cl)n1
Reactant: c1c[nH]cn1
Solvent: C1CCOC1
Product: c1cn(-c2ccnc(-n3ccnc3)n2)cn1
Yield: 76.9 %

Procedure:
In anhydrous tetrahydrofuran, 149 mg of 2,4-dichloropyrimidine was substituted with 136 mg of imidazole. The reaction mixture was treated according to the procedure of Example 1 to yield 163 mg of 2,4-bis(1-imidazolyl)pyrimidine, recrystallized from a mixture of n-hexane and ethyl acetate, the compound had a melting point of 131°-132° C.
Reaction SMILES: [C:1](=[O:7])([O:3][CH2:4][CH2:5][CH3:6])[NH2:2].C(Cl)(=O)[C:9](Cl)=[O:10]>>[CH2:4]([O:3][C:1]([N:2]=[C:9]=[O:10])=[O:7])[CH2:5][CH3:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCOC(N)=O
Product: CCCOC(=O)N=C=O

Procedure:
When propyl carbamate is reacted with oxalyl chloride as described in the procedure of Example 13, propoxycarbonyl isocyanate is obtained.
Reaction SMILES: C([O:3][CH:4]=[C:5]([C:11]#[N:12])[C:6](OCC)=O)C.[CH3:13][S:14][C:15](=[NH:17])[NH2:16].C[O-].[Na+].[Na]>CO>[OH:3][C:4]1[C:5]([C:11]#[N:12])=[CH:6][N:16]=[C:15]([S:14][CH3:13])[N:17]=1
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: CSC(=N)N
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CSc1ncc(C#N)c(O)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 48 %

Procedure:
To a 5° C. solution of 119 g (703 mmol) of freshly distilled ethyl (ethoxymethylene)cyanoacetate in 800 mL of methanol is added 108 g (599 mmol) of 2-methyl-2-thiopseudourea. To this mixture is added a solution of sodium methoxide prepared by dissolving 35.6 g (1.55 mol) of sodium metal in 800 mL of methanol. The solution is warmed to room temperature and stirred for 6 hours. After standing overnight, the solvent is removed under reduced pressure, the residue is dissolved in 1.5 L of water at 50° C. with stirring, and the solution is filtered hot. The filtrate is acidified to pH 2 with concentrated HCl and kept at room temperature overnight. The precipitated product is collected and dried to give 48.3 g (48%) of the title compound, which is used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C@H:8]2[CH2:10][C@H:9]2[C:11](O)=[O:12])=O)=[CH:4][CH:3]=1.O.[NH2:17][NH2:18]>C(O)C>[NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]2[CH:8]3[CH:9]([C:11](=[O:12])[NH:17][N:18]=2)[CH2:10]3)=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)[C@H]2C[C@H]2C(=O)O)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc(C2=NNC(=O)C3CC23)cc1
Yield: 94.8 %

Procedure:
20 g (97.5 millimoles) of cis-2-(p-aminobenzoyl)-cyclopropanecarboxylic acid, 5.9 g (118 millimoles) of hydrazine hydrate and 100 ml of ethanol are refluxed for 5 hours. After filtering off the product at 10° C. and drying it under reduced pressure at 50° C., 18.6 g (95% of theory) of 2-(p-aminophenyl)-3,4-diaza-bicyclo[4.1.0]-hept-2-en-5-one are obtained as pale yellow crystals, which are identical with the compound from Example 8a.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[C:8]([CH3:16])=[C:9]([C:13]([OH:15])=O)[NH:10][C:11]=1[CH3:12])=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.Cl.[CH:52]([N:55]1[CH2:60][CH2:59][CH:58]([NH2:61])[CH2:57][CH2:56]1)([CH3:54])[CH3:53]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:4])[CH2:5][CH2:6][C:7]1[C:8]([CH3:16])=[C:9]([C:13](=[O:15])[NH:61][CH:58]2[CH2:59][CH2:60][N:55]([CH:52]([CH3:54])[CH3:53])[CH2:56][CH2:57]2)[NH:10][C:11]=1[CH3:12]
Reactant: CC(C)N1CCC(N)CC1
Reactant: COC(=O)CCc1c(C)[nH]c(C(=O)O)c1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCc1c(C)[nH]c(C(=O)NC2CCN(C(C)C)CC2)c1C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 40.6 %

Procedure:
263 mg of (1.17 mmol) 4-(2-methoxycarbonyl-ethyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid were dissolved in DMF (10 mL). 488.4 mg (1.28 mmol) of HATU and DIEA (224 μl) were added and the resulting mixture was stirred for 45 minutes at RT. A solution of 276.3 mg (1.28 mmol) of 1-isopropyl-piperidine-4-ylamine-dihydrochloride and 448 μl of DIEA was added. The reaction mixture was stirred over night after which it was concentrated. The residue was diluted with DCM and washed with a saturated NaHCO3 solution and brine. The organic layer was dried over MgSO4 and concentrated. Preparative HPLC(CH3CN/H2O gradient+0.05% formic acid) gave pure 3-[5-(1-isopropyl-piperidin-4-ylcarbamoyl)-2,4-dimethyl-1H-pyrrol-3-yl]-propionic acid methyl ester (166 mg) as a colorless amorphous material. MS (ESI+): m/e=351 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[NH:7][C:6](=[O:15])/[C:5]/2=[CH:16]/OC.[N:19]1([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[NH:7][C:6](=[O:15])[C:5]2=[CH:16][NH:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:31][CH:30]=1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Reactant: CO/C=C1/C(=O)NC(=O)c2cc(OC)c(Br)cc21
Solvent: CN(C)C=O
Product: COc1cc2c(cc1Br)C(=CNc1ccc(CN3CCCCC3)cc1)C(=O)NC2=O
Temperature: 110 °C
Yield: 57 %

Procedure:
A mixture of (4E)-6-bromo-7-methoxy-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (156 mg, 0.50 mmole), N,N-dimethylformamide (1 mL) and 4-piperidin-1-ylmethyl-phenylamine (95 mg, 0.50 mmole) is stirred and heated at 110° C. for one hour, cooled in the refrigerator. The reaction mixture is evaporated to dryness, taken up in 5% methanol in chloroform and passed through a short pad of Florisil eluting with 5% methanol in chloroform. The eluate is evaporated in vacuo, treated with acetonitrile, filtered and dried to give a dull yellow solid 134 mg (57%), mp 264-7° C.; MS (ESI): m/z 470.1 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([NH2:19])[CH:10]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28].C(Cl)Cl>C1COCC1.O.CCOC(C)=O.CO>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:19][C:27](=[O:28])[O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(Nc2cc(N)cc(C(F)(F)F)c2)CC1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN1CCC(Nc2cc(NC(=O)Oc3ccccc3)cc(C(F)(F)F)c2)CC1
Temperature: -30 °C
Reaction time: 3 h
Yield: 103 %

Procedure:
Dissolve the compound obtained in Step 2 (2.9 g, 10.61 mmol) in THF (30 mL), cool to −30° C., then add pyridine (1.68 g, 21.22 mmol) and phenyl chloroformate (1.83 g, 11.67 mmol). Stir at room temperature for 3 hrs. TLC (DCM:MeOH=10:1) shows the reaction is complete. Pour the solution to a mixture of EtOAc and water, separate the organic layer, and wash with brine, dry over anhydrous Na2SO4. Concentrate under reduced pressure to give the crude product (4.3 g). MS: (M+1): 394.1.