Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[N:4][C:3]=1[C:18]([NH2:20])=[O:19].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](OC)=O)=[CH:25][CH:24]=1>>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]2[NH:20][C:18](=[O:19])[C:3]3[N:4]=[N:5][N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:2]=3[N:1]=2)=[CH:25][CH:24]=1
Reactant: COC(=O)Cc1ccc(OC)cc1
Reactant: CC(CCCc1ccccc1)n1nnc(C(N)=O)c1N
Product: COc1ccc(Cc2nc3c(nnn3C(C)CCCc3ccccc3)c(=O)[nH]2)cc1

Procedure:
Analogously to the procedure of Example 5, the title compound is prepared from 1.0 g (3.8 mmol) of 5-amino-1-(1-methyl-4-phenyl-butyl)-1H-[1,2,3]triazole-4-carboxamide and 2.05 g (11.4 mmol) of methyl 4-methoxyphenylacetate.
Reaction SMILES: C(OC([N:8]1[CH2:26][C@@H:25]([CH3:27])[N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][C:20]([F:23])([F:22])[F:21])=O)(C)(C)C.[ClH:28]>CCOCC.O>[ClH:28].[CH3:27][C@H:25]1[N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9][NH:8][CH2:26]1)=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][C:20]([F:23])([F:22])[F:21]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2c3cccc(OC(F)(F)F)c3C(=O)N12
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: C[C@@H]1CNC[C@H]2c3cccc(OC(F)(F)F)c3C(=O)N12
Reaction time: 1 h

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(4R,10bR)-1,3,4,10b-tetrahydro-4-methyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one(30 mg, 0.08 mmol) in dry ether (2 mL) was added hydrochloric acid (1 mL). The reaction was stirred for 1 h and then conc. in vacuo to a white solid. The solid was dissolved in water and lyophilized to 21 mg of a white solid. MS (ESI) 271 (M−Cl).
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([N:38]2[CH2:43][C@H:42]([CH3:44])[O:41][C@H:40]([CH3:45])[CH2:39]2)=[C:22]([F:37])[C:23](F)=[C:24]([C:26]([C:29]2[CH:34]=[N:33][C:32](Cl)=[CH:31][N:30]=2)=[N:27][OH:28])[CH:25]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:46][S-:47].[Na+].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OC(=O)C)C>[CH3:44][C@@H:42]1[CH2:43][N:38]([C:21]2[C:20]([CH2:19][OH:18])=[CH:25][C:24]3[C:26]([C:29]4[CH:34]=[N:33][C:32]([S:47][CH3:46])=[CH:31][N:30]=4)=[N:27][O:28][C:23]=3[C:22]=2[F:37])[CH2:39][C@H:40]([CH3:45])[O:41]1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=NO)c3cnc(Cl)cn3)c(F)c2F)C[C@H](C)O1
Reactant: C[S-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1cnc(-c2noc3c(F)c(N4C[C@@H](C)O[C@@H](C)C4)c(CO)cc23)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.3 %

Procedure:
1-{5-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2,3-difluorophenyl}-1-(5-chloropyrazin-2-yl)-N-hydroxymethanimine (Intermediate 200, 400 mg, 0.61 mmol) in DMF (5 mL) was treated with sodium thiomethoxide (45.3 mg, 0.61 mmol) at room temperature, the mixture was stirred at room temperature for 10 min. K2CO3 (5 eq) was added and the mixture was heated to 100° C. for 1 hour. The reaction mixture was diluted with ethylacetate (20 ml). Organic layer washed with water and brine, then dried over sodium sulfate, filtered, and the filtrate was concentrated, purified by silica gel column chromatography (Hexanses/EtOAc, gradient) to give the desired product (97 mg, 39.0%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:20])=O.[NH2:21][C:22]([NH2:24])=[S:23]>CCO>[F:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:21]=[C:22]([NH2:24])[S:23][CH:2]=3)=[C:6]([CH3:20])[CH:7]=2)=[CH:14][CH:15]=1
Reactant: Cc1cc(Oc2ccc(F)cc2)cc(C)c1C(=O)CBr
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1cc(Oc2ccc(F)cc2)cc(C)c1-c1csc(N)n1
Yield: 84.2 %

Procedure:
A mixture of 2-bromo-1-(4-(4-fluorophenoxy)-2,6-dimethylphenyl)ethanone (5.74 g, 17.0 mmol) and thiourea (1.30 g, 17.1 mmol) in 95% EtOH (24.3 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(4-(4-fluorophenoxy)-2,6-dimethylphenyl)thiazol-2-amine (4.50 g) as yellow solids in 84% yield: 1H NMR (500 MHz, CDCl3) δ 7.05-6.97 (m, 4 H), 6.66 (s, 2 H), 6.28 (s, 1 H), 5.95 (bs, 2 H), 2.14 (s, 6 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)(=[O:10])=[O:9])=[C:4]([CH2:22][NH2:23])[CH:3]=1.C(Cl)Cl.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:9])(=[O:10])[NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)=[C:4]([CH:3]=1)[CH2:22][NH:23][C:27](=[O:29])[CH3:28]
Reactant: NCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
A solution of 4-amino-2-(aminomethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (500 mg, 1.5 mmol) in pyridine (15 ml) was stirred at room temperature for 30 mins. DCM (40 ml) and acetic anhydride (168 mg, 1.65 mmol) was then added to the mixture. And it was stirred at room temperature for overnight. The mixture was concentrated in vacuo and the residue was purified by prep. HPLC (column: Luna 300×50.0 mm, 10 u; liquid phase: [A-H2O+0.025% TFA; B-MeCN] B %: 10%-30%, 20 min) to give the title compound (226 mg, 40.2%) as a light yellow solid. 1H NMR: DMSO 400 MHz. δ9.99 (s, 1H), 9.19 (s, 1H), 8.24 (d, J=12.0 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.12 (dd, J=10.0 Hz, 1H), 6.45 (s, 1H), 6.35 (dd, J=10.8 Hz, 1H), 5.95 (brs, 2H), 4.85 (s, 2H), 4.54 (s, 2H), 1.92 (s, 3H). ESI-MS m/z 374 (M−H, positive); HPLC purity: 90.13% (MaxPlot 190-370 nm), 96.33% (220 nm).
Reaction SMILES: [Na].[NH:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.CN1[CH:14]=[CH:13][C:12](=[O:15])N(C)C1=O>CCO>[N:2]1[N:3]2[CH:14]=[CH:13][C:12]([OH:15])=[N:7][C:4]2=[CH:5][CH:6]=1
Reactant: Nc1cc[nH]n1
Reactant: Cn1ccc(=O)n(C)c1=O
Agent: [Na]
Solvent: CCO
Product: Oc1ccn2nccc2n1
Yield: 52.8 %

Procedure:
To a solution of dry EtOH (500 mL) was added sodium (22.1 g, 481 mmol) under a cold water bath. After complete dissolution, 1H-pyrazol-3-amine (40.0 g, 481 mmol) and 1,3-dimethylpyrimidine-2,4(1H,3H)-dione (101 g, 722 mmol) were added. The reaction mixture was heated at reflux for 4 hours. After cooling, the white solid was collected by filtration, washed with cold EtOH and dried under vacuum. The crude solid was suspended in minimum amount of water and the pH of the solution was adjusted to 5 by dropwise addition of acetic acid. The precipitated solid was collected by filtration, re-dissolved in MeOH and concentrated by rotary evaporation to azeotrope any remaining water to afford pyrazolo[1,5-a]pyrimidin-5-ol (34.3 g, 53%).
Reaction SMILES: [Cl:1][C:2]1[C:6]2[NH:7][C:8]([C:10]([O:12]C)=[O:11])=[CH:9][C:5]=2[S:4][CH:3]=1.[OH-].[Li+]>CO>[C:10]([C:8]1[NH:7][C:6]2[C:2]([Cl:1])=[CH:3][S:4][C:5]=2[CH:9]=1)([OH:12])=[O:11]
Reactant: COC(=O)c1cc2scc(Cl)c2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc2scc(Cl)c2[nH]1
Yield: 99.9 %

Procedure:
3-Chloro-5-methoxycarbonyl-4H-thieno[3,2-b]pyrrole (Method 4; 0.61 g, 2.83 mmol) was taken up in MeOH (10 ml) and was heated under reflux. Aqueous lithium hydroxide (2.0 M, 3.0 ml, 6.0 mmol) was added portionwise over 45 minutes. The mixture was heated under reflux for 30 minutes before being cooled and concentrated. Water (20 ml) was added and the solution was neutralised using aqueous hydrochloric acid (2.0 M, 3.0 ml). The solution was extracted using EtOAc, and the combined organic layers were concentrated to afford the title compound as a yellow solid (0.57 g, 100%). NMR: 12.4 (1H, br), 7.4 (1H, s), 7.0 (1H, s); m/z 200.3.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([C:16]2[N:25]=[C:24]([NH:26][C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[N:32](C(OC(C)(C)C)=O)[N:31]=[CH:30]4)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH:13]=[CH:14][CH:15]=1)=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:32]1[C:33]2[C:29](=[CH:28][C:27]([NH:26][C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:16]([C:12]4[CH:11]=[C:10]([NH:9][C:7]([C@@H:3]5[CH2:4][CH2:5][CH2:6][N:2]5[CH3:1])=[O:8])[CH:15]=[CH:14][CH:13]=4)[N:25]=3)=[CH:35][CH:34]=2)[CH:30]=[N:31]1
Reactant: CN1CCC[C@H]1C(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCC[C@H]1C(=O)Nc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1

Procedure:
To tert-butyl 5-(2-(3-((S)-1-methylpyrrolidine-2-carboxamido)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate (22 mmol) was added a solution of 1:1 TFA:CH2Cl2 (2 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the crude product was purified by prep HPLC (method 10-35_90 mins) to afford (2S)—N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-1-methylpyrrolidine-2-carboxamide. (25 mg, 25%)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:29][C:30]1[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[C:38]([F:39])[C:30]=2[F:29])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccc(F)c1F
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: O=C1OC2(CCN(C(=O)c3cn(C(=O)c4cccc(F)c4F)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure VII as described above, the acylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with commercially available 2,3-difluorobenzoyl chloride gave the title compound. ES-MS m/e (%): 539.3 (M+H+).
Reaction SMILES: [CH2:1]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([N:16]=[C:17]=[O:18])(=[O:15])=[O:14])(=[O:6])=[O:5])[CH2:2][CH3:3].[NH2:19][C:20]1[N:25]=[C:24]([Cl:26])[CH:23]=[C:22]([O:27][CH2:28][CH3:29])[N:21]=1>C(#N)C>[Cl:26][C:24]1[CH:23]=[C:22]([O:27][CH2:28][CH3:29])[N:21]=[C:20]([NH:19][C:17]([NH:16][S:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])(=[O:15])=[O:14])=[O:18])[N:25]=1
Reactant: CCOc1cc(Cl)nc(N)n1
Reactant: CCCS(=O)(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: CC#N
Product: CCCS(=O)(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(Cl)cc(OCC)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-propylsulfonylbenzenesulfonyl isocyanate (1.67 g, 5.76 mmol) in dry acetonitrile was added 2-amino-4-chloro-6-ethoxypyrimidine (1.00 g, 5.76 mmol). After stirring at room temperature overnight, the reaction mixture was filtered and the solid washed with 1-chlorobutane to give the product as a white powder melting at 220°-222° C.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][CH2:19][O:20][CH3:21])[CH:15]=2)[O:10][C:9]([C:22]2[N:27]=[CH:26][N:25]3[CH:28]=[CH:29][CH:30]=[C:24]3[CH:23]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pt]>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:15]=2)[O:10][C:9]([C:22]2[N:27]=[CH:26][N:25]3[CH:28]=[CH:29][CH:30]=[C:24]3[CH:23]=2)=[CH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: COCC#Cc1ccc2oc(-c3cc4cccn4cn3)cc(=NOC(C)(C)C)c2c1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: COCCCc1ccc2oc(-c3cc4cccn4cn3)cc(=NOC(C)(C)C)c2c1
Yield: 59.2 %

Procedure:
A solution of 6-(3-Methoxy-prop-1-ynyl)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime (example 83B) (30 mg, 0.075 mmol) and 10% platinum black (10 mg) in ethyl acetate (10 ml) was hydrogenated at room temperature under 1 atmosphere of hydrogen during 48 hours. The catalyst was removed by filtration over Celite® and the filtrates concentrated to dryness to yield the title compound (18 mg, 60%) as a yellow solid that was used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:7][CH2:6][C:5]2[C:8]([CH:13]([OH:21])[C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:9][N:10]=[C:11]([CH3:12])[C:4]=2[O:3]1.[C:23](OC(=O)C)(=[O:25])[CH3:24].C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:22])[O:7][CH2:6][C:5]2[C:8]([CH:13]([O:21][C:23](=[O:25])[CH3:24])[C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:9][N:10]=[C:11]([CH3:12])[C:4]=2[O:3]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ncc(C(O)c2ccc(Cl)cc2)c2c1OC(C)(C)OC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)OC(c1ccc(Cl)cc1)c1cnc(C)c2c1COC(C)(C)O2
Reaction time: 18 h
Yield: 100 %

Procedure:
210 mg (0.66 mmoles) of (+)-2,2,8-trimethyl-5-(4-chloro-α-hydroxybenzyl)-pyrido-[4,3-e]-1,3-dioxane are poured into a 2 ml vial and dissolved in 500 μl of pyridine and 110 μl of acetic anhydride (1.16 mmole). The reaction mixture is stirred for 18 hours, then poured into 30 ml of saturated NaHCO3. The mixture is allowed to stir at room temperature for 1 hour, then extracted with 3×30 ml of CH2Cl2. The combined CH2Cl2 layers are washed with 3×20 ml of 2N HCl. The organic phase is dried over Na2SO4, filtered and the filtrate is evaporated to dryness. 24 g are obtained as a white solid with a yield of 100%.
Reaction SMILES: [CH2:1]([NH:7][CH2:8][C:9]([OH:11])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:12]([NH2:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C(O)C>[CH2:12]([NH:18][C:9](=[O:11])[CH2:8][NH:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCN
Reactant: CCCCCCNCC(=O)O
Solvent: CCO
Product: CCCCCCNCC(=O)NCCCCCC

Procedure:
Into an autoclave, 5.6 gr (0.03 mol) of ethyl ester of 2-(n-hexylamino)acetic acid, 15 ml (0.1125 mol) of n-hexylamine and 1 mml of ethanol were added. The mixture was heated to 120° for 40 hours. The solvent and excess amine were then evaporated. The residue was solidified in pentene at low temperature (-80° C.), recrystallized three times from hexane, then dissolved in ether and added with a saturated HCl solution in ether till acid pH. The hydrochloride was recrystallized from isopropanol.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[C:20]([N+:21]([O-])=O)=[CH:19][N:18]([CH:24]5[CH2:29][CH2:28][CH2:27][CH2:26][O:25]5)[N:17]=4)[NH:13][C:12]=3[CH:30]=2)[CH2:4][CH2:3]1.[H][H]>CO.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[C:20]([NH2:21])=[CH:19][N:18]([CH:24]5[CH2:29][CH2:28][CH2:27][CH2:26][O:25]5)[N:17]=4)[NH:13][C:12]=3[CH:30]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc3nc(-c4nn(C5CCCCO5)cc4[N+](=O)[O-])[nH]c3c2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2ccc3nc(-c4nn(C5CCCCO5)cc4N)[nH]c3c2)CC1
Yield: 104.9 %

Procedure:
A suspension of 370 mg of 6-(4-methylpiperazin-1-yl)-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-1H-benzimidazole in 10 mL of methanol and 37 mg of palladium-on-charcoal is hydrogenated under 1 bar of hydrogen pressure at ambient temperature for 18 hours. The reaction medium is filtered through celite and the filtrate is concentrated under reduced pressure in a rotary evaporator. 360 mg of 3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-ylamine are obtained in the form of a black oil. 1H NMR (300 MHz, DMSO-d6, δ in ppm): 1.50 to 2.21 (m, 6H); 2.23 (s, 3H); 2.50 (m masked, 4H); 3.08 (m, 4H); 3.61 (m, 1H); 3.94 (m, 1H); from 4.89 to 4.98 (m, 2H); 5.30 (broad d, J=10.0 Hz, 1H); from 6.85 to 7.12 (m, 2H); from 7.25 to 7.46 (m, 2H); from 12.2 to 12.35 (m, 1H).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH3:7][C:8]([CH3:41])([CH2:39][CH3:40])[CH2:9][C:10]1[N:11]=[C:12]([C:21]([OH:38])([CH3:37])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[S:35][CH3:36])=[CH:25][CH:24]=2)[N:13]([S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:14]=1>C(O)C.O>[CH3:7][C:8]([CH3:41])([CH2:39][CH3:40])[CH2:9][C:10]1[N:11]=[C:12]([C:21]([OH:38])([CH3:37])[CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[S:35]([CH3:36])=[O:2])=[CH:27][CH:28]=2)[N:13]([S:15]([N:18]([CH3:19])[CH3:20])(=[O:16])=[O:17])[CH:14]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(-c3ccccc3SC)cc2)n1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(-c3ccccc3S(C)=O)cc2)n1
Temperature: 25 °C

Procedure:
Sodium periodate (40 mg, 0.19 mmol) was added to an ambient temperature solution of 4-(2,2-dimethylbutyl)-2-{1-hydroxy-1-methyl-2-[2′-(methylthio)biphenyl-4-yl]ethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide (65 mg, 0.13 mmol) in ethanol/water (1:1) (5 mL). After stirring at ambient temperature until no further reaction (LCMS), the reaction mixture was quenched with saturated aqueous sodium thiosulfate and extracted with methylene chloride. Combined extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-30% acetone/methylene chloride afforded 4-(2,2-dimethylbutyl)-2-{1-hydroxy-1-methyl-2-[2′-(methylsulfinyl)biphenyl-4-yl]ethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9](O)[C:10]2[C:11]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:12][N:13]([C:18]3[C:19]([O:27][CH3:28])=[N:20][C:21]([N:24]([CH3:26])[CH3:25])=[N:22][CH:23]=3)[C:14]=2[CH:15]([CH3:17])[CH3:16])=[CH:5][C:4]=1[F:35])#[N:2].[NH2:36][C:37]1[CH:38]=[C:39]([Cl:53])[C:40](=[O:52])[N:41]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=2)[CH:42]=1>>[Cl:53][C:39]1[C:40](=[O:52])[N:41]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=2)[CH:42]=[C:37]([NH:36][CH:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:35])[CH:5]=2)[C:10]2[C:11]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:12][N:13]([C:18]3[C:19]([O:27][CH3:28])=[N:20][C:21]([N:24]([CH3:26])[CH3:25])=[N:22][CH:23]=3)[C:14]=2[CH:15]([CH3:17])[CH3:16])[CH:38]=1
Reactant: CCOC(=O)c1nn(-c2cnc(N(C)C)nc2OC)c(C(C)C)c1C(O)c1ccc(C#N)c(F)c1
Reactant: COc1ccc(Cn2cc(N)cc(Cl)c2=O)cc1
Product: CCOC(=O)c1nn(-c2cnc(N(C)C)nc2OC)c(C(C)C)c1C(Nc1cc(Cl)c(=O)n(Cc2ccc(OC)cc2)c1)c1ccc(C#N)c(F)c1

Procedure:
The title compound was prepared in analogy to the procedure described in step 184.2 but using ethyl 4-((4-cyano-3-fluorophenyl)(hydroxy)methyl)-1-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-5-isopropyl-1H-pyrazole-3-carboxylate (intermediate 191.3) and 5-amino-3-chloro-1-(4-methoxy-benzyl)-1H-pyridin-2-one (product from step 155.4). After the extraction, the crude product was purified by chromatography (Silicagel, Hexane/EtOAc 50:50 to 20:80). Pure fractions were collected and evaporated to dryness to afford a brown solid.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH2:36][CH3:37])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH2:36][CH3:37])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: CCCc1cccc2sc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1cccc2sc(Sc3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)nc12
Yield: 69.9 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4-propylbenzothiazole (97 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (6×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 116 mg (70%) of the title compound as an amorphous solid. mp 109°-111°. FDMS: m/e=436. α[D]589 =+45.00 (c=0.80, chloroform).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH2:23][N:22]3[C:30]([C:33]([NH:35][CH2:36][C:37]4[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=4)=[O:34])=[CH:31][CH:32]=[C:21]3[CH2:20]2)=[O:18])=[CH:13][CH:12]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]([N:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH2:23][N:22]3[C:30]([C:33]([NH:35][CH2:36][C:37]4[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=4)=[O:34])=[CH:31][CH:32]=[C:21]3[CH2:20]2)=[O:18])=[CH:15][CH:16]=1
Reactant: [N-]=[N+]=NCc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 10-{[2′-(azidomethyl)-1,1′-biphenyl-4-yl]carbonyl}-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide (0.49 mmole) of Step B in tetrahydrofuran (3 mL) was added solid triphenylphosphine (0.55 mmole). The mixture was stirred at room temperature for 16 hours. Water (0.3 mL) was then added and the reaction mixture was heated to 45° C. for 3 hours. The solvent was removed by evaporation and the residue was extracted with dichloromethane. The organic solution was dried over anhydrous sodium sulfate, and evaporated. The residue was purified by HPLC (normal phase, 20-70% gradient of [20% methanol in dichloromethane] and hexane, Luna CN bonded packing) and crystallized upon solvent evaporation, m.p. 115-120° C.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][C:10]2[N:15]=[CH:16][C:17]([C:19]([O:21]C)=[O:20])=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>CO>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][C:10]2[N:15]=[CH:16][C:17]([C:19]([OH:21])=[O:20])=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cnc2c(c1)N(Cc1ccccc1)C(=O)CO2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnc2c(c1)N(Cc1ccccc1)C(=O)CO2
Temperature: 100 °C

Procedure:
The product from Step 1 was dissolved in MeOH (1 mL) and water (0.5 mL) and placed in a 2 mL microwave vial with a magnetic stirrer bar. Lithium hydroxide (40 mg, 0.96 mmol) was added to the vial. The vial was capped and vortexed to dissolve the LiOH, and the reaction was heated for 5 minutes at 100° C. under microwave irradiation. The reaction was quenched by the addition of aqueous 1M HCl (960 μL). The volatiles were evaporated to dryness. This yielded a white/yellow solid which was used without further purification. LCMS (+ESI) m/z=285.0 [M+H]+.