Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=O)[C:6]=2[CH:18]=1.[B].CSC.CO>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH2:7][C:6]=2[CH:18]=1
Reactant: O=c1[nH]c2ccccc2c(=O)c2cc(Cl)ccc12
Agent: [B]
Solvent: CO
Solvent: C1CCOC1
Solvent: CSC
Product: Clc1ccc2c(c1)Cc1ccccc1NC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.7 %

Procedure:
To a mixture of 7.28 g of 9-chloro-5H-dibenz[b,e]azepin-6,11-dione in 25 ml of tetrahydrofuran under argon is added 8.5 ml of 10 molar boron-dimethylsulfide in tetrahydrofuran. The mixture is stirred 18 hours at room temperature, 30 ml of tetrahydrofuran added and the mixture refluxed for 3 hours (solids dissolved). The solution is cooled to room temperature and 25 ml of methanol added dropwise. The volatiles are removed under vacuum. To the residue is added 100 ml of 2N NaOH. The mixture is refluxed overnight and filtered. The solid is extracted with dichloromethane and the extract is washed with 2N citric acid, water and dried (Na2SO4). The solvent is removed to give 4.2 g of solid which is triturated with ethyl acetate-hexane (1:2) to give crystals, m.p. 137° C. to 141° C.
Reaction SMILES: [NH:1]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C@H:2]([C:5]([OH:7])=O)[CH2:3][OH:4].[NH2:18][C@H:19]([C:28]([O:30][CH3:31])=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.ON1C(=O)CCC1=O.CCN=C=NCCCN(C)C>CN(C=O)C>[NH:1]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C@H:2]([C:5]([NH:18][C@H:19]([C:28]([O:30][CH3:31])=[O:29])[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1)=[O:7])[CH2:3][OH:4]
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 92.4 %

Procedure:
Z-Ser-OH 23.9 g and 23.2 g of H-Tyr-OMe were dissolved in 50 mL of DMF, 12.7 g of HOSu and 20 mL of WSC were added to the solution, then the mixture was stirred at 0° C. for 5 minutes then at room temperature overnight. After confirmation with ninhydrin, the reaction mixture was concentrated under reduced pressure. Ethyl acetate 500 mL was added to the residue, and the mixture was washed twice with 200 mL of 1N hydrochloric acid, twice with 200 mL of saturated aqueous sodium bicarbonate, twice with saturated saline, in this order. The ethyl acetate layer was concentrated under reduced pressure. The residue was solidified by treatment with hexane. Thus 38.44 g of Z-Ser-Tyr-OMe (92.3% yield) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:12](=[CH:13][C:14]=1[O:15][CH2:16][CH3:17])[CH:11]=[C:10]1[N:5]2[C@H:6]([CH3:19])[CH2:7][NH:8][C:9]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>COC(C)(C)C>[Cl:1][C:2]1[N:3]=[C:4]2[C:12](=[CH:13][C:14]=1[O:15][CH2:16][CH3:17])[CH:11]=[C:10]1[N:5]2[CH:6]([CH3:19])[CH2:7][NH:8][CH2:9]1
Reactant: CCOc1cc2cc3n(c2nc1Cl)[C@H](C)CNC3=O
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: COC(C)(C)C
Product: CCOc1cc2cc3n(c2nc1Cl)C(C)CNC3
Temperature: 25 °C

Procedure:
A suspension consisting of 0.51 g (1.82 mmol) (R)-6-chloro-7-ethoxy-4-methyl-3,4-dihydro-2H-2,4a,5-triaza-fluoren-1-one and 0.28 g (7.30 mmol) lithium aluminium hydride in 10 mL tert-butyl methyl ether was heated at reflux for 1 h. After cooling to room temperature the reaction mixture was poured into 10% aqueous sodium potassium tartrate solution and extracted twice with ethyl acetate. The organic fractions were washed with brine, dried over magnesium sulfate, filtered and evaporated. The so-obtained crude 6-chloro-7-ethoxy-4-methyl-1,2,3,4-tetrahydro-2,4a,5-triaza-fluorene was dissolved in 10 mL dichloromethane and 0.48 g (2.19 mmol) di-tert-butyl dicarbonate and 22.3 mg (0.18 mmol) 4-(dimethylamino)pyridine were added. After 1 h the solvent was evaporated and the residue was purified by column chromatography over silica gel (0.030–0.063 mm) with ethyl acetate:n-hexane (1:4) as eluant to give the product as a light yellow solid (63.9%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.[O:12]1[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18][C:19](O)=[O:20])[CH2:13]1.O>C1COCC1>[O:12]1[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18][CH2:19][OH:20])[CH2:13]1
Reactant: O=C(O)CC1CCCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: OCCC1CCCOC1
Reaction time: 1 h

Procedure:
A solution of lithium aluminium hydride in Et2O (4.16 ml, 4.16 mmol) was added dropwise to a solution of tetrahydro-2H-pyran-3-ylacetic acid (Tet. Lett. 2003, 44, 6355) (0.6 g, 4.16 mmol) in THF (5 ml) at room temperature under nitrogen. The mixture was stirred for 1 hour and was treated very slowly dropwise with water (1 ml). After the reaction was quenched, aqueous sodium hydroxide (2N, 1 ml) was added and the mixture was stirred for 5 min. The suspension was filtered through Hyflo and evaporated to the title compound as a colourless oil (0.3 g).
Reaction SMILES: C([S:4][C@@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[CH:7]([C:8](=[O:25])[CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1)(=O)C.C([S-])CC.[Na+].Cl.O>CO>[SH:4][C@@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[CH:7]([C:8](=[O:25])[CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1
Reactant: CC(=O)S[C@@H]1CC[C@@]2(C)C(C1)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: CCC[S-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@@H](S)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99.7 %

Procedure:
To a suspension of 3α-acetylthioandrostane-6,17-dione (1.07 g) in MeOH (30 mL), sodium propanethiolate (0.28 g) was added and the reaction stirred for 20 minutes at room temperature. The mixture was neutralized with 1N HCl. Water was added and the mixture extracted with EtOAc. The organic layer was separated, washed with brine, and dried over Na2SO4 and evaporated to dryness to give 3α-mercaptoandrostane-6,17-dione (943 mg, 100%), used without further purification. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 3.54 (1H, m), 2.77 (1H, m), 2.54 (1H, d), 2.45-1.10 (19H, m), 0.78 (3H, s), 0.66 (3H, s).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(OC[C@@H]2CCCN2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.5 %

Procedure:
A mixture of methyl (S)-4-[1-(tert-butoxycarbonyl)-2-pyrrolidinylmethoxy]benzoate (3.34 g, 9.96 mmol) in TFA (20 mL) and CH2Cl2 (35 mL) was stirred at room temp for 15 hr. The mixture was concentrated in vacuo and made basic with sat. NaHCO3. The mixture was extracted with CHCl3, washed with brine, and dried over Na2CO3. The organic layer was evaporated to give 1.70 g (73%) methyl (S)-4-(2-pyrrolidinylmethoxy)benzoate as a yellow oil. 1H-NMR (CDCl3) δ 1.54–1.61 (m, 1 H), 1.77–1.86 (m, 2 H), 1.87–1.97 (m, 1 H), 2.00 (bs, 1 H), 2.93–3.06 (m, 2 H), 3.52–3.57 (m, 1 H), 3.88 (s, 3 H), 3.90–3.99 (m, 2 H), 6.92 (d, J=9.0 Hz, 2 H), 7.98 (d, J=9.0 Hz, 2 H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCCc1ccccn1
Product: O=C(NCCc1ccccn1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (150 mg, 0.41 mmol) and 2-(2-aminoethyl)pyridine (65 mg, 0.49 mmol). The title compound was obtained as a solid (55 mg, 30% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, s), 8.94 (1H, m), 8.49 (2H, m), 8.38 (1H, s), 7.69 (1H, m), 7.23 (1H, m), 3.56 (2H, m), 2.96 (2H, m). MS m/z: 453.02, 455.01 [M+H]+.
Reaction SMILES: [CH2:1]1[C:4](=[O:5])[N:3]([C@H:6]([C:12]([OH:14])=[O:13])[C@H:7]([OH:11])[CH2:8][CH2:9][NH2:10])[CH2:2]1.NN=CS(O)(=O)=O.[NH:22](CCC[C@H](N1CCC1=O)C(O)=O)[C:23](N)=[NH:24]>>[OH:11][CH:7]([CH2:8][CH2:9][NH:10][C:23]([NH2:24])=[NH:22])[CH:6]([N:3]1[CH2:2][CH2:1][C:4]1=[O:5])[C:12]([OH:14])=[O:13]
Reactant: NCC[C@@H](O)[C@@H](C(=O)O)N1CCC1=O
Reactant: N=C(N)NCCC[C@@H](C(=O)O)N1CCC1=O
Agent: NN=CS(=O)(=O)O
Product: N=C(N)NCCC(O)C(C(=O)O)N1CCC1=O
Yield: 53 %

Procedure:
Proclavaminic acid (84.5 mg, 0.42 mmol) was treated aminoiminomethane-sulphonic acid in the fashion described above for the preparation 5-guanidino-2-(2-oxoazetidin-1-yl)pentanoic acid (Compound B) to give 3-hydroxy-5-guanidino-2-(2-oxoazetidin-1-yl)pentanoic acid as a white solid (62 mg, 53%), (Found: C, 38.76; H, 6.83; N, 19.54. C9H16N4O4. 2H2O requires: C, 38.57; H, 7.19; N, 19.99% (FAB; thioglycerol) MH+ 245, C9H16N4O4 requires 245; νmax.(KBr) 3 363, 1 719, 1 673, and 1 600cm-1, δH(400 MHz; D2O) 1.73-1.93 (2H, m, 4-H), 3.07(2H, t, J=4.0 Hz, 3'-H), 3.41 (2H, t, J=6.5 Hz, 5-H), 3.42-3.60 (1H, m), 3.60-3.68 (1H, m) 4'-H), 4.12 (1H, d, J=5.4 Hz, 2-H), 4.22 (1H, m, 3-H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:13].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:23][C:24]=1[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:8][C:7]=1[CH3:13]
Reactant: CCO[C@@H](Cc1ccc(O)cc1C)C(=O)OC
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1C)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 f], (2S)-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (example 1 d]) was reacted with 4-chloromethyl-5-methyl-2-phenyl-oxazole in the presence of cesium carbonate and potassium iodide to yield (S)-2-ethoxy-3-[2-methyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid methyl ester as colorless liquid.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.C([N:17]1[C:29]2[C:28](O)=[C:27]3[N:31](C(OC(C)(C)C)=O)[C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Cl:46])[CH:22]=2)(OC(C)(C)C)=O.[OH:47][CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][CH:53]([NH:56]C(=O)OC(C)(C)C)[CH2:52][CH2:51]1>>[Cl:38][C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:27]1[C:28]([O:47][CH2:48][CH2:49][N:50]3[CH2:51][CH2:52][CH:53]([NH2:56])[CH2:54][CH2:55]3)=[C:29]3[NH:17][C:18]4[CH:19]=[CH:20][C:21]([Cl:46])=[CH:22][C:23]=4[C:24]3=[CH:25][C:26]2=1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Cl)cc2c2cc3c4cc(Cl)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Agent: c1ccc2[nH]ccc2c1
Product: NC1CCN(CCOc2c3[nH]c4ccc(Cl)cc4c3cc3c2[nH]c2ccc(Cl)cc23)CC1

Procedure:
The title compound was prepared in a manner analogous to Example 28 except the starting indole is 5,7-diBOC-2,10-dichloro-6-hydroxyindolo[2,3-b]carbazole and the reagent is tert-butyl 1-(2-hydroxyethyl)piperidin-4-ylcarbamate. 1H-NMR (400 MHz, CDCl3) δ ppm 9.92 (s, 2H), 8.37 (s, 1H), 8.08 (d, J=1.6 Hz, 2H), 7.41-7.30 (m, 4H), 4.39 (t, J=4.6 Hz, 2H), 3.21-3.11 (m, 2H), 2.98-2.85 (m, 1H), 2.75 (t, J=4.6 Hz, 2H), 2.37-2.25 (m, 2H), 2.06-1.96 (m, 2H), 1.78-1.65 (m, 2H); MS (ESI) m/z 465.1 (M−H)−; MS (ESI) m/z 467.1 (M+H)+
Reaction SMILES: [CH2:1]([C:7]1[C:8](/[CH:21]=[CH:22]/[C:23]2[S:27][C:26]([C:28]([O:30]C)=[O:29])=[CH:25][CH:24]=2)=[CH:9][C:10]2[C:11]([CH3:20])([CH3:19])[CH2:12][CH2:13][C:14]([CH3:18])([CH3:17])[C:15]=2[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+].C1COCC1.Cl>C(O)C.O>[CH2:1]([C:7]1[C:8](/[CH:21]=[CH:22]/[C:23]2[S:27][C:26]([C:28]([OH:30])=[O:29])=[CH:25][CH:24]=2)=[CH:9][C:10]2[C:11]([CH3:19])([CH3:20])[CH2:12][CH2:13][C:14]([CH3:18])([CH3:17])[C:15]=2[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cc2c(cc1/C=C/c1ccc(C(=O)OC)s1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCCCCCc1cc2c(cc1/C=C/c1ccc(C(=O)O)s1)C(C)(C)CCC2(C)C
Temperature: 45 °C
Reaction time: 2.5 h
Yield: 90.7 %

Procedure:
A solution of 1.084 g of methyl (E)-5-[2-(3-hexyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-vinyl]-thiophene-2-carboxylate (from Example 8.1) in 15 ml ethanol was treated with a solution of 2.77 g KOH in 8 ml H20, followed by the addition of 7 ml THF. The mixture was stirred at 45° C. for 2.5 hours. The reaction mixture was diluted with 40 ml water and acidified to pH 2 with HCl 25%. The mixture was extracted with 4 portions of 50 ml of ethyl acetate. The combined extracts were washed with 50 ml water and 50 ml of aqueous saturated sodium chloride solution. Drying (MgSO4), filtration and concentration in vacuo gave a pale yellow solid. Trituration in pentane and filtration afforded 952 mg of the title product as a pale yellow solid. M.p. 164-165° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([C:11]1[S:15][C:14](B(O)O)=[CH:13][CH:12]=1)#[N:10].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:14]2[S:15][C:11]([C:9]#[N:10])=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: Nc1cnc(Br)cn1
Reactant: N#Cc1ccc(B(O)O)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: COCCOC
Product: N#Cc1ccc(-c2cnc(N)cn2)s1
Yield: 14.1 %

Procedure:
A mixture of 2-amino-5-bromopyrazine (300 mg, 1.724 mmol), dichlorobis(triphenylphosphine)palladium(II) (175 mg, 0.249 mmol), 5-cyanothiophene-2-boronic acid acid (540 mg, 3.53 mmol) and a saturated aqueous sodium carbonate solution (2 mL) in ethylene glycol dimethyl ether (5 mL) and ethanol (5 mL) was heated under reflux overnight. The reaction mixture was cooled, diluted with ethyl acetate, and washed with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 2/3 to 1/9 hexanes/ethyl acetate) afforded 5-(5-amino-pyrazin-2-yl)-thiophene-2-carbonitrile (49.1 mg, 14.1%) as a yellow solid: LRMS for C9H6N4S (M+H)+ at m/z=203.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=3)[NH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C1(C)C=CC=CC=1>[CH2:29]([O:28][C:26]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=3)[NH:16][CH:15]=2)[CH2:9]1)=[O:27])[CH3:30]
Reactant: CCOC(=O)Cl
Reactant: N#Cc1ccc2[nH]cc(CC3CCN(Cc4ccccc4)C3)c2c1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(Cc2c[nH]c3ccc(C#N)cc23)C1
Yield: 79 %

Procedure:
A mixture containing 41 mmol of the compound of Example 14 and 209 mmol of ethyl chloroformate in 400 ml of toluene is brought to reflux for two hours. After evaporation of the solvent, the expected product is obtained by purification of the residue by chromatography on a silica column, using a dichloromethane/methanol/aqueous ammonia (98/2/0.2) mixture as solvent.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24]([O:26]C)=O)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl.[OH-].[NH4+:30]>C1COCC1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:26])[NH2:30])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cc(C)cc(C)c1
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C)cc(Cn2c3cccc(O)c3c3c(C(N)=O)cccc32)c1
Yield: 47 %

Procedure:
A solution of the 9-[(3,5-dimethylphenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (200 mg, 0.55 mM) in 10 mL THF and 30 mL concentrated aqueous ammonium hydroxide was sonicated for 4 days at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 2.5 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient hexanes/ethyl acetate) to afford 90 mg (47%) of the 9-[(3,5-dimethylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as an off-white solid. 1H NMR (DMSO-d6) δ10.5 (s, 1H), 8.6 (s, 1H), 8.4 (s, 1H), 7.75 (d, 1H, J=8 Hz), 7.45 (m, 2H), 7.3 (t, 1H, J=8 Hz), 7.1 (d, 1H, J=8 Hz), 6.85 (s, 1H), 6.7 (s, 2H), 6.6 (d, 1H, J=8 Hz), 5.6 (s, 2H), and 2.2 (s, 6H). IR (KBr, cm−1) 3417, 3198, 3113, 3063, 1631, 1601, 1562, 1438, 1332, 1263, 1217, 781, and 773. MS (ES) m/e 343, 345.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([C:23]2[N:27]=C(C)O[N:24]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=1.[C:29]1(=O)[CH2:33][CH2:32][CH2:31][CH2:30]1>>[C:23]([C:21]1[CH:20]=[CH:19][C:3]([CH2:4][NH:5][C:6](=[O:18])[C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=2)=[C:2]([NH:1][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:22]=1)(=[NH:27])[NH2:24]
Reactant: O=C1CCCC1
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2N)cc(OC)c1C
Product: COc1cc(C(=O)NCc2ccc(C(=N)N)cc2NC2CCCC2)cc(OC)c1C

Procedure:
Compound 1g (50 mg, 0.13 mmol) was reductively aminated with cyclopentanone (0.012 mL, 0.14 mmol) and subsequently hydrogenated following a procedure analogous to the preparation of compound 11a, to give example 12. ESI-MS m/e 411.4 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[NH:5][NH:4][C:3]1=[O:8].C1C=CC=CC=1.CN(C)C=O.CC(C)([O-])C.[K+].[CH:26]([C:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:29])=[CH2:27]>CN(C)C=O>[O:29]=[C:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:26][CH2:27][N:4]1[C:3](=[O:8])[N:2]([CH3:1])[C:6](=[O:7])[NH:5]1
Reactant: C=CC(=O)CCCCC
Reactant: Cn1c(=O)[nH][nH]c1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCCCCC(=O)CCn1[nH]c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 47453.9 %

Procedure:
A solution of 4-methyl-1,2,4-triazolidine-3,5-dione (16 g; 0.14 mmole) in dry 1:1 benzene-dimethylformamide (100 ml) was heated under reflux, with stirring under nitrogen, and potassium t-butoxide (17.62 g), was added. The resultant suspension was heated under reflux for 2 hr. and then n-pentyl vinyl ketone (12,568; 0.10 mole) in dry dimethylformamide (10 ml) added dropwise. After 2 days the mixture was allowed to cool to room temperature and partitioned between 5 M HCl (200 ml) and ethyl acetate (100 ml). The aqueous layer was extracted with ethyl acetate (5×70 ml) and the combined organic layers washed with water (2×100 ml) and brine (100 ml) and dried (Na2SO4). Evaporation in vacuo gave an oil. Recrystallisation from ethyl acetate - 60/80 petroleum ether gave 2-(3'-oxo-octyl)-4-methyl-1,2,4-triazolidine-3,5-dione (16.03 g; 66%). m.pt., 75°-76°
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:30])[C:5]([N:8]([CH2:26][CH:27]([CH3:29])[CH3:28])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19]C3CCOCC3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[N:6][CH:7]=1.[B-](F)(F)(F)[C:32]([CH3:34])=[CH2:33].[K+].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1>[CH2:26]([N:8]([C:5]1[C:4]([CH3:30])=[CH:3][C:2]([C:2]([CH3:3])=[CH2:7])=[CH:7][N:6]=1)[S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH:15]2[CH2:14][CH2:34][CH2:32][CH2:33][O:18]2)=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH:27]([CH3:28])[CH3:29]
Reactant: Cc1cc(Cl)cnc1N(CC(C)C)S(=O)(=O)c1ccc(OCC2CCOCC2)cc1
Reactant: C=C(C)[B-](F)(F)F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)c1cnc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCCCO3)cc2)c(C)c1
Temperature: 110 °C
Yield: 85 %

Procedure:
N-(5-chloro-3-methylpyridin-2-yl)-N-isobutyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide (140 mg, 0.31 mmol), potassium trifluoro(prop-1-en-2-yl)borate (69 mg, 464 μmol) and Buchwald's Suzuki-Miyaura cross-coupling pre-catalyst (prepared according to ref. J. Am. Chem. Soc. 2010, 132, 14073) (5 mg, 6.18 μmol) were dissolved in anhydrous THF (1 mL). To this solution was added degassed potassium phosphate (0.5 M aqueous) (2 mL, 1.0 mmol) then the reaction vessel sealed and heated by microwaves to 110° C. for 30 minutes. The reaction was cooled, combined with a previous identical trial reaction on a smaller (0.06 mmol) scale and concentrated in vacuo. The crude product was then extracted to the organic phase of an aqueous work up between ethyl acetate and water. The organic phase was passed through a hydrophobic frit, concentrated in vacuo, then purified by mass directed autoprep (formic acid modifier) to give the title compound 85% purity (87 mg). LCMS (2 min, formic) Rt 1.44 min, m/z (ES+) 459 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[C:14]([F:27])([F:26])[C:15]([N:17]([F:25])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=[CH:6][CH:5]=1)([O-])=O>C1COCC1.CO.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[C:14]([F:27])([F:26])[C:15]([N:17]([F:25])[CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])=[CH:6][CH:5]=1
Reactant: O=C(N(F)Cc1ccccc1)C(F)(F)C1CCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)C(C(F)(F)C(=O)N(F)Cc1ccccc1)CCC2
Reaction time: 1 h

Procedure:
To a stirred solution of 2-(7-nitro-(1,2,3,4-tetrahydronaphthyl))-N (phenylmethyl)trifluoroacetamide (2.55 g, 6.75 mmol) in THF/MeOH (100 ml, 1:1) was added a catalytic amount of 10% Pd/C. The mixture was hydrogenated at 50 psi for 1 hr, filtered through celite, and concentrated to give 2-(7-amino-(1,2,3,4-tetrahydronaphthyl))-N-(phenylmethyl) trifluoroacetamide which was homogeneous by TLC and used immediately in the next step.