Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[S:18][C:17]2[C:16](=[O:19])[N:15]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:14](=[O:26])[N:13]([CH2:27][C:28]3[N:29]=[N:30][N:31]([CH2:33][CH3:34])[N:32]=3)[C:12]=2[CH:11]=1.[CH2:35]([O:37][C:38]1[C:47]([O:48][CH3:49])=[CH:46][C:45]2[C:44]([C:50]3[CH:58]=[CH:57][C:53]([C:54](O)=[O:55])=[CH:52][CH:51]=3)=[N:43][C@@H:42]3[CH2:59][CH2:60][S:61][CH2:62][C@@H:41]3[C:40]=2[CH:39]=1)[CH3:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[S:18][C:17]2[C:16](=[O:19])[N:15]([CH:20]3[CH2:21][CH2:22][N:23]([C:54]([C:53]4[CH:57]=[CH:58][C:50]([C:44]5[C:45]6[CH:46]=[C:47]([O:48][CH3:49])[C:38]([O:37][CH2:35][CH3:36])=[CH:39][C:40]=6[C@H:41]6[CH2:62][S:61][CH2:60][CH2:59][C@H:42]6[N:43]=5)=[CH:51][CH:52]=4)=[O:55])[CH2:24][CH2:25]3)[C:14](=[O:26])[N:13]([CH2:27][C:28]3[N:29]=[N:30][N:31]([CH2:33][CH3:34])[N:32]=3)[C:12]=2[CH:11]=1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4cccc(F)c4F)cc32)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6cccc(F)c6F)cc5n(Cc5nnn(CC)n5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
6-(2,3-difluorophenyl)-1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (40 mg; compound B83) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (31 mg; compound C10) and HBTU (33 mg) in DCM/DMF (15 ml/1 ml) in the presence of DIPEA (41 mg) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: Cyclohexane/EtOAc/DCM, 100/0/0 to 65/30/5 to 30/60/10 to 0/90/10 (v/v/v)] and by preparative TLC [20×20 cm TLC plates with 0.5 mm thickness, eluation gradient: EtOAc/methanol/triethylamine, 91/5/4 (v/v/v)] as a solid.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH:11][C:12](=O)[CH3:13])[CH2:5]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].CO.Br[C:24]([CH3:33])([CH3:32])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].[OH-].[Na+]>C1COCC1.O>[CH2:12]([NH:11][CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([S:1][C:24]([CH3:33])([CH3:32])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:3]=2)[CH2:7]1)[CH3:13]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: CC(=O)NC1Cc2ccc(S)cc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCNC1Cc2ccc(SC(C)(C)C(=O)OC(C)(C)C)cc2C1
Temperature: 6 °C

Procedure:
N-(5-Mercapto-indan-2-yl)-acetamide (330.0 g, 1.59 mol) was dissolved in a warm THF (1.65 L) at 50° C. The solution was then slowly added to LAH solution (1 M in THF) (2.385 L, 2.385 mol) at about 60-66° C. over 25 minutes to allow gentle reflux and slow gas evolution. After addition, the light yellow suspension was stirred under reflux for 4 hours. The reaction was cooled to about 5-7° C. in an ice-water bath. The reaction was quenched by the slow addition of methanol (203.7 g, 6.36 mol) under a nitrogen atmosphere and the reaction temperature was maintained below 25° C. by adjusting the addition rate. After quenching, the resulted green suspension was cooled to 5-7° C. and treated with tert-butyl 2-bromo-2-methylpropionate (354.7 g, 1.59 mol). The resulted mixture was warmed to room temperature while stirring and then maintained with stirring at room temperature for 2 hours. The reaction mixture was treated by the slow addition of H2O (90.6 mL) and 15% of aqueous NaOH (90.6 mL) sequentially. The resulted granular solid was removed by vacuum filtration through a 3 L coarse frit funnel lined with Celite filter aid. The filter cake was rinsed twice with THF (2×500 mL). The combined filtrate was concentrated in vacuo to remove about 70-80% of THF. The filter cake was suspended in EtOAc (2 L) and stirred for 30 minutes. The suspension was filtered through a 3 L coarse frit funnel. The filtrate was combined with the crude concentrated THF solution obtained above. The combined organic layer was washed with H2O (2 L). After separation of layers, the organic layer was concentrated in vacuo at 50° C. to remove the most of volatiles. The concentrated solution was diluted with anhydrous ethanol (800 mL) and re-concentrated to yield a purple oil. The crude product was used for the next step without further purification.
Reaction SMILES: [S:1]1[N:5]=[CH:4][C:3]([C:6](O)=O)=[N:2]1.[NH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[NH2:19])[NH:15][C:14](=[O:20])[C:13]2([CH3:22])[CH3:21]>>[CH3:21][C:13]1([CH3:22])[C:12]2[C:16](=[CH:17][C:18]3[NH:19][C:6]([C:3]4[CH:4]=[N:5][S:1][N:2]=4)=[N:9][C:10]=3[CH:11]=2)[NH:15][C:14]1=[O:20]
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Reactant: O=C(O)c1cnsn1
Product: CC1(C)C(=O)Nc2cc3[nH]c(-c4cnsn4)nc3cc21
Temperature: 0 °C

Procedure:
2.0 g. (15.3 mmol) 1,2,5-thiadiazole-3-carboxylic acid and 2.6 g. (13.6 mmol) 5,6-diamino-3,3-dimethyl-indolin-2-one are heated in 40 ml. polyphosphoric acid under an atmosphere of nitrogen for 2 hours at 160° C. The warm solution is poured on to ice water, worked up and the crystals obtained are filtered off with suction. The residue is again suspended in water, neutralised with an aqueous solution of ammonia, filtered off with suction and recrystallised from methanol with the addition of charcoal. Yield: 2.6 g. (66% of theory); m.p. >300° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19])[CH:13]=[C:12]2[CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])C1C=CC=CC=1.Cl>C(O)C.[Pd]>[CH3:30][N:28]([CH3:29])[CH2:27][CH2:26][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([OH:8])[CH:10]=2)[N:14]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[CH:13]=1
Reactant: CN(C)CCc1cn(C(=O)c2ccccc2)c2ccc(OCc3ccccc3)cc12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CN(C)CCc1cn(C(=O)c2ccccc2)c2ccc(O)cc12
Yield: 51.9 %

Procedure:
A solution of [5-benzyloxy-3-(2-dimethylamino-ethyl)-1H-indol-1yl]phenylmethanone (300 mg, 0.75 mmol) and 4N hydrochloric acid (190 ml, 0.76 mmol) in ethanol (10 ml) was hydrogenated over 10% palladium on carbon (100 mg) at 35 psi for 3 hours. The catalyst was removed by filtration. The filtrate was evaporated, and the residue was partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. The aqueous was further extracted with dichloromethane (×2). The combined extracts were dried (K2CO3), filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with dichloromethane/methanol/aqueotus ammonia (80:8:1) to give the title compound (120 mg, 52%), as a colourless solid; mp 154°-156° C. δH (360 MHz, CDCl3) 2.40 (6H, s), 2.70-2.75 (2H, m), 2.83-2.88 (2H, m), 6.86-6.90 (2H, m), 7.04 (1H, s), 7.49-7.61 (3H, m), 7.68-7.71 (2H, m), 8.17 (0.5H, s), 8.20 (0.5H, s). m/z (CI+) 309 [MH]+. Found: C, 73.22; H, 6.48; N, 8.74. C19H20N2O2.0.2 H2O requires C, 73.15; H, 6.59; N, 8.98%.
Reaction SMILES: [CH3:1][CH:2]([S:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)[CH3:3].Br[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]3[O:33][N:32]=[C:31]([CH:34]([CH3:36])[CH3:35])[N:30]=3)[CH2:25][CH2:24]2)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[CH3:36][CH:34]([C:31]1[N:30]=[C:29]([N:26]2[CH2:25][CH2:24][CH:23]([CH2:22][O:21][C:18]3[CH:17]=[CH:16][C:15]([C:8]4[CH:9]=[CH:10][C:5]([S:4][CH:2]([CH3:3])[CH3:1])=[CH:6][CH:7]=4)=[CH:20][CH:19]=3)[CH2:28][CH2:27]2)[O:33][N:32]=1)[CH3:35]
Reactant: CC(C)c1noc(N2CCC(COc3ccc(Br)cc3)CC2)n1
Reactant: CC(C)Sc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)Sc1ccc(-c2ccc(OCC3CCN(c4nc(C(C)C)no4)CC3)cc2)cc1
Yield: 5.2 %

Procedure:
1-[3-(1-Methylethyl)-1,2,4-oxadiazol-5-yl]-4-[({4′-[(1-methylethyl)thio]-4-biphenylyl}oxy)methyl]piperidine (20 mg, 5%) was prepared as a white solid from {4-[(1-methylethyl)thio]phenyl}boronic acid (167 mg, 0.85 mmol), 4-{[(4-bromophenyl)oxy]methyl}-1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]piperidine (322 mg, 0.85 mmol), Pd(PPh3)2Cl2 (50 mg, 0.07 mmol), 2M Na2CO3 (5 mL) and DME (5 mL) in a manner similar to Example 21, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.57-7.39 (m, 6H), 6.94 (d, 2H, J=8.9 Hz), 4.28-4.18 (m, 2H), 3.87 (d, 2H, J=6.4 Hz), 3.46-3.30 (m, 1H), 3.20-3.08 (m, 2H), 2.98-2.85 (m, 1H), 2.16-2.03 (m, 1H), 2.03-1.93 (m, 2H), 1.55-1.39 (m, 2H), 1.36-1.24 (m, 12H); LRMS (ESI), m/z 452 (M+H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:8]1[CH:12]=[C:11]([CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[N:10]=[CH:9]1>[Pd].C(O)(=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[N:10]=[CH:9]1
Reactant: O=C(O)CCCC=Cc1c[nH]cn1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: O=C(O)CCCCCc1c[nH]cn1
Reaction time: 13 h
Yield: 79.7 %

Procedure:
4 ml of acetic acid and 80 mg of palladium-on-charcoal at 10% are added to 218 mg (0.741 mmol) of 6-(1H-imidazol-4-yl)hex-5-enoic acid trifluoroacetate. The reaction medium is placed under a hydrogen atmosphere at atmospheric pressure. After 13 hours, the reaction medium is filtered through celite. After the solvents have been evaporated off, 175 mg of 6-(1H-imidazol-4-yl)hexanoic acid trifluoroacetate in the form of a yellow oil are obtained with a yield of 80%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].[C:36]([O:40][CH:41](Cl)[CH:42]([CH3:44])[CH3:43])(=[O:39])[CH2:37][CH3:38]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[Br-]>[C:36]([O:40][CH:41]([N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:18])[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=2[F:33])=[CH:15]1)[CH:42]([CH3:44])[CH3:43])(=[O:39])[CH2:37][CH3:38]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Reactant: CCC(=O)OC(Cl)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(OC(=O)CC)C(C)C)c3ncc(-c4ccc(Cl)cc4)cc23)c1F

Procedure:
The title compound was prepared according to the procedure as described in Example 10 Step 2 using a solution of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.2 g, 0.4 mmol) in DMF (1 mL), KOH (46 mg, 0.80 mmol), a solution of TBAB (264 mg, 0.81 mmol) in DMF (0.5 mL) and a solution of 1-chloro-2-methylpropyl propionate (81 mg, 0.49 mmol) in DMF (0.5 mL). The title compound was obtained as a white solid (114 mg, 45%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].Cl[CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19].O>C1COCC1>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5 g, 32.6 mmol) in THF (50 mL) was added NaH (30%, 4 g, 50.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour before the addition of (2-(chloromethoxy)ethyl)-trimethylsilane (15 g, 90.0 mmol). The reaction was stirred at ambient temperature for 3 hours. It was then treated with water (5 mL) and extracted with EtOAc. The organic layer was concentrated under reduced pressure, and the residue was purified by chromatography to give the title compound. MS (m/z): 284 (M+H)+ (35Cl), 286 (M+H)+ (37Cl).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.CN1CCN(C2C=CC(N[C:29]([C:31]3[C:32]4[N:33]=[CH:34][CH:35]=[N:36][C:37]=4[C:38]([C:41]4[C:50]5[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=5)[CH:44]=[CH:43][CH:42]=4)=[CH:39][CH:40]=3)=[O:30])=CC=2)CC1>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:29]([C:31]3[C:32]4[N:33]=[CH:34][CH:35]=[N:36][C:37]=4[C:38]([C:41]4[C:50]5[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=5)[CH:44]=[CH:43][CH:42]=4)=[CH:39][CH:40]=3)=[O:30])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc(NC(=O)c3ccc(-c4cccc5ccccc45)c4nccnc34)cc2)CC1
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Product: CN1CCN(c2ccc(NC(=O)c3ccc(-c4cccc5ccccc45)c4nccnc34)cn2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but stirring the reaction mixture for 20 h at rt and using 6-(4-methylpiperazin-1-yl)-pyridin-3-ylamine (prepared as described in Example 33 but using N-methyl-piperazine in Step 33.2) and 8-naphthalen-1-yl-quinoxaline-5-carboxylic acid (Example 46). Title compound: ESI-MS: 475.0 [M+H]+; tR=3.76 min (System 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:12])[NH:7]2.[H-].[Na+].CCCCCC.Cl[CH2:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:30]>CN(C=O)C.O>[Cl:29][C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:30])[C:23]=1[CH2:22][N:7]1[C:8]2[C:4](=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=2)[CH:5]=[C:6]1[CH3:12]
Reactant: ClCc1c(Cl)cccc1Cl
Reactant: COc1cccc2[nH]c(C)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1cccc2c1cc(C)n2Cc1c(Cl)cccc1Cl
Reaction time: 0.67 h
Yield: 84.3 %

Procedure:
4-Methoxy-2-methyl-1H-indole (805 mg, 5 mmol) was added to a mixture of 160 mg (4 mmol) of 60% sodium hydride/mineral oil (washed with hexane before adding DMF) in 10 mL of DMF and after stirring for 0.67 hours, 782 mg (4 mmol) of α,2,6-trichlorotoluene was added. The mixture was stirred at room temperature for 5 hours, diluted with water and extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried (MgSO4) and after concentrating at reduced pressure, the residue was chromatographed on silica gel eluting with 20% EtOAc/hexane to give 1.08 g (84% yield) of 1-[(2,6-dichlorophenyl)methyl]-4-methoxy-2-methyl-1H-indole, melting at 154-157° C.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH:28]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[C@H:29]([C:45]([NH:47][C@H:48]([C:53](O)=[O:54])[CH2:49][C:50](=[O:52])[NH2:51])=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:33][CH:32]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[NH:28]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[C@H:29]([C:45]([NH:47][C@H:48]([C:53]([NH:1][C@H:2]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:54])[CH2:49][C:50](=[O:52])[NH2:51])=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)NCCCCNC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@@H](CC(N)=O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Yield: 28.4 %

Procedure:
compound SP323C2. Same procedure as above with Trp-NH(CH2)4NHBoc (108.7 mg, 0.29 mmol), N-Boc-Tyr(Bn)-Asn-OH (140.9 mg, 0.29 mmol), EDC (61.8 mg, 0.32 mmol) and HOBt (43.6 mg, 0.32 mmol) in CH2Cl2/DMF (2 mL, 1/1). The crude residue was purified by flash column chromatography on silica gel (2-6% MeOH/CH2Cl2) to give an white solid (69.3 mg, 28%). 1H NMR (300 MHz, DMSO-d6) δ 1.18-1.37 (m, 4H, 2 CH2 putrescine), 1.28 (s, 9H, (CH3)3), 1.37 (s, 9H, (CH3)3), 2.42-3.2 (m, 10H, CH2 Tyr, CH2 Trp, CH2 Asn, 2 CH2 putrescine), 4.1 (m, 1H, CHα), 4.36 (m, 1H, CHα), 4.53 (m, 1H, CHα), 5.03 (s, 2H, CH2 (Bn)), 6.71 (m, 1H), 6.8-7.53 (m, 17H), 7.84 (m, 1H), 8.01 (d, J=9 Hz, 1H), 8.13 (d, J=7.6 Hz, 1H), 10.73 (s, 1H). 13C NMR (75 MHz, DMSO-d6) δ 26.4, 27 (2 CH2 putrescine), 27.4 (CH2 Trp), 28.4 ((CH3)3), 36.6, 37.2 (CH2 Tyr, CH2 Asn), 38.4, 39.4 (2 CH2 putrescine), 49.8, 54, 55.9 (CHα Tyr, Asn, Trp), 69.2 (CH2 (Bn)), 77.5, 78.2 (C(CH3)3), 110.2, 111.3, 114.4, 118.3, 120.9, 123.6, 127.4, 127.7, 127.9, 128.5, 130.3, 130.4, 136.1, 137.4 (19 aromatic C), 155.4, 155.7, 157 (Car-O, 2 CO carbamate), 170.7, 170.9, 171.8, 172.1 (4 CO amide). Anal. Calcd. for C45H59N7O9: C, 64.19; H, 7.06; N, 11.64. Found: C, 63.97; H, 7.05; N, 11.76.
Reaction SMILES: C(OC[N:10]1[C:14]2=[N:15][CH:16]=[CH:17][C:18]([O:19][C:20]3[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=3)=[C:13]2[CH:12]=[CH:11]1)C1C=CC=CC=1>CO.Cl.[C].[Pd]>[NH:10]1[C:14]2=[N:15][CH:16]=[CH:17][C:18]([O:19][C:20]3[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=3)=[C:13]2[CH:12]=[CH:11]1
Reactant: Nc1ccc(Oc2ccnc3c2ccn3COCc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1ccc(Oc2ccnc3[nH]ccc23)cc1
Temperature: 50 °C
Reaction time: 7 h
Yield: 75.3 %

Procedure:
4-(1-Benzyloxymethyl-1H-pyrrolo[2,3-b]pyridin-4-yloxy)aniline (21.3 g, 61.7 mmol) was dissolved in methanol (300 mL) and 10 N hydrochloric acid (20 mL), and palladium carbon (10%, 800 mg) was added thereto. The resulting mixture was stirred under a hydrogen atmosphere at 50° C. for 7 hours. The catalyst was removed by celite filtration, and the resulting methanol solution was concentrated. The residue was added to THF (500 mL) and a 5 N sodium hydroxide aqueous solution (100 mL), and the resulting mixture was stirred. The solid was immediately dissolved, and the reaction solution was separated into two layers. The solution was subsequently stirred at room temperature for 3 hours, and saturated brine (300 mL) was added thereto. The THF layer was isolated and washed with saturated brine (100 mL). The organic layer was dried over anhydrous sodium sulfate and then concentrated. The residue was purified by amino-silica gel (Fuji Silysia, 1 L of ethyl acetate) to give 4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)aniline (10.46 g, yield: 75%).
Reaction SMILES: [C-:1]#[N:2].[K+].C#N.S(=O)(=O)(O)O.O[C:12]([CH3:24])([CH3:23])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:21][CH3:22])=[C:18]([OH:20])[CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[CH3:22][O:21][C:17]1[CH:16]=[C:15]2[C:14]([CH2:13][C:12]([CH3:24])([CH3:23])[N:2]=[CH:1]2)=[CH:19][C:18]=1[OH:20]
Reactant: COc1ccc(CC(C)(C)O)cc1O
Reactant: [C-]#N
Agent: C#N
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1cc2c(cc1O)CC(C)(C)N=C2
Yield: 27.4 %

Procedure:
To a flask (ice cooled) containing acetic acid (7.2 ml) was added potassium cyanide (1.29 mg, 36.7 mmol) in small portions (CARE: HCN may be evolved). To this was added a mixture of acetic acid (3.6 ml) and sulfuric acid (7.3 g) slowly with stirring. The ice bath was removed and a solution of 5-(2-hydroxy-2-methylpropyl)-2-methoxyphenol (6.0 mg, 30.6 mmol) in acetic acid (4 ml) was added dropwise by syringe over 15 min. The reaction mixture was stirred at rt for 24 h. The reaction mixture was poured onto ice-water and the aqueous solution neutralised with sodium Carbonate, then extracted with diethyl ether (2×) and ethyl acetate (2×) after saturation with sodium chloride. Purification by column chromatography eluting with DCM:EtOAc; 1:1 then EtOAc:MeOH; 4:1 afforded the title compound (1.72 g, 30%) as a colourless solid. mp=152-157° C. 1H NMR (270 MHz; CDCl3) 1.21 (6H, s, 2×CH3), 2.62 (2H, s, CH2), 3.91 (3H, s, OCH3), 5.69 (1H, brs, OH), 6.60 (1H, s, CH), 6.85 (1H, s, CH), 8.07 (1H, s, CH). 13C NMR (67.5 MHz; CDCl3) 28.07 (CH3), 37.96 (CH2), 54.74 (C(CH3)2), 56.04 (CH3), 110.63 (CH), 113.83 (CH), 120.88 (C), 128.02 (C), 144.86 (C), 149.47 (C), 157.19 (C). LC/MS (ES+) tr=0.97 min, m/z 205.9 (M++H). HRMS (ES+) calcd. for C12H15NO2 (M++H) 206.1176, found 206.1169.
Reaction SMILES: N1C(C)=CC=CC=1C.[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[C:11]=1[N:18]1[C:22](=[O:23])[CH2:21][C:20]([NH:24][C:25]2[CH:30]=[C:29]([NH:31][C:32](=[O:46])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:28]=[CH:27][C:26]=2[Cl:47])=[N:19]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:52](Cl)(=[O:54])[CH3:53].Cl>ClCCl>[Cl:17][C:12]1[CH:13]=[C:14]([Cl:16])[CH:15]=[C:10]([Cl:9])[C:11]=1[N:18]1[C:22](=[O:23])[CH:21]=[C:20]([NH:24][C:25]2[CH:30]=[C:29]([NH:31][C:32](=[O:46])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:28]=[CH:27][C:26]=2[Cl:47])[N:19]1[C:52](=[O:54])[CH3:53]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(Nc2cc(=O)n(-c3c(Cl)cc(Cl)cc3Cl)n2C(C)=O)c1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
1.07 g (0.01 mole) of lutidine is added to a solution of 30.7 g (0.05 mole) of 1-(2,4,6-trichlorophenyl)-3-(2-chloro-5-myristoylaminoanilino)-2-pyrazolin-5-one and 8 g (0.06 mole) of anhydrous aluminium chloride in 100 ml of dichloromethane. The solution is cooled to 10° C and 5.90 g (0.075 mole) of acetylchloride are added. 8 g (0.075 mole) of lutidine divided into 4 portions of 2 g each (one portion every 15 min) are added in a total period of time of 1 h, the temperature being kept below 10° C. The reaction mixture is stirred for 2 h more and then poured out into 1 l of 1N aqueous hydrochloric acid. The dichloromethane layer is washed until free from acid, dried, and concentrated by evaporation. The product is agitated with methanol.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:19]([CH2:20][CH2:21][C@:3]12[CH3:4])[C@:16]1([CH2:17][OH:18])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][C@@H:15]1[CH3:22])[CH2:10][C@H:9]3[CH3:24].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:22][C@@H:15]1[C@@:16]2([CH:17]=[O:18])[C:11]([CH2:10][C@@H:9]([CH3:24])[C@@H:8]3[C@@H:19]2[CH2:20][CH2:21][C@@:3]2([CH3:4])[C@H:5]3[CH2:6][CH2:7][C:2]2=[O:1])=[CH:12][C:13](=[O:23])[CH2:14]1
Reactant: C[C@@H]1CC2=CC(=O)C[C@H](C)[C@]2(CO)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: C[C@@H]1CC2=CC(=O)C[C@H](C)[C@]2(C=O)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Reaction time: 0.5 h

Procedure:
To a solution of 17β, 19-dihydroxy-1α,7α-dimethyl-4-androsten-3-one in acetone at 20° C. is added two equivalents of Jones Reagent and the mixture stirred for 30 minutes. The acetone layer is poured onto water with vigorous stirring. The crystals are removed by suction filtration and air dried. Crystallization from an acetone-hexane solution yields 1α,7α-dimethyl-4-androstene-3,17,19-trione.
Reaction SMILES: [O:1]1[C:5]2[N:6]=[CH:7][C:8]3[N:9]([CH:11]=[CH:12][CH:13]=3)[CH2:10][C:4]=2[CH:3]=[CH:2]1>C(O)C.[Pd]>[O:1]1[C:5]2[NH:6][CH2:7][C:8]3[N:9]([CH:11]=[CH:12][CH:13]=3)[CH2:10][C:4]=2[CH:3]=[CH:2]1
Reactant: C1=Nc2occc2Cn2cccc21
Agent: [Pd]
Solvent: CCO
Product: c1cc2n(c1)Cc1ccoc1NC2

Procedure:
A solution of 1 mmol of 4H-furo[2,3-e]-pyrrolo[1,2-a][1,4]diazepine and 0.2 g of 10% Pd/C in 10 ml of 10 ml of ethanol is hydrogenated for 18 hours. The reaction mixture is filtered through diatomaceous earth and the filtrate is evaporated in vacuo to give the desired product as a solid.