Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([CH3:13])[C:10]2[C:14]([CH3:17])=[CH:15][S:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].C1C(=O)N([Br:25])C(=O)C1>CC(O)=O.C(Cl)(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([CH3:13])[C:10]2[C:14]([CH3:17])=[C:15]([Br:25])[S:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2scc(C)c2C(C)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCc2sc(Br)c(C)c2C(C)C1
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
The product of step (b) (92 mg, 0.36 mmol) was dissolved in 4 mL of 1:1 HOAc/CHCl3 and treated with NBS (67 mg, 0.38 mmol). After stirring for ½ hour, the reaction was diluted with EtOAc (70 mL) was washed with water (3×30 mL) and 1M NaOH (2×30 mL). The organic solution was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (EtOAc/Hex) to give 90 mg of the sub-title compound.
Reaction SMILES: [CH:1]#[C:2][C@@H:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].I[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>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.CN(C=O)C.CCN(CC)CC>[OH:9][C@@H:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:2]#[C:1][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#C[C@@H](O)CCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCC[C@H](O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, (S)-(-)-1-octyn-3-ol (61 mg, 0.53 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.41 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and Cul (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 18 h to yield (S)-(Z)-1,3-dihydro-4-(3-hydroxy-1-octynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 101 mg, 68%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].ClCCl>>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[CH3:25][N:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[S:21]([CH3:24])(=[O:23])=[O:22]
Reactant: CN(c1ccccc1C1CCN(C(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(c1ccccc1C1CCNCC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-[2-(1-t-Butoxycarbonylpiperidin-4-yl)phenyl]-N-methylmethanesulfonamide (662 mg) was dissolved in trifluoroacetic acid-dichloromethane (10%, 50 mL) and stirred at room temperature 2 h. The solvent was evaporated under reduced pressure to give the title compound as a colourless gum (670 mg), m/e (ES+) 269 (MH+).
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[N+]([O-])([O-])=O.[NH4+].[Ce].[OH2:13].[C:14](#[N:16])[CH3:15]>>[C:14]([NH:16][CH:1]1[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1)(=[O:13])[CH3:15]
Reactant: CC#N
Reactant: C1=CCCCC1
Reactant: O
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Product: CC(=O)NC1C=CCCC1

Procedure:
Briguet, C. Freppel, J.-C. Richer and M. Zador (Can. J. Chem. 1974, 52, 3201) describe a process for the oxidation of cyclohexene with cerium ammonium nitrate in acetonitrile which contains 1% of water, and they obtain acetamido-2-cyclohexene. Here, the use of stoichiometric amounts of cerium ammonium nitrate stands in the way of industrial use. Y. Leblanc, R. Zamboni, M. A. Bernstein (J. Org. Chem. 1991, 56, 1971) describe an ene reaction of cyclohexene with bis-(2,2,2-trichloroethyl) azodicarboxylate at 155° C. which, after work-up, affords a yield of 70% of the desired tetrahydroaniline derivative.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[C:42](Cl)(=O)[O:43]C1C=CC([N+]([O-])=O)=CC=1.[CH3:55][N:56]([CH3:60])[CH2:57][CH2:58][NH2:59]>C(Cl)Cl>[CH3:55][N:56]([CH3:60])[CH2:57][CH2:58][NH:59][C:42](=[O:43])[NH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)CCN
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCNC(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (100 mg, 0.22 mmol) in anhydrous CH2Cl2 (2 mL) added Et3N (45 mg, 0.44 mmol) and 4-nitrophenyl carbonochloridate (47 mg 0.23 mmol). The solution was stirred at RT for 2 h. To the reaction mixture added N,N-dimethylethane-1,2-diamine (36 μL, 0.33 mmol) and stirred for 16 h. Concentrated in vacuo to afford the crude tert-butyl 5-(2-(3-(3-(2-(dimethylamino)ethyl)ureido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate.
Reaction SMILES: Cl[C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]([NH2:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:7][CH:6]1[NH:8][C:2]2[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:3]=2[O:4][CH2:5]1
Reactant: CC(N)COc1cccc([N+](=O)[O-])c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1COc2cccc([N+](=O)[O-])c2N1
Reaction time: 8 h
Yield: 79.2 %

Procedure:
6 g (0.026 mol) of 1-(2-chloro-3-nitrophenoxy)propan-2-amine, 3.6 g (0.026 mol) of potassium carbonate and 20 ml of N,N-dimethylformamide are heated at 110° C. with stirring overnight. The reaction mixture is poured into water and extracted 3 times with ether. The organic phase is recovered, washed with water, dried and the solvent evaporated to dryness. There are obtained 4 g of product in the form of a crystalline residue which is used as is in the following stage.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[NH:4][C@@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=2)[NH:8][C@H:7]([CH2:19][CH3:20])[CH2:6]1.N1C=CC=CC=1.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(Cl)Cl>[CH2:32]([O:31][C:29]([N:8]1[C:9]2[C:14](=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=2)[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:21])[CH2:6][C@H:7]1[CH2:19][CH3:20])=[O:30])[CH3:33]
Reactant: CC[C@@H]1C[C@H](NC(=O)OC)c2cc(C(F)(F)F)ccc2N1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@@H](NC(=O)OC)C[C@H]1CC
Temperature: -10 °C
Reaction time: 20 h
Yield: 88.2 %

Procedure:
A clean, dry and nitrogen gas purged 100 L glass tank was charged with (2R, 4S)-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid methyl ester (5191 g, 17.17 mol), methylene chloride (21 L), and pyridine (4.16 L, 51.4 mol). The reaction vessel was cooled to −10° C. Ethyl chloroformate (4.10 L, 42.9 mol) was slowly added at such a rate that the internal temperature did not exceed −5° C. The reaction solution was brought to 0° C. and held for 20 hours. The reaction was quenched by adding to a mixture of diisopropyl ether (IPE) (36 L), methylene chloride (6.2 L) and 1.5M hydrochloric acid solution (52 L). The resulting phases were separated and the organic layer was extracted with 1M sodium hydroxide solution (15 L). The resulting phases were separated and the organic layer was washed with saturated aqueous sodium chloride NaCl (15 L). The resulting phases were separated and the organic layer was concentrated by distillation to a volume of 40 L. Crystallization initiated at lower volume. The methylene chloride was displaced with IPE by distilling the mixture and periodically adding IPE to maintain a constant volume at 40L until a temperature of 68° C. was maintained (46 L total IPE used). The mixture was cooled and allowed to granulate with stirring at room temperature for 19 hours. The solids were filtered, rinsed with IPE (8 L), and dried under vacuum at 40° C. to afford 5668 g of the title compound (88%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]1[CH2:10][S:9][C:8]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[N+:21]([O-])=O)=[N:7]1)[CH3:2].[O:25]1[C:29]2([CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]2)[O:28][CH2:27][CH2:26]1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]1[CH2:10][S:9][C:8]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[NH:21][CH:32]2[CH2:33][CH2:34][C:29]3([O:28][CH2:27][CH2:26][O:25]3)[CH2:30][CH2:31]2)=[N:7]1)[CH3:2]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CCOC(=O)C[C@@H]1CSC(c2cc3cc(C)cc([N+](=O)[O-])c3[nH]2)=N1
Product: CCOC(=O)C[C@@H]1CSC(c2cc3cc(C)cc(NC4CCC5(CC4)OCCO5)c3[nH]2)=N1

Procedure:
{(R)-2-[5-methyl-7-nitro-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic acid ethyl ester prepared in Preparation 54 and 1,4-dioxa-spiro[4,5]decan-8-one were reacted according to the same procedure as Example 1 to give the title compound.
Reaction SMILES: ClC(OCC(C)C)=O.[CH2:9]([N:11]([CH2:18][CH3:19])[CH2:12][C:13]#[C:14][C:15]([OH:17])=O)[CH3:10].CN1CCOCC1.[NH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[CH:33][C:32]([C:38]#[N:39])=[C:31]2[NH:40][C:41]1[CH:46]=[CH:45][C:44]([F:47])=[C:43]([Cl:48])[CH:42]=1>O1CCCC1.N1C=CC=CC=1>[Cl:48][C:43]1[CH:42]=[C:41]([NH:40][C:31]2[C:30]3[C:35](=[CH:36][CH:37]=[C:28]([NH:27][C:15](=[O:17])[C:14]#[C:13][CH2:12][N:11]([CH2:9][CH3:10])[CH2:18][CH3:19])[CH:29]=3)[N:34]=[CH:33][C:32]=2[C:38]#[N:39])[CH:46]=[CH:45][C:44]=1[F:47]
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(F)c(Cl)c1
Reactant: CCN(CC)CC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCN(CC)CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Isobutyl chloroformate (0.061 g, 0.448 mmol) was dropwise added into an ice cold solution of 4-diethylamino-2-butynoic acid (0.104 g, 0.672 mmol) and N-methyl-morpholine (0.068 g, 0.672 mmol) in 10 mL of tetrahydrofuran under N2. After stirring for 30 min, a solution of 0.1 g (0.32 mmol) of 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-3-quinolinecarbonitrile in 1.5 mL of pyridine was added dropwise and the mixture was stirred at 0° C. for 1.5 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by thin-layer chromatography eluted with 15% methanol in ethyl acetate. The product was collected, and dried in vacuo to give 0.046 g (32%) of light brown solid; ESMS m/z 450.2, (M+H+); mp 117-120° C.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[C:20]([CH3:22])[N:19]=[C:18](Cl)[CH:17]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:24][CH3:25])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>CN1CCCC1=O>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([N:26]5[CH:30]=[CH:29][N:28]=[CH:27]5)[CH:17]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:24][CH3:25])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1c[nH]cn1
Reactant: CCc1[nH]n(C2CCCC2)c2nc(-c3cc(C)nc(Cl)c3)nc(=O)c1-2
Solvent: CN1CCCC1=O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3cc(C)nc(-n4ccnc4)c3)nc(=O)c1-2
Temperature: 25 °C
Yield: 5.5 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-6-(2-chloro-6-methyl-4-pyridyl)pyrazolo[3,4-d]pyrimidin-4-one (0.30 g, 0.84 mmol), imidazole (0.06 g, 0.9 mmol) and N-methyl-2-pyrrolidinone (10 ml) was refluxed for 60 hours. The mixture was cooled to room temperature, filtered through a plug of celite and the plug was rinsed with methanol. The solvent was removed in vacuo and the residue was washed with ethanol and the solution was filtered. The filtrate was treated with charcoal, filtered, and the solvent was removed in vacuo. The residue was triturated with ether and a dark solid was collected by filtration. The product was recrystallized from ether/methanol to afford 0.018 g (10%) of 1-cyclopentyl-3-ethyl-6-[2-(1-imidazolyl)-6-methyl-4-pyridyl]pyrazolo[3,4-d]pyrimidin-4-one. 1/4 hydrate as a beige powder, m.p. 277°-278° C.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[NH2:8][C:9]1[CH:10]=[C:11]([C:21](=[O:23])[CH3:22])[CH:12]=[C:13]([S:15]([F:20])([F:19])([F:18])([F:17])[F:16])[CH:14]=1.C(N(CC)CC)C.C(OC(=O)C)(=O)C>C(Cl)Cl>[C:21]([C:11]1[CH:10]=[C:9]([NH:8][C:3](=[O:5])[CH3:2])[CH:14]=[C:13]([S:15]([F:16])([F:20])([F:17])([F:18])[F:19])[CH:12]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1cc(N)cc(S(F)(F)(F)(F)F)c1
Reactant: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)Nc1cc(C(C)=O)cc(S(F)(F)(F)(F)F)c1
Reaction time: 8 h
Yield: 99 %

Procedure:
1-[3-Amino-5-(pentafluorosulfanyl)phenyl]ethanone trifluoroacetic acid salt (100 mg, example 4d) was dissolved in methylene chloride (10 ml), and triethylamine (120 μl) was added. Acetic anhydride (30 μl) was then added dropwise while stirring. After stirring for 4 h, the mixture was left to stand overnight and then further acetic anhydride (30 μl) was added. After stirring for a further 6 h, the reaction mixture was again left to stand overnight and then concentrated. The residue was taken up with ethyl acetate and water, and adjusted to pH 9 with saturated sodium hydrogencarbonate solution, and the aqueous phase was extracted twice more with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 80 mg of the desired compound were obtained.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:10][CH2:11][N:12]([C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])[CH2:13][CH2:14]Cl.O>CC(C)=O>[CH2:1]([N:8]1[CH2:10][CH2:11][N:12]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:13][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)c1cccc(N(CCCl)CCCl)c1
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cccc(N2CCN(Cc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 41 h
Yield: 51 %

Procedure:
Benzylamine (1.2 mL, 11 mmol), 120b (1.0 g, 3.6 mmol), water (50 mL), and acetone (50 mL) were heated at reflux for 28 h, then stirred at room temperature an additional 41 h. After evaporation of the acetone, the mixture was extracted with EtOAc (2×). The organic phase was extracted further with water and brine, then dried (Na2SO4), filtered and concentrated. The product was purified by chromatography on silica gel, eluting with 30% to 50% EtOAc in hexanes, then evaporated to yield a yellow oil (0.57 g). IR(neat): cm-1 1722. 1H NMR (300 MHz, CDCl3): 7.57-7.08 (m, 9H), 3.88 (s, 3H), 3.56 (s, 2H), 3.24 (m, 4H), 2.61 (m, 4H). HR-MS: Calc'd. 311.1760, Found 311.1764.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[NH:9][C:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][C:17]([O:23][CH3:24])=[CH:18][CH:19]=5)[C:14]=4[C:13]4[C:25](=[O:30])[N:26]([CH3:29])[C:27](=[O:28])[C:12]=4[C:11]=3[C:5]=2[CH:4]=1.[H-].[Na+].[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37]Cl.C(OC(C)C)(C)C.C(OCC)(=O)C>CN(C)C=O>[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37][N:9]1[C:10]2[C:22]3[NH:21][C:20]4[CH:19]=[CH:18][C:17]([O:23][CH3:24])=[CH:16][C:15]=4[C:14]=3[C:13]3[C:25](=[O:30])[N:26]([CH3:29])[C:27](=[O:28])[C:12]=3[C:11]=2[C:5]2[C:6]1=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2
Reactant: COc1ccc2[nH]c3c4[nH]c5ccc(OC)cc5c4c4c(c3c2c1)C(=O)N(C)C4=O
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: COc1ccc2[nH]c3c(c4c(c5c6cc(OC)ccc6n(CCCN(C)C)c35)C(=O)N(C)C4=O)c2c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 2.0 g (5 mmol) 6,7,12,13-tetrahydro-3,9-dimethoxy-6-methyl-5,7-dioxo-5H-indolo[2,3-a]-pyrrolo[3,4-c]carbazole in 100 ml dry dimethylformamide is added dropwise at 20° C. to a suspension of 182 mg (6.1 mmol) sodium hydride (80% in paraffin oil) in 5 ml dimethylformamide. After stirring for 1 hour at 20° C. 738 mg (6.1 mmol) 3-dimethylaminopropyl chloride are added thereto and the reaction mixture is stirred for 20 hours at 20° C. The solvent is distilled off in a vacuum, the residue is mixed with 150 ml ethyl acetate and 150 ml of water and the solid material insoluble in both phases is filtered off. The solid material is taken up in tetrahydrofuran, the tetrahydrofuran solution is washed with a saturated sodium chloride solution, dried over anhydrous sodium sulphate, filtered and evaporated. The residue, together with the residue from the ethyl acetate solution, is chromatographed on silica gel with ethyl acetate/methanol (4:1 v/v). The fraction with the Rf 0.2 in ethyl acetate/methanol (3:1 v/v) is isolated and stirred with diisopropyl ether/ethyl acetate (9:1 v/v). The crystals formed are filtered off. 12-(3-Dimethylaminopropyl)-6,7,12,13-tetrahydro-3,9-dimethoxy-6-methyl-5,7-dioxo-5H-indolo-[2,3-a]pyrrolo[3,4-c]carbazole is obtained in the form of yellow-brown crystals.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][NH2:25])[CH2:18][CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH2:33]([S:35]([Cl:38])(=[O:37])=[O:36])[CH3:34]>C(Cl)Cl.CO>[ClH:38].[ClH:38].[CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][NH:25][S:35]([CH2:33][CH3:34])(=[O:37])=[O:36])[CH2:18][CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCS(=O)(=O)Cl
Reactant: CCCCc1cc(OC2CCN(CCCN)CC2)c2ncccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCc1cc(OC2CCN(CCCNS(=O)(=O)CC)CC2)c2ncccc2c1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)amine (for example, as prepared for Intermediate 36) (30 mg, 0.09 mmol) was dissolved in DCM (1 ml), and treated with triethylamine (38 μl, 0.27 mmol), and ethanesulfonyl chloride (commercially available, for example, from Aldrich) (17 μl, 0.18 mmol). The mixture was stirred in a stoppered vial at room temperature for 1 h, then left to stand at room temperature overnight. The mixture was diluted with methanol and applied to an SCX-2 cartridge (5 g) eluting with methanol, followed by 10% aqueous 0.88 s.g. ammonia in methanol. The relevant fractions were concentrated, and the residue was purified by MDAP. The appropriate fractions were combined and concentrated to give the title compound as the monoformate salt (29 mg, 67%): LCMS RT=2.62 min, ES+ve m/z 434 (M+H)+. The material was dissolved in methanol and treated with 1.25 M hydrogen chloride in methanol (excess). The volatiles were removed under a stream of nitrogen to give the title compound (30 mg): LCMS RT=2.63 min, ES+ve m/z 434 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C.[NH2:34][C:35]1[C:43]2[C:38](=[CH:39][C:40]([C:44]3[CH:49]=[CH:48][C:47]([C:50]4[NH:54][C:53]([C@@H:55]5[CH2:59][CH2:58][CH2:57][N:56]5[C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])=[N:52][CH:51]=4)=[CH:46][CH:45]=3)=[CH:41][CH:42]=2)[N:37]([C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[N:36]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[C:63]([O:62][C:60]([N:56]1[CH2:57][CH2:58][CH2:59][C@H:55]1[C:53]1[NH:54][C:50]([C:47]2[CH:48]=[CH:49][C:44]([C:40]3[CH:39]=[C:38]4[C:43]([C:35]([NH:34][C:13]([C@@H:9]5[CH2:10][CH2:11][CH2:12][N:8]5[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15])=[N:36][N:37]4[C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])=[CH:42][CH:41]=3)=[CH:45][CH:46]=2)=[CH:51][N:52]=1)=[O:61])([CH3:66])([CH3:65])[CH3:64]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4c(N)nn(C(=O)OC(C)(C)C)c4c3)cc2)[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1nn(C(=O)OC(C)(C)C)c2cc(-c3ccc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)ccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.1 %

Procedure:
To a solution (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (97.1 mg, 0.451 mmol) in CH2Cl2 (2 mL) was added ethyl 2-ethoxyquinoline-1(2H)-carboxylate (EEDQ, 181.2 mg, 0.733 mmol) followed by (S)-tert-butyl 3-amino-6-(4-(2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-1H-indazole-1-carboxylate (209.7 mg, 0.385 mmol) after about 5 min. The reaction mixture as allowed to stir at room temperature for 12 h and the solution was treated with EEDQ (79 mg, 0.365 mmol) and stirred for 48 h. The solution was treated with (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (60 mg, 0.279 mmol). After stirring a further 12 h the mixture was treated with MeOH (4 mL) followed by iPr2NEt (0.1 mL) and allowed to stir for 2 h. The solvent was removed in vacuo and the residue was purified by prep HPLC (CH3CN—H2O—NH4OAc) to give the title compound (197.4 mg, 69%) as a light yellow glass. 1H NMR (400 MHz, DMSO-d6) δ 11.90-11.95 (m, 1H), 11.13-11.20 (m, 1H), 8.33 (s, 1H), 8.09 (d, J=8 Hz, 1H), 7.88 (app d, J=8 Hz, 2H), 7.65-7.78 (m, 3H), 7.55-7.58 (m, 1H), 4.75-4.87 (m, 2H), 4.36-4.43 (m, 1H), 4.06-4.12 (m, 1H), 3.51-3.59 (m, 1H), 3.42-3.47 (m, 1H), 3.35-3.37 (m, 2H, partially obscured by H2O signal), 2.12-2.32 (m, 2H), 1.79-2.01 (m, 4H), 1.66 (s, 9H), 1.40 (s, 9H), 1.32 and 1.15 (s, 9H, rotamers). LCMS: Anal. Calcd. for C40H51N7O7: 741; found: 742 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[O:25]1[CH2:29][CH2:28]CC1.[C:30]1(C)C=CC=CC=1>CN(C)C=O.O>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][CH2:30][C@@H:29]([OH:25])[CH3:28])=[CH:9][CH:8]=2)=[CH:11][CH:12]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: C1CCOC1
Reactant: Cc1ccccc1
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(-c2ccc(OC[C@H](C)O)cc2)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A solution of (2S)-2-(2'-tetrahydropyranyloxy)-1-(p-toluenesulfonyloxy)-propane (20 g) in N,N-dimethylformamide (hereinafter abbreviated to DMF) (300 ml) was added to a mixture of sodium hydride (60%) (2 g), 4-hydroxy-4'-octyloxy-biphenyl(10 g) and tetrahydrofuran (hereinafter abbreviated to THF) (200 ml), followed by agitating the resulting mixture at 60° C. for 4 hours, allowing it to cool down to room temperature, adding toluene (300 ml) and water (300 ml), separating the resulting organic layer, washing it with an alkali solution and then with water, concentrating it, adding ethanol (300 ml) and pyridium p-toluenesulfonate (hereinafter abbreviated to PPTS) (2 g), agitating the mixture at 50° C. for 3 hours, distilling off ethanol, adding toluene (300 ml), washing the resulting organic layer with water, concentrating it and recrystallizing the concentrate, to obtain (S)-1-(4'-octyloxy-4-biphenylyloxy)-propan-2-ol (8 g).