Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].O=S(Cl)[Cl:14]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([Cl:14])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(I)c(C(=O)O)c1
Solvent: Cc1ccccc1
Product: Cc1ccc(I)c(C(=O)Cl)c1
Temperature: 100 °C

Procedure:
To a solution of 5-methyl-2-iodobenzoic acid (3.0 g, 11.4 mmol) in toluene (150 mL), SOCl2 (8.35 mL, 114 mmol) was added and the mixture was heated at 100° C. for 3 hours. The solvent was concentrated in vacuum and the residue was co-evaporated from toluene twice to give the title compound as a grey solid. Yield (3.2 g, 100%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH3:16][C:17](C)([O-])[CH3:18].[K+].IC(C)C>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:17]([CH3:18])[CH3:16])[N:6]=[C:5]2[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)c1n[nH]c2ccc(F)cc12
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)I
Product: CCOC(=O)c1nn(C(C)C)c2ccc(F)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.6 %

Procedure:
To a stirred solution of ethyl 5-fluoro-1H-indazole-3-carboxylate (487 mg, 2.3 mmol, J. Heterocycl. Chem. 1964, 1, 239-241) in tetrahydrofuran (4 mL) was added potassium tert-butoxide (289 mg, 2.57 mmol) at 0° C. After stirring at 0° C. for 1 h, 2-iodopropane (438 mg, 2.57 mmol) was added to the mixture. The resulting mixture was stirred at room temperature for 20 h and concentrated under reduced pressure. The mixture was diluted with ethyl acetate (50 mL), washed with water (30 mL) and brine (30 mL). The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (10:1 to 2:1) to give 205 mg (35%) of the title compound as a yellow crystal.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([CH3:12])([OH:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.[CH3:15][C:16]([CH3:18])=O.O1CCCC1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2([CH3:12])[CH2:9][O:10][C:16]([CH3:18])([CH3:15])[O:11]2)=[CH:13][CH:14]=1
Reactant: CC(O)(CO)COc1ccc(Br)cc1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(COc2ccc(Br)cc2)COC(C)(C)O1
Temperature: 25 °C
Reaction time: 67 h
Yield: 40.2 %

Procedure:
3-(4-Bromophenoxy)-2-methylpropane-1,2-diol (261 mg, 1.00 mmol), acetone (77 mg, 1.3 mmol), tetrahydrofuran (5 mL), and a boron trifluoride diethyl ether complex (3 drops) were mixed. The mixture was stirred at room temperature for 67 hours, and acetone (102 mg, 1.76 mmol) was added thereto, followed by stirring for 2 hours. Sodium carbonate, ethyl acetate, and water were added to the reaction mixture to conduct extraction. The organic layer was washed with a saline solution twice. A residue was obtained by concentrating the organic layer under reduced pressure, and the residue was subjected to chromatography refining (methylene chloride) using silica gel, obtaining 121 mg of the objective compound (yield: 40%).
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C@@H:16]([C:21]3[CH:25]=[CH:24][O:23][N:22]=3)[CH2:17][C:18]([OH:20])=[O:19])=[CH:12][CH:11]=2)=[CH:6][C:5]=1[O:28][C:29]([F:32])([F:31])[F:30])[CH3:3].C1(C2C=C(C=CC=2OC(F)(F)F)COC2C=CC([C@@H](C3C=CON=3)CC(O)=O)=CC=2)CCCC1>>[CH:2]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C@@H:16]([C:21]3[CH:25]=[CH:24][O:23][N:22]=3)[CH2:17][C:18]([OH:20])=[O:19])=[CH:14][CH:15]=2)=[CH:6][C:5]=1[O:28][C:29]([F:32])([F:31])[F:30])([CH3:3])[CH3:1]
Reactant: C=C(C)c1ccc(COc2ccc([C@H](CC(=O)O)c3ccon3)cc2)cc1OC(F)(F)F
Agent: O=C(O)C[C@@H](c1ccc(OCc2ccc(OC(F)(F)F)c(C3CCCC3)c2)cc1)c1ccon1
Product: CC(C)c1ccc(COc2ccc([C@H](CC(=O)O)c3ccon3)cc2)cc1OC(F)(F)F

Procedure:
Compound 37 was synthesized from compound 35 using the procedure described above for the preparation of 23. 1H NMR (CD3CN) δ 1.25 (d, J=6.9 Hz, 6H), 2.96 (dd, J=7.4, 16.4 Hz, 1 H), 3.20 (dd, J=7.4, 16.4 Hz, 1 H), 3.34 (m, 1 H), 4.56 (m, 1 H), 5.09 (s, 2 H), 6.27 (d, J=1.7 Hz, 1H), 6.97 (d, J=6.6 Hz, 2 H), 7.25 (d, J=6.6 Hz, 2H), 7.37 (s, 1 H), 7.42 (d, J=8.1 Hz, 1H), 7.48 (d, J=8.1 Hz, 1 H), 8.45 (d, J=1.7 Hz, 1H). MS ESI (pos.) m/e: 450 (M+H).
Reaction SMILES: [Na].Cl.[NH2:3][C:4]([NH2:6])=[NH:5].Cl.Cl[C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[CH:22][CH:21]=2)[CH:12]=1)=[O:10]>CO>[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20]([N:13]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:19]3[C:11]([C:9]([NH:5][C:4]([NH2:6])=[NH:3])=[O:10])=[CH:12]2)=[CH:21][CH:22]=1
Reactant: O=C(Cl)c1cn(-c2ccnc3ccccc23)c2ncccc12
Reactant: N=C(N)N
Agent: Cl
Agent: [Na]
Solvent: CO
Product: N=C(N)NC(=O)c1cn(-c2ccnc3ccccc23)c2ncccc12
Yield: 40 %

Procedure:
1.5 g (65 mmol) of sodium (washed beforehand in toluene) were added gradually to 100 cm3 of methanol at a temperature in the region of 20° C. under an argon atmosphere. After dissolving with stirring, 6.5 g (68 mmol) of guanidine hydrochloride were added and the mixture was stirred at a temperature in the region of 20° C. for 2 h. The reaction mixture was subsequently concentrated to dryness under reduced pressure (2.7 kPa) and the residue was twice in succession taken up in 70 cm3 of dichloromethane (stabilized over amylene) and concentrated to dryness under reduced pressure (2.7 kPa). The residue was subsequently taken up in a mixture of 50 cm3 of tetrahydrofuran and 50 cm3 of dichloromethane under an argon atmosphere at a temperature in the region of 20° C. and then 11.8 mmol of 3-chlorocarbonyl-1-(quinolin-4-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride were added thereto with stirring. After stirring at a temperature in the region of 20° C. for 15 h, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa). The solid residue was taken up in 70 cm3 of 0.1N sodium hydroxide and the insoluble material was filtered off and then dissolved in 200 cm3 of dichloromethane. After separation by settling, the organic phase was dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2.7 kPa). The residue was purified by flash chromatography on a column of silica gel (0.04–0.06 mm), elution being carried out with a dichloromethane/methanol/triethylamine (88/10/2 by volume) mixture. The fractions comprising the expected product were combined and concentrated to dryness under reduced pressure (2.7 kPa) and the solid residue was taken up in a mixture of 60 cm3 of pentane, 10 cm3 of diethyl ether and 0.1 cm3 of methanol which was brought to reflux for 10 minutes. After returning to a temperature in the region of 20° C., filtering and washing with 10 cm3 of pentane, the solid was dried at a temperature in the region of 40° C. under reduced pressure (2.7 kPa). 1.56 g of N-[1-(quinolin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine were thus obtained in the form of a cream solid melting at 230° C. (the product was partially salified with 3.7% of hydrochloric acid, the base form melts at 164° C.). Mass spectrum: DCI: m/z=331 MH+ base peak.
Reaction SMILES: N1(S(N[C:9](=O)[C:10]2[CH:15]=C(Cl)C(OCC3(C(F)(F)F)CCCC3)=CC=2F)(=O)=O)CCC1.[N:30]1([S:34]([NH:37][C:38](=[O:58])[C:39]2[CH:44]=[C:43](Cl)[C:42]([O:46][CH2:47][CH:48]3[CH2:56][CH2:55][C:51]4([CH2:54][CH2:53][CH2:52]4)[CH2:50][CH2:49]3)=[CH:41][C:40]=2[F:57])(=[O:36])=[O:35])[CH2:33][CH2:32][CH2:31]1>>[N:30]1([S:34]([NH:37][C:38](=[O:58])[C:39]2[CH:44]=[C:43]([CH:15]3[CH2:10][CH2:9]3)[C:42]([O:46][CH2:47][CH:48]3[CH2:56][CH2:55][C:51]4([CH2:54][CH2:53][CH2:52]4)[CH2:50][CH2:49]3)=[CH:41][C:40]=2[F:57])(=[O:36])=[O:35])[CH2:33][CH2:32][CH2:31]1
Reactant: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(OCC2CCC3(CCC3)CC2)cc1F
Reactant: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(OCC2(C(F)(F)F)CCCC2)cc1F
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC2CCC3(CCC3)CC2)cc1F

Procedure:
Following the procedure as described in Example 165 and making variations as required to replace N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((1-(trifluoromethyl)-cyclopentyl)methoxy)benzamide with N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-(spiro[3.5]nonan-7-ylmethoxy)benzamide, the title compound was obtained (0.06 g 19%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.66 (d, J=16.2 Hz, 1H), 7.59 (d, J=9.1 Hz, 1H), 6.56 (d, J=14.5 Hz, 1H), 4.24 (t, J=7.7 Hz, 4H), 3.81 (d, J=6.1 Hz, 2H), 2.26 (q, J=7.7 Hz, 2H), 2.09-2.00 (m, 1H), 1.90-1.63 (m, 10H), 1.36-1.10 (m, 5H), 0.96-0.89 (m, 2H), 0.69-0.63 (m, 2H); MS (ES−) m/z 449.3 (M−1).
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][O:7][C:8]1[C:9]([CH2:31][CH2:32][CH3:33])=[C:10]([CH:18]=[CH:19][C:20]=1[C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])[O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CCCCCC>[CH3:6][O:7][C:8]1[C:9]([CH2:31][CH2:32][CH3:33])=[C:10]([CH:18]=[CH:19][C:20]=1[C:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])=[CH2:1])[O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17]
Reactant: [Li]CCCC
Reactant: CCCc1c(OCCCCC#N)ccc(C(=O)c2ccccc2OC)c1OC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C(c1ccccc1OC)c1ccc(OCCCCC#N)c(CCC)c1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 0.56 g of methyltriphenylphosphonium bromide in 10 ml of dry tetrahydrofuran were added 0.88 ml of a 1.6 molar n-butyllithium solution in hexane. After stirring for 3 hours under a nitrogen atmosphere, 0.5 g of 5-[3-methoxy-4-(2-methoxybenzoyl)-2-propylphenoxy]pentanenitrile were added in 5 ml of tetrahydrofuran. The reaction was stirred for 40 hours at 25° C. and then at 65° C. for 24 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by preparative thin layer chromatography using a solvent system of 10% ethyl acetate in hexane. The appropriate band was isolated, extracted with ethyl acetate, dried over sodium sulfate, and evaporated in vacuo providing 50 mg of the desired title product as an oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:15]([Cl:16])=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[C:5]([F:17])[CH:4]=1.[Cl:18][C:19]1[CH:20]=[C:21]([OH:28])[CH:22]=[N:23][C:24]=1[CH:25]1[CH2:27][CH2:26]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:16][C:15]1[C:3]([CH2:2][O:28][C:21]2[CH:22]=[N:23][C:24]([CH:25]3[CH2:27][CH2:26]3)=[C:19]([Cl:18])[CH:20]=2)=[CH:4][C:5]([F:17])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: Oc1cnc(C2CC2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(COc2cnc(C3CC3)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.2 %

Procedure:
To a stirred solution of tert-butyl 4-(bromomethyl)-5-chloro-2-fluorobenzoate (Preparation 25, 2.50 g, 7.99 mmol) and 5-chloro-6-cyclopropylpyridin-3-ol (Preparation 42 WO2012007869, 1.13 g, 6.66 mmol) in DMSO (25 mL) was added K2CO3 (2.76 g, 19.9 mmol). The resulting mixture was stirred under nitrogen at room temperature for 18 hours. The reaction mixture was then quenched with water (30 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with water (30 mL), dried over MgSO4 and evaporated under reduced pressure to give the crude product (2.69 g). Purification was accomplished by column chromatography on silica (eluting with 1:9 Et2O/cyclohexane) affording the title compound (1.24 g, 46%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([NH:14][S:15]([C:18]1[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=1[CH3:26])(=[O:17])=[O:16])[C:11](O)=[O:12])=[O:7])(C)(C)C.[C:27]([O:31][C:32](=[O:43])[NH:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1)([CH3:30])([CH3:29])[CH3:28].[CH:44]1[CH:45]=[CH:46][C:47]2N(O)N=N[C:48]=2[CH:49]=1.Cl.C(N=C=N)C>CN(C=O)C>[CH2:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH:10]([C:11](=[O:12])[NH:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][CH2:34][NH:33][C:32]([O:31][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:43])=[CH:37][CH:38]=1)[NH:14][S:15]([C:18]1[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=1[CH3:26])(=[O:17])=[O:16])[C:48]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:49]=1
Reactant: Cc1cc(C)c(S(=O)(=O)NC(CNC(=O)OC(C)(C)C)C(=O)O)c(C)c1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=N
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(C)c(S(=O)(=O)NC(CNC(=O)OCc2ccccc2)C(=O)Nc2ccc(CCNC(=O)OC(C)(C)C)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
To a mixture of 3-tert-Butoxycarbonylamino-2-(2,4,6-trimethyl-benzenesulfonylamino)-propionic acid (200 mg, 0.51 mmol), [2-(4-Amino-phenyl)-ethyl]-carbamic acid tert-butyl ester (130 mg, 0.55 mmol), HOBT (82 mg, 0.612 mmol) in DMF (25 mL), was added 1-(3-dimethylamino) propyl)-3-ethylcarbodiimide hydrochloride (118 mg, 0.612 mmol). The reaction was stirred overnight at room temperature. Insoluble particles were removed by filtration and the solvent was evaporated. Purification of the residue on silica gel (1:4 hexane:EtOAc) gave 144 mg (42%) of pure [2-[4-(2-tert-Butoxycarbonylamino-ethyl)-phenylcarbamoyl]-2-(2,4,6-trimethyl-benzenesulfonylamino)-ethyl]-carbamic acid benzyl ester (Y-2).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][O:7][CH2:6][CH2:5][NH:4]1.[F:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].C(N(CC)CC)C.[OH-].[Na+]>ClCCl>[F:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH:3]1[CH2:2][OH:1])=[O:13]
Reactant: OCC1COCCN1
Reactant: O=C(Cl)c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1F)N1CCOCC1CO
Reaction time: 0.5 h
Yield: 2339 %

Procedure:
To a solution of 3-(hydroxymethyl)morpholine (345 mg; 2.95 mmol) in dichloromethane (10 mL) was carefully added 2-fluorobenzoyl chloride (0.35 mL; 2.95 mmol) and triethylamine (0.62 mL; 4.42 mmol) and the reaction stirred for 0.5 h. The product was combined with 4 N NaOH (10 mL) to hydrolyse any ester and the organic layer extracted (dichloromethane, 3×). The combined organic layers were dried (Na2SO4) and the solvent evaporated to give an oil, which was purified by flash column chromatography on silica (gradient elution, dichloromethane-methanol 1:0 to 9:1) to give 4-(2-fluorobenzoyl)-3-(hydroxymethyl)morpholine (165 mg; o.69 mmol), EIMS: m/z=240.2 (M+H)+. This product and caesium carbonate (0.544 g) were heated to 120° C. in dimethylformamide (10 ml) solution under nitrogen for 4 hours. The solvent was evaporated, and the residue taken up in water and extracted with dichloromethane (3×). The combined dichloromethane extracts were dried (Na2SO4) and the solvent evaporated to give a crude solid which was purified by flash column chromatography on silica, eluting with ether to give the title compound (77 mg). M.p. 105-107° C.; EIMS: m/z=220.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[C:13]12([NH2:23])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2>CN(C=O)C>[C:13]12([NH:23][C:4]3[C:5]4[S:10][CH:9]=[C:8]([CH3:11])[C:6]=4[N:7]=[C:2]([Cl:1])[N:3]=3)[CH2:20][CH:19]3[CH2:18][CH:17]([CH2:16][CH:15]([CH2:21]3)[CH2:14]1)[CH2:22]2
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Reactant: NC12CC3CC(CC(C3)C1)C2
Solvent: CN(C)C=O
Product: Cc1csc2c(NC34CC5CC(CC(C5)C3)C4)nc(Cl)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 103 %

Procedure:
In DMF was dissolved 700 mg (3.2 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and then an aqueous solution of 1.13 g (7.5 mmol) of 1-adamantaneamine was added dropwise to the resulting rid solution under ice cooling over 5 minutes. The reaction mixture was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for one hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/10) to give 1.10 g (yield: 100%) of the title compound.
Reaction SMILES: [CH:1]1[C:6]2[NH:7][C:8]3[C:9](=[CH:10][CH:11]=[C:12]4[C:20]=3[NH:19][C:18]3[C:13]4=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[I:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31]>C1COCC1>[I:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([N:7]1[C:8]2[C:9](=[CH:10][CH:11]=[C:12]3[C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[NH:19][C:20]3=2)[C:5]2[C:6]1=[CH:1][CH:2]=[CH:3][CH:4]=2)(=[O:32])=[O:31]
Reactant: c1ccc2c(c1)[nH]c1c2ccc2c3ccccc3[nH]c21
Reactant: O=S(=O)(Cl)c1ccccc1I
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1I)n1c2ccccc2c2ccc3c4ccccc4[nH]c3c21
Temperature: 40 °C
Reaction time: 12 h

Procedure:
43 g (169 mmol) of 11,12-dihydroindolo[2,3-a]carbazole are initially introduced in 1000 ml of THF, and 8.9 g (223.3 mmol) of NaH (60% in oil) are added at 0° C. 24 g (80 mmol) of 2-iodobenzenesulfonyl chloride are subsequently added to the mixture, which is then stirred at 40° C. for 12 h. The organic phase is dried over MgSO4, and the solvent is removed in vacuo. The residue is recrystallised from acetone and finally sublimed in a high vacuum. Yield: 29 g (574 mmol), 72% of theory, purity according to HPLC 99.9%.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[N+:7]([C:10]1[CH:11]=[C:12]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]([NH2:16])=[N:14][CH:15]=1)([O-:9])=[O:8].I[CH2:26]C.O>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:16]1[C:13]2=[N:14][CH:15]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=[C:12]2[CH:17]=[C:18]1[C:19]1[CH:24]=[CH:23][C:22]([CH3:26])=[CH:21][CH:20]=1)[CH3:2]
Reactant: Nc1ncc([N+](=O)[O-])cc1C#Cc1ccccc1
Reactant: CC(C)(C)[O-]
Reactant: CCI
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCn1c(-c2ccc(C)cc2)cc2cc([N+](=O)[O-])cnc21
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a suspension of potassium ter-butoxide (0.41 g, 3.7 mmol) in anhydrous DMF (5 ml) a solution of 5-nitro-3-(phenylethynyl)pyridin-2-amine (0.70 g, 2.8 mmol), in DMF (25 ml) was added dropwise while stirring at room temperature. After 1.5 days, iodoethane (0.38 ml, 4.7 mmol) was added and the whole stirred for additional 1.5 days. To the reaction H2O (50 ml) and EtOAc (100 ml) were then added. The mixture was poured into a separatory funnel, the organic layer separated, the aqueous one thoroughly extracted with EtOAc (50 ml) and combined organic layers washed with brine (2×100 ml). The organic solvent was removed by evaporation under reduced pressure and the residue was purified by column chromatography on silica gel (Et2O/n-hexane, Et2O 10%→20%) to give 1-ethyl-2-(4-methylphenyl)-5-nitro-1H-pyrrolo[2,3-b]pyridine:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][NH:12][CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1.C([NH:31][C@H:32]([C:34](O)=[O:35])[CH3:33])(OC(C)(C)C)=O>>[NH2:31][CH:32]([CH3:33])[C:34]([N:12]1[CH2:13][CH2:14][C:10]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[CH2:9]2)[CH2:11]1)=[O:35]
Reactant: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Cl)ccc21
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC(N)C(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Examples 19 and 20, with the exceptions that 5-chloro-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide was used instead of bromo-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide, and that N-Boc alanine was used instead of N-Boc glycine.
Reaction SMILES: I[C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:5]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:6]=[CH:2][CH2:3][C@H:4]1[C:14]([O:16][CH3:17])=[O:15].[N:5]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH:2]=[CH:3][C@H:4]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)[C@@H]1C[C@H](I)CN1C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)[C@@H]1C=CCN1C(=O)OC(C)(C)C
Product: COC(=O)[C@@H]1CC=CN1C(=O)OC(C)(C)C
Temperature: 85 °C
Reaction time: 10 h

Procedure:
To a solution of 27.3 g of the compound obtained in Step 19-1 in toluene (500 ml) was added 1,8-diaza bicyclo[5,4,0]undec-7-ene (DBU) (12.7 ml) and the reaction mixture was stirred for 10 hours at an external temperature of 85° C. After being to cool, the precipitation was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was separated and purified by column chromatography (silicagel 60; mobile phase: EtOAc/n-hexane=1/10 to 1/5; v/v) to obtain 4.15 g of 1-tert-butyl 2-methyl (2S)-2,3-dihydro-1H-pyrrole-1,2-dicarboxylate (colorless oil) and 12.5 g of 1-tert-butyl 2-methyl (2S)-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate (colorless oil).
Reaction SMILES: [CH2:1]([C:3]([OH:36])([CH2:34][CH3:35])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH2:31][CH3:32])([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[C:17]([CH3:30])[CH:16]=2)[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:33])[CH3:2].[CH2:37]([O:39][C:40](=[O:49])[CH2:41][C:42]1[CH:43]=[N:44][C:45](Br)=[N:46][CH:47]=1)[CH3:38].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:37]([O:39][C:40](=[O:49])[CH2:41][C:42]1[CH:43]=[N:44][C:45]([C:18]2[CH:19]=[CH:20][C:15]([C:12]([CH2:13][CH3:14])([C:9]3[CH:10]=[CH:11][C:6](/[CH:5]=[CH:4]/[C:3]([CH2:34][CH3:35])([OH:36])[CH2:1][CH3:2])=[C:7]([CH3:33])[CH:8]=3)[CH2:31][CH3:32])=[CH:16][C:17]=2[CH3:30])=[N:46][CH:47]=1)[CH3:38]
Reactant: CCOC(=O)Cc1cnc(Br)nc1
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)c(C)c2)cc1C)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)Cc1cnc(-c2ccc(C(CC)(CC)c3ccc(/C=C/C(O)(CC)CC)c(C)c3)cc2C)nc1
Temperature: 100 °C
Reaction time: 13 h
Yield: 53 %

Procedure:
Degassed N,N-dimethylformamide (0.63 mL) was added to (E)-3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol (Example 28; 52.6 mg, 0.107 mmol), 2-bromopyrimidine-5-acetic acid ethyl ester (Example 43-(3); 63 mg, 0.26 mmol), tetrakis(triphenylphosphine)palladium (0) (62.8 mg, 0.0543 mmol) and potassium phosphate (75 mg, 0.35 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 96 to 104° C. for 13 hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to give the title compound (30 mg, 53%).