Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.[N+:18]([O-])([O-:20])=[O:19].[K+]>OS(O)(=O)=O.[OH-].[K+]>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([C:14]([F:16])([F:17])[F:15])[C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: O=c1[nH]c2cc(Cl)cc(C(F)(F)F)c2[nH]c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])c(C(F)(F)F)c2[nH]c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
To a solution of 7-chloro-5-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione (29 mg, 0.16 mmol) in concentrated H2SO4 (0.5 mL) at 0° C. was added KNO3 (11.6 mg, 0.115 mmol). The mixture was stirred at 0° C. for 0.5 h, then at room temperature for 12 h and it was poured into ice water (2 g). The precipitate was collected by filtration, affording 31 mg (91.4%) of crude title compound. It was dissolved in 1N KOH (1 mL) and filtered. The filtrate was acidified to pH=2 with 4N HCl to give a yellow precipitate, which was collected by filtration, and dried at 50° C. for 4 h, affording the title compound (23 mg, 67%) as a yellow powder. Recrystallization from DMSO/H2O gave pure title compound as yellow microcrystals. Mp: 278°-80° C., IR (KBr, cm-1): 3425, 3150, 3125, 1712, 1618, 1556; 1H NMR (DMSO-d6): δ7.531 (s, 1H), 11.803 (s, 1H), 12.459 (s, 1H). HRMS: calcd. for C9H3ClF3N3O4 (M+) m/z: 308.9763, found: 308.9759.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[S:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].[C:26]([C:28]([C:31]1[CH:32]=[C:33]([NH:37][C:38](=O)[O:39]C2C=CC=CC=2)[CH:34]=[CH:35][CH:36]=1)([CH3:30])[CH3:29])#[N:27]>C1COCC1.CN(C1C=CN=CC=1)C>[C:26]([C:28]([C:31]1[CH:32]=[C:33]([NH:37][C:38]([NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:19]([S:18][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:20]=2)=[O:39])[CH:34]=[CH:35][CH:36]=1)([CH3:30])[CH3:29])#[N:27]
Reactant: CC(C)(C#N)c1cccc(NC(=O)Oc2ccccc2)c1
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cccc(C(C)(C)C#N)c4)c3)c2cc1OC
Yield: 22.8 %

Procedure:
Using the procedure described in Example 278B, to a solution of 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline (102 mg, 0.3 mmol), prepared as described in Example 230A, in THF (3 ml) was added DMAP (18 mg, 0.15 mmol) and phenyl 3-(2-cyanopropan-2-yl)phenylcarbamate (92 mg, 0.33 mmol) described in Example 278A to afford 1-(3-(2-cyanopropan-2-yl)phenyl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)phenyl)urea (37.2 mg, 23%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.67 (s, 6H), 3.76 (s, 3H), 4.00 (s, 4H), 4.34 (s, 3H), 7.11 (d, J=6 Hz, 1H), 7.24-7.43 (m, 7H), 7.66 (s, 1H), 7.84 (s, 1H), 8.69 (s, 1H), 8.92 (d, J=9 Hz, 2H); LC-MS (ESI) m/z 544 (M+H)+.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]([NH:22][NH:23][C:24](=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>O1CCCC1>[Si:1]([O:18][CH2:19][C:20]1[S:40][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:23][N:22]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)NNC(=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1nnc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.8 %

Procedure:
To a solution of ethyl [2-({[tert-butyl(diphenyl)silyl]oxy}acetyl)hydrazino](oxo)acetate (3.20 g) in tetrahydrofuran (30 mL) was added Lawesson's reagent (3.02 g), and the mixture was stirred at room temperature for 24 hr. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography, and the title compound (3.05 g, yield 96%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])([OH:3])=O.O>P(Cl)(Cl)(Cl)=O>[CH3:21][S:20][C:17]1[CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]2[NH:10][C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1](=[O:3])[C:19]=2[CH:18]=1
Reactant: CSc1ccc(Nc2ccccc2C(=O)O)c(C(=O)O)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CSc1cc(C(=O)O)c2[nH]c3ccccc3c(=O)c2c1

Procedure:
The product of part (i) above (2 g) in phosphorus oxychloride (6 ml) was heated at reflux for 1 h. The solution was then cooled (to 0°), and water (15 ml) was added slowly. The mixture was then heated at 100° for 10 min and then poured onto cracked ice. The resulting precipitate was filtered off, washed with water, and crystallised from methanol to give the title compound (1.6 g). IR includes peaks at 1690 cm-1 (CO2H) and 1620 cm-1 (CO).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([CH2:14][N:15]=[N+:16]=[N-:17])[CH2:9]1)=[O:7])(C)(C)C.Cl.FC1C(OC([C:29]2[N:30]=[N:31][C:32]([CH2:48][CH2:49][CH2:50][CH3:51])=[C:33]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:37][CH:36]=3)[CH:34]=2)=O)=C(F)C(F)=C(F)C=1F>C(Cl)Cl.O1CCOCC1.C(OCC)(=O)C>[N:15]([CH2:14][C@@H:10]1[O:11][CH2:12][CH2:13][N:8]([C:6]([C:29]2[N:30]=[N:31][C:32]([CH2:48][CH2:49][CH2:50][CH3:51])=[C:33]([C:35]3[CH:36]=[CH:37][C:38]([O:41][CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:39][CH:40]=3)[CH:34]=2)=[O:7])[CH2:9]1)=[N+:16]=[N-:17]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](CN=[N+]=[N-])C1
Reactant: CCCCc1nnc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCc1nnc(C(=O)N2CCO[C@@H](CN=[N+]=[N-])C2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 105.8 %

Procedure:
To a stirred solution of (R)-2-azidomethyl-morpholine-4-carboxylic acid tert-butyl ester (0.82 mmol, 0.2 g) in DCM (2 mL) was added 4 N HCl in dioxane (4 mL) and continued stirring at ambient temperature for 45 min. The volatiles were removed under reduced pressure, and the residue was dissolved in NMP (4 mL). To this was added 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid pentafluorophenyl ester (Example 93, 0.77 mmol, 0.4 g) followed by TEA (0.5 mL) and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water, followed by saturated sodium bicarbonate. The organic layer was dried, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography using ethyl 30% acetate in hexanes to provide ((R)-2-azidomethyl-morpholin-4-yl)-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yl]-methanone (0.39 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>CCO.CN(C1C=CN=CC=1)C>[NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:27][CH:24]2[CH2:26][CH2:25]2)[CH:12]=3)[CH:7]=1
Reactant: NC1CC1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2C)cc2cnc(Cl)cc21
Agent: CN(C)c1ccncc1
Solvent: CCO
Product: CCn1c(=O)c(-c2cc(N)c(F)cc2C)cc2cnc(NC3CC3)cc21
Temperature: 100 °C
Reaction time: 240 h
Yield: 23.3 %

Procedure:
A solution of Example A6 (500 mg, 1.507 mmol) and cyclopropylamine (860 mg, 15.07 mmol) in EtOH (15 mL) was heated at 100° C. in a sealed vessel. After 20 h the reaction mixture was treated with additional cyclopropylamine (860 mg, 15.07 mmol) and catalytic DMAP (10 mg) and heated at 100° C. for 23 h, then 115° C. for 10 days. The mixture was cooled to RT, concentrated to dryness and the resulting residue dissolved in EtOAc (30 mL) and washed successively with water (30 mL), satd. NaHCO3 (30 mL) and brine (30 mL). The organic phase was dried over Na2SO4, concentrated to dryness and purified by reverse phase chromatography (MeCN/H2O with 0.1% TFA). The aqueous solution was treated with satd. NaHCO3 (5 mL) and allowed to stand. A solid formed which was collected by filtration to yield 3-(5-amino-4-fluoro-2-methylphenyl)-7-(cyclopropylamino)-1-ethyl-1,6-naphthyridin-2(1H)-one (124 mg, 23% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.36 (s, 1H), 7.60 (s, 1H), 7.28 (s, 1H), 6.83 (d, 1H), 6.58 (d, 1H), 6.38 (s, 1H), 4.87 (s, 2H), 4.18-4.12 (m, 2H), 2.59 (m, 1H), 1.94 (s, 3H), 1.21 (t, 3H), 0.75 (m, 2H), 0.47 (m, 2H); MS (ES-API) m/z: 353.1 [M+H]+.
Reaction SMILES: CN([CH2:20][CH2:21][OH:22])C/C(/C)=C/C1C=CC(CC2C=NC=CC=2)=CC=1.[CH2:23]=[C:24]1[O:28][C:26](=[O:27])[CH2:25]1>C(OCC)(=O)C>[C:26]([O:28][CH2:24][CH3:23])(=[O:27])[CH2:25][C:21]([CH3:20])=[O:22]
Reactant: C/C(=C\c1ccc(Cc2cccnc2)cc1)CN(C)CCO
Reactant: C=C1CC(=O)O1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(C)=O
Yield: 65.8 %

Procedure:
In 5 ml of ethyl acetate was dissolved 1.26 g of 2-[N-methyl-N-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]2-methylallyl]amino]ethanol, and to the resulting solution was dropwise added a mixture of 0.36 ml of diketene and 1 ml of ethyl acetate under reflux over one hour, after which the resulting mixture was subjected to reaction at the same temperature for 30 minutes. Subsequently, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: benzene:ethyl acetate (1:1 by volume)] to obtain 1.06 g (yield 65.8%) of colorless, oily 2-[N-methyl-N-[(E)-3-[4-pyridin-3-ylmethyl)phenyl]-2-methylallyl]amino]ethyl acetoacetate.
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][NH2:7].C(N(CC)CC)C.[N:19]1[C:28]2[C:23](=[CH:24][N:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[C:29](O)=[O:30].O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[CH3:2][S:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][NH:7][C:29]([C:20]1[CH:21]=[CH:22][C:23]2[C:28](=[CH:27][CH:26]=[N:25][CH:24]=2)[N:19]=1)=[O:30]
Reactant: O=C(O)c1ccc2cnccc2n1
Reactant: CSc1ccccc1CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1ccccc1CNC(=O)c1ccc2cnccc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.3 %

Procedure:
To a stirring mixture of 2-methylsulfanylbenzylamine hydrochloride (81.7 mg, 0.431) in anhydrous DMF (1.0 mL) was added triethylamine (60.0 μL, 0.431 mmol). After 5 minutes, 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol), 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol) were added sequentially. The resulting mixture was allowed to stir at room temperature overnight. The solvent was removed under vacuum. Flash column chromatography of the residue (50% hexane/ethyl acetate to 100% ethyl acetate) afforded the desired product as a light brown solid (88.2 mg, 99%): m.p. 102-103° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH2:4][O:3]1.C(=O)([O-])[O-].[K+].[K+].F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1.O>C(#N)C.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:12])[C:10]2[CH:9]=[C:8]([O:11][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)[CH:7]=[CH:6][C:5]=2[CH2:4][O:3]1
Reactant: CC1(C)OCc2ccc(O)cc21
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC1(C)OCc2ccc(Oc3ccc([N+](=O)[O-])cc3)cc21
Temperature: 70 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
3,3-Dimethyl-1,3-dihydro-2-benzofuran-5-ol (Intermediate 18, 500 mg, 3.04 mmol) and potassium carbonate (1.05 g, 7.6 mmol) were suspended in acetonitrile (7.5 mL). 1-Fluoro-4-nitrobenzene (386 mg, 2.74 mmol) was added and the mixture was stirred under nitrogen at 70° C. overnight and then for 4 hours at 80° C. Further 1-fluoro-4-nitrobenzene (86 mg, 0.6 mmol) was added and the mixture heated to reflux until achieving reaction completion. After cooling water and ethyl acetate were added and the two layers were separated. The organic phase was washed three times with brine, then it was dried over anhydrous Na2SO4 and concentrated to dryness. The residue was triturated in isopropanol and the solid washed with further isopropanol to give the title compound (500 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: Clc1ccncc1
Agent: Cl
Product: CS(=O)(=O)c1ccc(Oc2ccncc2)cc1
Temperature: 150 °C
Reaction time: 4 h
Yield: 19.1 %

Procedure:
A mixture of 4-methylsulfonylphenol (2.93g, 17 mmol) and 4-chloropyridine hydrochloride (2.93 g, 19.5 mmol) was heated at 150° C., resulting in a gradual melt, which was stirred at 150° C. for 4 h, then partitioned between ethyl acetate and 1N NaOH. The organic extract was dried over MgSO4, filtered, and concentrated to 1.3 g of a yellow solid. The solid was recrystallized from ethyl acetate-ether to give 0.81 g of the title compound as a white solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2F)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].[CH3:39]C1C=C(CC(=O)C(OCC)=O)C=CC=1.[H-].[Na+].[Br-].C(O[C@@H]1[C@@H](OC(=O)C)[C@@H](OC(=O)C)[C@@H](COC(=O)C)O[C@@H]1O)(=O)C>>[C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]2[CH:27]=[C:26]([CH3:39])[CH:25]=[CH:24][CH:23]=2)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccccc1F)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCOC(=O)C(=O)Cc1cccc(C)c1
Agent: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Br-]
Agent: [H-]
Product: CCOC(=O)/C(=C/c1cccc(C)c1)O[C@H]1O[C@@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 25 %

Procedure:
The title compound was prepared as described for C4 using ethyl 3-(3-methylphenyl)-2-oxopropanoate B15 (100 mg, 0.485 mmol), sodium hydride (11.64 mg, 0.485 mmol) and 2,3,4,6-tetra-O-acetyl-α-D-galactose bromide (199 mg, 0.485 mmol). The compound was isolated in the form of white solid in 25% yield.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.N1C=C(C)C(C)=CC=1C.[Li+].[I-]>>[O:10]1[C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:11][C:7]=2[CH:8]=[CH:9]1
Reactant: COc1ccc2occc2c1
Agent: Cc1cc(C)c(C)cn1
Agent: [I-]
Agent: [Li+]
Product: Oc1ccc2occc2c1

Procedure:
5-Methoxybenzofuran was treated with 2,4,5-collidine and LiI at 170° C. to provide benzofuran-5-ol, which was reacted with 2-chloroethyl-p-toluenesulfonate and Cs2CO3 to give 5-(2-chloroethoxy)-1-benzofuran.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH3:20][N:21]1[C:33]2[CH:32]=[CH:31][C:30]([CH:34]=O)=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:34][C:30]2[CH:31]=[CH:32][C:33]3[N:21]([CH3:20])[C:22]4[C:27]([C:28]=3[CH:29]=2)=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: Cn1c2ccccc2c2cc(C=O)ccc21
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc2c(c1)c1ccccc1n2C

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 9-methyl-9H-carbazole-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.94 min.; [M+H]+: 429.28 g/mol.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=1)[CH2:11][N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].[OH:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>COCCOC.O.C1(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)C=CC=CC=1>[OH:24][C:25]1[CH:30]=[CH:29][C:28]([C:8]2[CH:23]=[CH:22][CH:21]=[C:10]([CH2:11][N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=2)=[CH:27][CH:26]=1
Reactant: CN(Cc1cccc(Br)c1)C(=O)OC(C)(C)C
Reactant: OB(O)c1ccc(O)cc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CN(Cc1cccc(-c2ccc(O)cc2)c1)C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 67.7 %

Procedure:
41.6 ml (83.2 mmol) of aqueous 2M potassium carbonate solution are added dropwise to a solution of 10 g (33 mmol) of tert-butyl (3-bromobenzyl)-N-methylcarbamate and 8.3 g (60 mmol) of 4-hydroxy-benzeneboronic acid in 100 ml of ethylene glycol dimethyl ether. The reaction medium is degassed and 1.9 g (1.7 mmol) of tetrakis(triphenylphosphino)palladium are added. After heating for 12 hours at 80° C., the reaction medium is cooled, diluted with water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with an 80/20 heptane/ethyl acetate mixture. 7 g of tert-butyl (4′-hydroxybiphenyl-3-ylmethyl)methylcarbamate are obtained in the form of a beige-colored solid, in a yield of 68%.
Reaction SMILES: [CH2:1]([C:9]1[C:10]([C:29]([F:32])([F:31])[F:30])=[C:11]2[C:15]3=[C:16]([CH2:18][NH:19][CH:20](C(OC(C)(C)C)=O)[CH2:21][N:14]3[CH:13]=[CH:12]2)[CH:17]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.O1CCOCC1>C(Cl)Cl>[CH2:1]([C:9]1[C:10]([C:29]([F:32])([F:31])[F:30])=[C:11]2[C:15]3=[C:16]([CH2:18][NH:19][CH2:20][CH2:21][N:14]3[CH:13]=[CH:12]2)[CH:17]=1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)C1Cn2ccc3c(C(F)(F)F)c(CCc4ccccc4)cc(c32)CN1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: FC(F)(F)c1c(CCc2ccccc2)cc2c3c1ccn3CCNC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 103 %

Procedure:
To a solution of tert-butyl 6-phenethyl-7-(trifluoromethyl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indole-2(1H)-carboxylate (1.4 g; 3.1 mmol) in CH2Cl2 at 0° C. was added 4M HCl in 1,4-dioxane (3.8 mL, 15.4 mmol). The resulting solution was warmed to room temperature and stirred overnight. The solid was collected to yield 6-phenethyl-7-(trifluoromethyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole (1.1 g).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]([S:14]([OH:17])(=O)=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][S:10]([CH3:13])(=[O:12])=[O:11].CN(C)C=O.P(Cl)(Cl)([Cl:25])=O>O.C1C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[C:5]([S:14]([Cl:25])(=[O:17])=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CS(=O)(=O)Oc1ccc(S(=O)(=O)O)cc1Cl
Agent: [Na]
Solvent: c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Oc1ccc(S(=O)(=O)Cl)cc1Cl
Yield: 74.7 %

Procedure:
Sodium salt of 3-chloro-4-methylsulfonyloxybenzene sulfonic acid (453 g: 1.47 moles), N,N-dimethylformamide (21.1 g: 0.288 mole) and benzene (2000 cc) were mixed and heated with stirring until the mixture was refluxed. Phosphorus oxychloride (237 g: 1.55 moles) was added dropwise to the mixture for 1 hour. The resultant mixture was refluxed with stirring for an additional 3 hours and then water (1000 cc) was added to the resultant mixture under the temperature 20° C.-30° C. with cooling. The mixture was stirred for 1 hour under the same temperature and then the layer of benzene was separated from the mixture. The benzene solution separated was washed with water two times and dried over anhydrous sodium sulfate. Benzene was removed from the benzene solution by distillation to obtain crude white crystals (335. g) of 3-chloro-4-methylsulfonyloxybenzene sulfonylchloride. The crude white crystals were recrystalized from benzene. Yield: 74.7%. Melting point: 100°-100.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(Cl)Cl>[Cl:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[C:4]([C:6](=[CH:12][NH:27][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: NC1CCCCC1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1ccc(I)cc1Cl
Solvent: ClCCl
Product: CCOC(=O)C(=CNC1CCCCC1)C(=O)c1ccc(I)cc1Cl
Reaction time: 6 h
Yield: 54.5 %

Procedure:
mf) A solution of 31.18 g of ethyl 2-(2-chloro-4-iodo-benzoyl)-3-ethoxy-acrylate in 500 ml of methylene chloride is treated dropwise with 7.95 g of cyclohexylamine while cooling with ice and stirring. After 6 hrs. at room temperature the reaction mixture is concentrated and, for crystallization, the residue is stirred with 200 ml of hexane. The precipitate is filtered off under suction, washed with 100 ml of hexane and dried. 19.2 g (55%) of ethyl 2-(2-chloro-4-iodo-benzoyl)-3-cyclohexylamino-acrylate are obtained as a colourless solid. M.p. 154°-156° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[CH2:6][C:5]2=[O:19].O1CCCC1.B.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[CH2:6][CH:5]2[OH:19]
Reactant: Cc1ccccc1C1CC(=O)c2cc(Br)ccc2O1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccccc1C1CC(O)c2cc(Br)ccc2O1
Temperature: 25 °C

Procedure:
To a solution of 6-bromo-2-o-tolyl-chroman-4-one (11.0 g, 34.7 mmol) in tetrahydrofuran (100 ml) at room temperature a solution of borane tetrahydrofuran adduct (1M in tetrahydrofuran, 86.7 ml, 2.5 eq) was added dropwise. The solution was heated to reflux for 1 h, cooled to room temperature and added with caution to a mixture of ice water and 1N aqueous hydrochloric acid. The aqueous layer was extracted with dichloromethane, and the combined organic layers washed with water, dried with sodium sulfate and filtered and the solvent removed under reduced pressure. 6-Bromo-2-o-tolyl-chroman-4-ol was obtained as a yellow oil (11.1 g, 100%) and used in the reduction to the chroman without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[N+:10]([O-])([OH:12])=[O:11]>ClCCl.S([O-])([O-])(=O)=O.[Ni+].[NH4+]>[F:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1cc(F)cc(F)c1
Agent: [Ni+]
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: ClCCl
Product: O=[N+]([O-])c1c(O)cc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a yellow solution of 3,5-difluorophenol (1.50 g, 11.5 mmol) in dichloromethane (20 mL) under a blanket of nitrogen is added ammonium nickel sulfate (4.56 g, 11.54 mmol) with vigorous stirring, followed by the addition of nitric acid (69%, 0.74 mL, 11.54 mmol). The resulting heterogeneous mixture is then stirred at ambient temperature vigorously for 30 minutes. It is filtered and dichloromethane is removed under reduced pressure. The residue is purified by column chromatography to afforded a yellow solid as the title compound.