Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][N:13]=[CH:14]3)=[CH:9][C:8]=2[OH:17])[CH:2]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][CH:20]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][CH:20]=[C:19]2[O:17][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:7]=1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH:14]=[N:13][CH:12]=[CH:11]2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1cc2ccncc2cc1-c1cccnc1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc4ccncc4cc3-c3cccnc3)c2cc1OC
Temperature: 140 °C
Reaction time: 4 h
Yield: 54.3 %

Procedure:
7-Pyridin-3-yl-isoquinolin-6-ol (7 mg), 4-chloro-6,7-dimethoxyquinoline (21 mg), and 4-dimethylaminopyridine (12 mg) were suspended in o-dichlorobenzene (1.5 ml), and the suspension was stirred at 140° C. for 4 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (7 mg, yield 55%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[NH2:11][C@H:12]([C:20](O)=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>C(O)C.O>[CH2:13]([C@@H:12]1[NH:11][C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[NH:8][C:20]1=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1Nc2ccccc2N[C@H]1Cc1ccccc1
Reaction time: 8 h
Yield: 63.1 %

Procedure:
To ortho-fluoronitrobenzene (18) (6.5 g, 46 mmol) in ethanol (200 mL) and water (200 mL) under nitrogen was added L-phenylalanine (5.10 g, 31 mmol) and sodium bicarbonate (5.19 g, 62 mmol) and the suspension heated at reflux for 48 h. The red solution was coled, extracted with ether (2×50 mL—to remove any unreacted ortho-fluoronitrobenzene and concentrated to ½ volume. Pd/C (20%, 0.5 g) was added and a hydrogen balloon was attached. After stirring overnight the mixture was filtered, acidifed with 1N HCl to pH 4 and the solid that formed was collected. This was dried under high vacuum to afford the title compound (4.66 g, 53%) of sufficient purity (19) to use directly.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[Cu](C#N)[C:13]#[N:14].CCOCC>CN(C=O)C>[C:2]([C:4]1[CH:9]=[C:8]([CH:7]=[CH:6][C:5]=1[OH:11])[C:13]#[N:14])(=[O:3])[CH3:1]
Reactant: N#C[Cu]C#N
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)c1cc(C#N)ccc1O
Temperature: 160 °C
Yield: 70.1 %

Procedure:
A solution of 5-bromo-2-hydroxyacetophenone (11, 10.00 g, 46.5 mmoles) in anhydrous DMF (25 mL) was mixed with copper cyanide (6.25 g, 69.75 mmoles) and the resulting reaction mixture was heated for about 8 to 16 hours at a temperature of about 160° C. The reaction mixture was cooled to room temperature and mixed with ether, the ether mixture was filtered through celite and the filtrate concentrated to afford a solid which was purified by flash column chromatography through silica using Hexane/EtOAc (4:1) as eluant to yield compound 12 as a clear colorless oil (5.25 g, 70%).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[CH2:8]1[O:10][CH2:9]1>>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][CH2:8][CH2:9][OH:10]
Reactant: CN(C)CCCN
Reactant: C1CO1
Product: CN(C)CCCNCCO
Temperature: 115 °C
Reaction time: 0.25 h

Procedure:
To a one liter stirred autoclave was charged 500 g 3-dimethylaminopropyl amine. A nitrogen atmosphere was provided and the sealed autoclave was heated to 115°C. Ethylene oxide (140 g) was added incrementally over 3 hours. Heating was continued for 15 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH3:14])[C:6]=2[CH:15]=1.[CH3:16][C:17]1[C:18]([O:20][C:21](=O)[C:22]=1[CH3:23])=[O:19].O>C(O)(=O)C>[CH2:12]([N:7]1[C:6]2[CH:15]=[C:2]([N:1]3[C:18](=[O:19])[C:17]([CH3:16])=[C:22]([CH3:23])[C:21]3=[O:20])[CH:3]=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11])[CH2:13][CH3:14]
Reactant: CCCN1C(=O)COc2ccc(N)cc21
Reactant: CC1=C(C)C(=O)OC1=O
Solvent: O
Solvent: CC(=O)O
Product: CCCN1C(=O)COc2ccc(N3C(=O)C(C)=C(C)C3=O)cc21
Yield: 49.1 %

Procedure:
2.27 g of 6-amino-4-propyl-2H-1,4-benzoxazin-3(4H)-one and 1.7 g of 2,3-dimethylmaleic anhydride were refluxed for 2 hours in acetic acid. After the reaction mixture was allowed to cool, 50 ml of water was added, and the precipitated crystals were collected by filtration and recrystallized from ethanol to give 1.7 g of 1-[4-propyl-2H-1,4-benzoxazin-3(4H)-on-6-yl]-3,4-dimethyl-2,5-dioxo-2,5-dihydropyrrole. m.p. 147°-149° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1I.[F:14][C:15]1[C:20]([F:21])=[CH:19][C:18](B(O)O)=[C:17]([O:25][CH3:26])[CH:16]=1>CCCCCCC.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:18]1[CH:19]=[C:20]([F:21])[C:15]([F:14])=[CH:16][C:17]=1[O:25][CH3:26]
Reactant: COc1cc(F)c(F)cc1B(O)O
Reactant: COC(=O)CNc1cnccc1I
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)CNc1cnccc1-c1cc(F)c(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-ylamino)-acetic acid methyl ester and 4,5-difluoro-2-methoxyphenylboronic acid (CAS RN 870777-32-5) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light yellow oil (82%). MS (ESI): m/z=309.104 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH2:7])[CH3:2].Br[CH2:12][CH:13]1[O:17][CH2:16][CH2:15][O:14]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH:7][CH2:12][CH:13]1[O:17][CH2:16][CH2:15][O:14]1)[CH3:2]
Reactant: CCOC(CCN)OCC
Reactant: BrCC1OCCO1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(CCNCC1OCCO1)OCC
Temperature: 25 °C

Procedure:
3,3-Diethoxypropylamine (0.11 mole), 2-bromomethyl-1,3-dioxolane (0.1 mole), triethylamine (20 ml) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction is heated at reflux for a period of about 12 hours. After this time the reaction mixture is allowed to cool to room temperature and is filtered. The reaction mixture is then stripped of solvent and unreacted starting materials under reduced pressure to yield the desired product N-(3,3-diethoxypropyl)-N-(1,3-dioxolan-2-ylmethyl)amine.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C>O.[Cu].CN(C)C=O>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: Cc1ccc(O)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2cc(Cl)ccc2C(=O)O)cc1

Procedure:
A mixture of 15 g. of 2,4-dichlorobenzoic acid, 10 g. of p-methylphenol, 0.5 g. of copper powder and 20 g. of anhydrous potassium carbonate in 200 ml. of dimethylformamide is heated to 165° C and maintained thereat with stirring and under a nitrogen atmosphere. After monitoring via tlc indicates the reaction is substantially complete, the reaction mixture is diluted with water, treated with charcoal, filtered and the clear filtrate acidified. The precipitate is isolated by suction filtration, washed neutral and dried to give 2-(p-methylphenyloxy)-4-chlorobenzoic acid.
Reaction SMILES: CO[C:3]1C=C(C=C(OC)[C:10]=1OC)C=O.[CH3:15][C:16]1[CH:35]=[CH:34][C:19]([N:20]=[CH:21][C:22]2[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=2)=[CH:18][CH:17]=1>>[CH2:15]([C:16]1[CH:17]=[CH:18][C:19]([N:20]=[CH:21][C:22]2[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=2)=[CH:34][CH:35]=1)[CH2:3][CH3:10]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: COc1cc(C=Nc2ccc(C)cc2)cc(OC)c1OC
Product: CCCc1ccc(N=Cc2cc(OC)c(OC)c(OC)c2)cc1
Yield: 87.6 %

Procedure:
From compounds 107g (4.2 g, 99%, 31.0 mmol) and 106 (6.0 g, 98%, 31.0 mmol), a similar procedure as described for 108a gave 108g (8.5 g, 87.6%) as a thick oil. 1H NMR (200 MHz, CDCl3) δ8.36 (s, 1H), 7.20 (d, J=8 Hz, 2H), 7.16 (s, 2H), 7.14 (d, J=8 Hz, 2H), 3.93 (s, 6H), 3.91 (s, 3H), 2.60 (t, J=8 Hz, 2H), 1.64 (sextet, J=8 Hz, 2H), 0.95 (t, J=8 Hz, 3H). EIMS (M+ 100).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:23])[CH:18]=2)[C:13]=1[OH:24])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)[F:26].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[C:20]([F:26])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:23])[CH:18]=2)[C:13]=1[OH:24])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(Cl)ccc2c1O
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)c(F)c2cc(Cl)ccc2c1O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(6-chloro-1-hydroxy-3-methylnaphthalen-2-yl)acetate (0.9705 g, 2.77 mmol) in anhydrous acetonitrile (20 mL) at 0° C. was added SelectFluor (1.078 g, 3.04 mmol) in one portion. The reaction mixture was stirred for 4 hours at 0° C., then 1 hour at room temperature. The reaction mixture was quenched with saturated Na2HPO4 solution and stirred for 20 minutes. The mixture was extracted with ethyl acetate (2×), dried (MgSO4), filtered, concentrated and stored overnight in a freezer. The residue was purified by flash column chromatography (silica gel, 0 to 15% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C19H21ClFO4: 367.8. Found: 366.9, 368.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14](=[O:35])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[CH:33]=[C:32]3[C:27]([CH2:28][CH2:29][CH2:30][NH:31]3)=[CH:26][CH:25]=2)=[O:23])=[CH:17][C:16]=1[Cl:34].N1C=CC=CC=1>ClCCl>[CH3:12][O:13][C:14](=[O:35])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[CH:33]=[C:32]3[C:27]([CH2:28][CH2:29][CH2:30][N:31]3[S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)(=[O:10])=[O:9])=[CH:26][CH:25]=2)=[O:23])=[CH:17][C:16]=1[Cl:34]
Reactant: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)NCCC3)cc1Cl
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(F)c2)CCC3)cc1Cl
Reaction time: 16 h

Procedure:
3-Fluorobenzenesulphonyl chloride (0.027 g, 0.137 mmol, 1.05 equiv.) was added to a mixture of 2-chloro-4-[(1,2,3,4-tetrahydro-quinoline-7-carbonyl)-amino]-benzoic acid methyl ester (0.045 g, 0.130 mmol) and pyridine (0.1 ml) in dichloromethane (2 ml) and the mixture shaken for 16 hours. The solution was washed with saturated sodium hydrogen carbonate (2 ml) and 1M aqueous HCl (2 ml) then dried over magnesium sulphate. The solution was evaporated to afford the crude 2-chloro-4-{[1-(3-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid methyl ester, 0.097 g, as a red oil. This material was taken onto the next step without further purification. LC @215 nm; Rt 1.64: 100%, m/z (ES+): 502 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]([O:15][C:16]1[CH:24]=[CH:23][C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:26][C:27]1[O:31][C:30]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)=[N:29][C:28]=1[CH2:37][CH2:38]OS(C1C=CC(C)=CC=1)(=O)=O>>[O:20]1[C:19]2[CH:23]=[CH:24][C:16]([O:15][C:5]([CH3:14])([CH2:6][C:7]3[CH:12]=[CH:11][C:10]([O:13][CH2:38][CH2:37][C:28]4[N:29]=[C:30]([C:32]5[S:33][CH:34]=[CH:35][CH:36]=5)[O:31][C:27]=4[CH3:26])=[CH:9][CH:8]=3)[C:4]([OH:3])=[O:25])=[CH:17][C:18]=2[O:22][CH2:21]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc2c(c1)OCO2
Product: Cc1oc(-c2cccs2)nc1CCOc1ccc(CC(C)(Oc2ccc3c(c2)OCO3)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(benzo[1,3]dioxol-5-yloxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester using the procedure of Example 78. 1H NMR (400 MHz, CDCl3) δ 7.57 (dd, 1H, J=3.90 Hz, J=1.47 Hz), 7.35 (dd, 1H, J=5.37 Hz, J=1.47 Hz), 7.13 (d, 2H, J=8.31 Hz), 7.04 (dd, 1H, J=5.37 Hz, J=3.90 Hz), 6.78 (d, 2H, J=8.79 Hz), 6.60 (d, 1H, J=8.30 Hz), 6.42 (d, 1H, J=2.44 Hz), 6.33 (dd, 1H, J=8.31 Hz, J=2.44 Hz), 5.88 (d, 2H, J=0.98 Hz), 4.15 (t, 2H, J=6.35 Hz), 3.16 (d, 1H, J=13.92 Hz), 3.04 (d, 1H, J=13.92 Hz), 2.93 (t, 2H, J=6.35 Hz), 2.31 (s, 3H), 1.30 (s, 3H); HRMS (ES+) m/z exact mass calcd for C27H26NO7S 508.1430, found 508.1425.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[C:12]([CH2:20][C:21](=O)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:11]=1>C(O)(=O)C>[Br:9][C:10]1[CH:11]=[C:12]2[C:13](=[CH:18][CH:19]=1)[C:14](=[O:15])[N:6]([C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)[C:21]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20]2
Reactant: COC(=O)CCCCC(=O)Cc1cc(Br)ccc1C(=O)OC
Reactant: Nc1ccc(F)cc1
Solvent: CC(=O)O
Product: COC(=O)CCCCc1cc2cc(Br)ccc2c(=O)n1-c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 50.5 %

Procedure:
4-Fluoroaniline (98 mg, 0.884 mmol, 1.0 equiv.) was added to a stirred mixture of methyl 4-bromo-2-(7-methoxy-2,7-dioxoheptyl)benzoate (328 mg, 0.884 mmol) in acetic acid (1 mL) and the mixture was stirred at 100° C. for 90 min. After cooling to room temperature, the excess solvent was concentrated, diluted with water and extracted with EtOAc (2×5 mL). The organic layer was dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with 0-10% EtOAc/hexanes to give 193 mg of methyl 5-(6-bromo-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate as a yellow oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:13]2[C:8](=[CH:9][N:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:14][C:15]1[CH:32]=[CH:31][C:18]2[N:19]([CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:20]([CH2:22]Cl)=[N:21][C:17]=2[CH:16]=1>>[Cl:14][C:15]1[CH:32]=[CH:31][C:18]2[N:19]([CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:28])=[O:29])[C:20]([CH2:22][N:7]3[C:8]4=[CH:9][N:10]=[CH:11][CH:12]=[C:13]4[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6]3)=[N:21][C:17]=2[CH:16]=1
Reactant: CS(=O)(=O)c1c[nH]c2cnccc12
Reactant: CS(=O)(=O)CCCn1c(CCl)nc2cc(Cl)ccc21
Product: CS(=O)(=O)CCCn1c(Cn2cc(S(C)(=O)=O)c3ccncc32)nc2cc(Cl)ccc21

Procedure:
The title compound was prepared in analogy to Example 1-2 by using 3-(methylsulfonyl)-1H-pyrrolo[2,3-c]pyridine and 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole instead of 3-(methylsulfonyl)-1H-indole and 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole.
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[Cl:22].[Cl:23][C:24]1[C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=[CH:26][C:25]=1/[N:39]=[C:40]1/[C:41]2[CH:51]=[CH:50][CH:49]=[CH:48][C:42]=2[N:43]([CH3:47])[C:44](=[O:46])[O:45]/1.CCO.C([O-])([O-])=O.[Na+].[Na+]>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.C1(C)C=CC=CC=1>[Cl:22][C:3]1[CH:4]=[C:5]([C:19]([NH2:21])=[O:20])[C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:2]=1[C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([N:39]2[C:40](=[O:45])[C:41]4[C:42](=[CH:48][CH:49]=[CH:50][CH:51]=4)[N:43]([CH3:47])[C:44]2=[O:46])[C:24]=1[Cl:23])=[CH:12][CH:11]=[C:10]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:9]=3
Reactant: Cn1c(=O)o/c(=N\c2cccc(B3OC(C)(C)C(C)(C)O3)c2Cl)c2ccccc21
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Cl)c(Br)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cn1c(=O)n(-c2cccc(-c3c(Cl)cc(C(N)=O)c4[nH]c5cc(C(C)(C)O)ccc5c34)c2Cl)c(=O)c2ccccc21
Temperature: 90 °C
Yield: 4.5 %

Procedure:
A mixture of 4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Intermediate 3] (36 mg, 0.094 mmol), (Z)-4-((2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)-1-methyl-1H-benzo[d][1,3]oxazin-2(4H)-one [Intermediate 40] (42.8 mg, 0.104 mmol), EtOH (1 mL), toluene (1 mL) and 2 M aqueous Na2CO3 (0.16 mL, 0.311 mmol) was bubbled with nitrogen for 5 min. The mixture was treated with tetrakis(triphenylphosphine)palladium (8.7 mg, 7.55 μmol), and the reaction vessel was sealed and heated at 90° C. for 16 h. The cooled mixture was partitioned between EtOAc and water, and the organic phase was dried and concentrated. The residue was purified by column chromatography on silica gel (4 g), eluting with MeOH-DCM containing 1% TEA (gradient from 0-5%). The resulting material was further purified using preparative HPLC (PHENOMENEX® Axia C18 30×100 mm), eluting with MeCN-water containing 0.1% TFA (gradient from 20-100%, 30 mL/min) The appropriate fractions were treated with saturated aqueous NaHCO3 and concentrated. The residue was partitioned between EtOAc and water, and the organic phase was washed with brine, dried and concentrated to give 3-chloro-4-(2-chloro-3-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (mixture of four atropisomers) as a white solid (2.5 mg, 4% yield). Mass spectrum m/z 569 (M+H—H2O)+. 1H NMR (400 MHz, chloroform-d) δ 8.38-8.23 (m, 1H), 7.73 (d, J=1.5 Hz, 2H), 7.70-7.66 (m, 1H), 7.64 (s, 1H), 7.60-7.55 (m, 1H), 7.51-7.45 (m, 1H), 7.37-7.28 (m, 2H), 7.26-7.20 (m, 1H), 7.10-6.78 (m, 1H), 3.70 (s, 2H), 3.67 (s, 1H), 1.65 (s, 4H), 1.64 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:14][CH2:13][C:12](=[CH:15][CH2:16][NH2:17])[C:4]=2[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2.C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>O1CCCC1.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[C:3]2[CH2:14][CH2:13][C:12](=[CH:15][CH2:16][NH:17][C:25](=[O:27])[CH3:26])[C:4]=2[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2
Reactant: CC(=O)OC(C)=O
Reactant: Cn1cc2c3c(c(Cl)cc2n1)CCC3=CCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCC=C1CCc2c(Cl)cc3nn(C)cc3c21
Reaction time: 0.17 h
Yield: 78.7 %

Procedure:
2-(5-Chloro-2-methyl-6,7-dihydrocyclopenta[e]indazol-8(2H)-ylidene)ethanamine (105 mg, 0.424 mmol) was dissolved in tetrahydrofuran (4 mL), triethylamine (88.6 μL, 0.636 mmol) and acetic anhydride (48.1 μL, 0.509 mmol) were added under ice-cooling, and the mixture was stirred for 10 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) to give the title compound (96.7 mg, yield 79%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([S:14]([N:17](C(OCC(C)C)=O)[C:18]3[C:23]([O:24][CH3:25])=[N:22][C:21]([CH3:26])=[CH:20][N:19]=3)(=[O:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.Br[CH2:35][C:36]([O:38]C)=[O:37].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:36]([CH2:35][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([S:14]([NH:17][C:18]3[C:23]([O:24][CH3:25])=[N:22][C:21]([CH3:26])=[CH:20][N:19]=3)(=[O:15])=[O:16])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1)([OH:38])=[O:37]
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1ccccc1-c1ccc(O)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1nc(C)cnc1NS(=O)(=O)c1ccccc1-c1ccc(OCC(=O)O)cc1
Reaction time: 18 h

Procedure:
4'-Hydroxy- N-(isobutoxycarbonyl)- N-(3-methoxy-5-methylpyrazin-2-yl)-2-biphenylsulphonamide (0.5 g) was added to a solution of methyl bromoacetate (0.12 ml) in acetone (20 ml) containing potassium carbonate (0.166 g). The mixture was stirred for 18 hours and then heated under reflux for 1 hour and cooled. The solvent was removed by evaporation and water (20 ml) was added to the residue. The mixture was then extracted with ethyl acetate (2×20 ml). The combined organic extracts were washed successively with 2M sodium hydroxide solution (15 ml), water (20 ml) and brine (10 ml) and then dried (MgSO4). The solvent was removed by evaporation and the residue was dissolved in dimethoxyethane (5 ml) and methanol (5 ml). 2M Sodium hydroxide solution (1 ml) was added and the mixture was stirred for 18 hours and evaporated to dryness. Water (20 ml) was added to the residue and the mixture was washed with ethyl acetate (2×15 ml). The aqueous phase was acidified to pH2 with 2M hydrochloric acid and extracted with ethyl acetate (3×15 ml). The combined organic phases were extracted with saturated aqueous sodium bicarbonate solution (2×15 ml) and the combined aqueous phase was acidified with 6M hydrochloric acid and extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with water (15 ml) and brine (15 ml) and dried (MgSO4). The solvent was removed by evaporation and the residue crystallised from ether to give 4'-carboxymethoxy-N-(3-methoxy-5-methylpyrazin-2-yl)-2-biphenylsulphonamide (0.123 g) as a solid, m.p. 165°-166° C.; microanalysis found: C, 55.9; H, 4.5; N, 9.9%; C20H19N3O6S requires: C, 55.9; H, 4.46; N, 9.78%; 1H NMR (d6 -DMSO): 2.24 (s, 3H), 3.84 (s, 3H), 4.67 (s, 2H), 6.78-6.95 (m, 2H), 7.16 (d, 2H), 7.27 (d, 1H); 7.49-7.66 (m, 3H), 8.06 (d, 1H), 9.50 (br s, 1H); mass spectrum (-ve ESP): 428 (M-H)-.
Reaction SMILES: [Li+].[CH3:2][C:3]1[C:4]([C:24]([O-])=[O:25])=[CH:5][C:6]2[O:10][C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:8][C:7]=2[CH:23]=1.C[N+](C)=C(N(C)C)O[N:31]1[C:35]2C=[CH:37][CH:38]=[CH:39][C:34]=2N=N1.F[P-](F)(F)(F)(F)F.N1CCCCC1>CN(C)C=O>[CH3:2][C:3]1[C:4]([C:24]([N:31]2[CH2:37][CH2:38][CH2:39][CH2:34][CH2:35]2)=[O:25])=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:8][C:7]=2[CH:23]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1cc2c(cc1C(=O)[O-])OC(c1ccccc1)(c1ccccc1)O2
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: Cc1cc2c(cc1C(=O)N1CCCCC1)OC(c1ccccc1)(c1ccccc1)O2
Temperature: 20 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
To a solution of 6-methyl-2,2-diphenyl-1,3-benzodioxole-5-carboxylic acid lithium salt (101.5 mg, 0.3 mmol) in N,N-dimethylformamide (3 mL) was added N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)-uronium-hexafluorophosphate (114 mg, 0.3 mmol, 1.0 eq.). The reaction mixture was stirred 1 h at 20° C. Piperidine (26 mg, 0.3 mmol, 1.0 eq.) was added and the reaction mixture was stirred 20 h at 20° C. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine and then dried over sodium sulfate, filtered and evaporated. Purification by flash chromatography afforded the title compound (73 mg, 61%) as a light yellow solid.