Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[C:3]([S:8]([NH2:11])(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:18][CH2:19][CH2:20][CH2:21]Br.Cl>CN(C)C=O>[F:18][CH2:19][CH2:20][CH2:21][S:1][C:2]1[C:3]([S:8]([NH2:11])(=[O:9])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: FCCCBr
Reactant: NS(=O)(=O)c1ncccc1S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ncccc1SCCCF
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 32 %

Procedure:
A mixture consisting of 0.285 g of 3-mercaptopyridin-2-ylsulfonamide, 0.455 g of potassium carbonate, 5 ml of dry dimethylformamide and 0.23 g of 3-fluoro-1-bromopropane is stirred for 90 minutes at a temperature of +25° C. in a nitrogen atmosphere. The reaction mixture is subsequently added to an ice/water mixture. After a pH of 2 has been established with 2.8 ml of 2N HCl, the reaction mixture is extracted twice with ethyl acetate. The combined organic phases are washed three times with water and subsequently dried over sodium sulfate. Concentration and subsequent chromatographic purification of the residue over silica gel with ethyl acetate/n-hexane (1:1 ) give 0.12 g of 3-(3-fluoropropythio)pyridin-2-ylsulfonamide of a melting point of 85° to +86° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=1)=[O:21]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([O:17][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=1)=[O:21])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1cccc(C(=O)CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCCC1CC(=O)OCC(=O)c1cccc(C#N)c1
Yield: 82.7 %

Procedure:
The title compound (1.51 g) was prepared from (RS)-2-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (1.15 g) and 2-bromo-3′-cyanoacetophenone (1.06 g) according to the method of description 36.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][O:17][C:18]([CH3:23])([CH3:22])[C:19](O)=[O:20].F[B-](F)(F)F.BrC1C=CC=C[N+]=1CC.CCN(C(C)C)C(C)C>ClCCl>[CH3:16][O:17][C:18]([CH3:23])([CH3:22])[C:19]([NH:15][C:12]1[CH:11]=[CH:10][C:9]([C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:14][N:13]=1)=[O:20]
Reactant: Nc1ccc(C#Cc2ccccc2)cn1
Reactant: COC(C)(C)C(=O)O
Agent: CC[n+]1ccccc1Br
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(C)(C)C(=O)Nc1ccc(C#Cc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 46.2 %

Procedure:
(100 mg, 0.515 mmol) 5-Phenylethynyl-pyridin-2-ylamine (Example 1, step 1) was dissolved in dichloromethane (5 ml) and 2-methoxy-2-methylpropionic acid (91 mg, 0.77 mmol, 1.5 equiv.), 2-bromo-1-ethyl pyridinium tetrafluoroborate (CAS 878-23-9) (211 mg, 0.77 mmol, 1.5 equiv.) and Hunig's Base (0.26 ml, 1.54 mmol, 3 equiv.) were added. The mixture was stirred for 14 hours at room temperature. The reaction mixture was extracted with saturated Na2CO3 solution and dichloromethane. The organic layer was dried over sodium sulfate and evaporated to dryness. The crude product was purified by prep HPLC to afford the desired 2-methoxy-2-methyl-N-(5-phenylethynyl-pyridin-2-yl)-propionamide (70 mg, 46% yield) was obtained as a yellow oil, MS: m/e=295.2 (M+H+).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:34])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:31])[C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[C:23]([F:30])[CH:22]=3)[CH2:16][CH:15]2[CH2:32][F:33])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].Cl>C(O)(C)C.[Fe]>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:34])[CH:15]([CH2:32][F:33])[CH2:16]2)=[O:31])=[CH:22][C:23]=1[F:30]
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc([N+](=O)[O-])c(F)c3)CC2CF)c1
Agent: [Fe]
Agent: Cl
Solvent: CC(C)O
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2CF)c1
Yield: 36.7 %

Procedure:
N-tert-butyl-3-((4-(3-fluoro-4-nitrobenzoyl)-2-(fluoromethyl)piperazin-1-yl)methyl)benzamide (435 mg, 0.92 mmol), iron powder (558 mg, 10 mmol) and 1M hydrochloric acid (1.5 mL, 1.5 mmol) were stirred in isopropyl alcohol (30 mL) for 1 hour. The reaction was concentrated under reduced pressure and the residue partitioned between dichloromethane and water. The organic layer was separated, dried (sodium sulfate) and concentrated under reduced pressure. The crude product was purified using silica chromatography to give the title compound (150 mg). MS (ESI) m/z 445.6 [M+H]+
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:5][NH:6][CH:7]=1.CCN(C1C=CC=CC=1)CC.P(Cl)(Cl)([Cl:25])=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C.O>[Cl:25][C:5]1[C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:3][C:2]([I:1])=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)C1=CC(I)=CNC1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: CCN(CC)c1ccccc1
Solvent: CC#N
Product: COC(=O)c1cc(I)cnc1Cl
Temperature: 25 °C
Yield: 52 %

Procedure:
To a mixture containing 2.0 g of methyl 5-iodo-1,2-dihydro-3-pyridinecarboxylate, 1.6 g of diethylaniline, 1.64 g of benzyltriethylammonium chloride and 3.6 ml of distilled phosphorus oxychloride in 100 ml of dry acetonitrile are added 15 drops of water. The mixture is heated under reflux for 18 hours. After cooling the reaction mixture to room temperature, the solvent is removed under reduced pressure and the residue taken up in methylene chloride and extracted with water. The organic solution is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on a column of flash silica gel using methylene chloride as the eluent. Evaporation of the eluent yields a pale yellowish solid which is recrystallized from aqueous ethanol to give 1.1 g (52%) of methyl 2-chloro-5-iodo-3-pyridinecarboxylate as a white solid: m.p. 73°-73.5° C.; NMR (80 MHz, CDCl3) delta 3.96 (s, 3H), 8.43 (d, 1H, J= 2.3 Hz), 8.71 (d, 1H, J=2.3 Hz).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([N:28]=[C:29]=[O:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>O1CCCC1>[CH2:20]([NH:28][C:29](=[O:30])[O:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][N:8]2[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCN=C=O
Reactant: Oc1cccc(C2CCCN2Cc2ccccc2)c1
Solvent: C1CCOC1
Product: CCCCCCCCNC(=O)Oc1cccc(C2CCCN2Cc2ccccc2)c1
Reaction time: 17 h
Yield: 52 %

Procedure:
To a solution of 3-(1-phenylmethyl-2-pyrrolidinyl)phenol (0.06 g) in dry tetrahydrofuran (30 ml) was added octyl isocyanate (0.44 ml) at ambient temperature, under nitrogen. The reaction mixture was stirred for 17 hrs and filtered through a pad of celite. The filter cake was washed with ethyl acetate and the combined filtrates were concentrated. The residue was purified by flash column chromatography (silica gel, dichloromethane). The appropriate fractions were collected and concentrated to give 0.50 g (52%) of product. The analytical sample was prepared by flushing the product through alumina with ether.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:7])=[CH:4][C:3]=1[CH3:15].[O:16]=[C:17]([CH:19]=[C:20]([CH3:22])[CH3:21])[CH3:18].C([O-])(O)=O.[Na+]>>[CH3:21][C:20]([CH3:22])([CH2:19][C:17](=[O:16])[CH3:18])[CH:8]([C:6](=[O:7])[C:5]1[CH:13]=[CH:14][C:2]([F:1])=[C:3]([CH3:15])[CH:4]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)CC(=O)c1ccc(F)c(C)c1
Reactant: CC(=O)C=C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)C(C(=O)c1ccc(F)c(C)c1)C(C)(C)CC(C)=O
Reaction time: 120 h

Procedure:
A mixture of methyl 4-fluoro-3-methylbenzoylacetate (1a) (26.95g, 0.128 mol) and mesityl oxide (2) (19.3g, 0.192 mol) was kept at 0°-5° C. for 5 days, poured onto cold saturated NaHCO3 and extracted with ether. The combined extracts were washed with H2O and brine and dried (MgSO4). Removal of the volatiles in vacuo furnished 3a which was used without further purification.
Reaction SMILES: [S:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[S:15])[NH:13][NH2:14])=[CH:7][CH:6]=1)([OH:4])(=[O:3])=[O:2].[Na].[Cl:17][C:18]1[C:19]([OH:27])=[C:20]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[CH:21]=O.Cl>C(O)C>[Cl:17][C:18]1[C:19]([OH:27])=[C:20]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[CH:21]=[N:14][NH:13][C:12]([NH:11][C:8]1[CH:7]=[CH:6][C:5]([S:1]([OH:4])(=[O:2])=[O:3])=[CH:10][CH:9]=1)=[S:15]
Reactant: NNC(=S)Nc1ccc(S(=O)(=O)O)cc1
Reactant: O=Cc1cc(Cl)cc(Cl)c1O
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: O=S(=O)(O)c1ccc(NC(=S)NN=Cc2cc(Cl)cc(Cl)c2O)cc1
Yield: 24 %

Procedure:
A mixture of 4-(4-sulfophenyl)-3-thiosemicarbazide, sodium salt (740 mg, 2.75 mmol), 3,5-dichloro-2-hydroxybenzaldehyde (577 mg, 3.02 mmol), concentrated aqueous hydrochloric acid (0.3 mL) and ethanol (10 mL) was heated under reflux for 20 min. then cooled. The solid was filtered, washed (water) and dried to give the title compound (277 mg, 24%) as a solid. MS (ES−) m/e 418, 420 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.O.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:23](#[N:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>[Cu]Br>[C:24]1([C:23]2[N:1]=[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]3[N:30]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ccccn1
Reactant: N#Cc1ccccc1
Agent: [Cu]Br
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: O
Product: c1ccc(-c2nc3ccccn3n2)cc1
Temperature: 130 °C

Procedure:
A mixture of 2-amino-pyridine (2.00 g, 21.0 mmol), copper (I) bromide (160 mg, 1.09 mmol), 1,10-phenanthroline monohydrate (225 mg, 1.12 mmol) and benzonitrile (25 mL) was heated in a 50-mL 3-necked flask to 130° C. During 27 h a gentle flow of (O2/N2 5:95) was bubbled through the reaction mixture (>99% conversion, HPLC method see below). The dark brown suspension was then cooled to 0-5° C. and filtered. The filtrate was evaporated at 60° C./0.1 mbar to dryness and the dark brown residue dissolved in DCM (30 mL). The organic solution was washed with water (30 mL), dried over sodium sulphate, filtered and evaporated to yield 6.07 g of crude 2-phenyl-[1,2,4]triazolo[1,5-a]pyridine containing approx. 4 g of residual benzonitrile.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:10][CH:9]=[N:8][CH:7]=1.C([Li])CCC.C([Sn](Cl)(CCCC)CCCC)CCC.C1(C)C(C([O:38][C@@H:39]2[C@@H:43]([CH2:44][O:45]C(C3C(C)=CC=CC=3)=O)[O:42][C@@H:41]([N:55]3[C:59]4=[N:60][CH:61]=[CH:62][C:63](I)=[C:58]4[CH:57]=[CH:56]3)[CH2:40]2)=O)=CC=CC=1>C(OCC)C.CN(C=O)C>[C@@H:41]1([N:55]2[C:59]3=[N:60][CH:61]=[CH:62][C:63]([C:9]4[S:10][C:6]([C:2]5[S:1][CH:5]=[CH:4][CH:3]=5)=[CH:7][N:8]=4)=[C:58]3[CH:57]=[CH:56]2)[O:42][C@H:43]([CH2:44][OH:45])[C@@H:39]([OH:38])[CH2:40]1
Reactant: c1csc(-c2cncs2)c1
Reactant: Cc1ccccc1C(=O)OC[C@H]1O[C@@H](n2ccc3c(I)ccnc32)C[C@@H]1OC(=O)c1ccccc1C
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: OC[C@H]1O[C@@H](n2ccc3c(-c4ncc(-c5cccs5)s4)ccnc32)C[C@@H]1O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-(2-thienyl)thiazole (0.4 mmol) in diethyl ether was cooled to −78° C., and n-butyllithium (0.4 mmol, 1.57 M solution in hexane) was added thereto, followed by stirring at −78° C. for 30 min. Furthermore, tributylstannyl chloride was added thereto, followed by stirring at room temperature for 30 min. The reaction solution was separated between ethyl acetate and water. The organic layer was washed with saturated brine and concentrated, and 1-[2-deoxy-3,5-di-O-(toluoyl)-β-D-ribofuranosyl]-4-iodo-pyrrolo[2,3-b]pyridine (120 mg, 0.2 mmol), chlorobistriphenylphosphine palladium (5% mol), and DMF (2 mL) were added thereto, followed by stirring at 100° C. for 1 hr. The reaction solution was separated between ethyl acetate and water, and the organic layer was washed with saturated brine and water, dried over anhydrous sodium sulfate, and concentrated. After purification with a silica gel column and addition of sodium methoxide (1.6 mL), the resulting mixture was stirred at room temperature for 30 min. dDvas nucleoside (34 mg) was purified with a silica gel column and by HPLC.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][O:16][CH3:17])[C:10]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:9][C:5]=1[C:6](O)=[O:7])#[N:2].[NH2:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1>C(O)(=O)C>[CH3:17][O:16][CH2:15][CH2:14][O:13][C:11]1[CH:12]=[C:4]2[C:5](=[CH:9][C:10]=1[O:18][CH2:19][CH2:20][O:21][CH3:22])[C:6]([OH:7])=[N:2][C:1]([NH:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1)=[CH:3]2
Reactant: Cc1cc(N)n[nH]1
Reactant: COCCOc1cc(CC#N)c(C(=O)O)cc1OCCOC
Solvent: CC(=O)O
Product: COCCOc1cc2cc(Nc3cc(C)[nH]n3)nc(O)c2cc1OCCOC
Temperature: 130 °C
Yield: 79.6 %

Procedure:
A mixture of 2-Cyanomethyl-4,5-bis-(2-methoxy-ethoxy)-benzoic acid (2 g, 6.47 mmol), 3-amino-5-methylpyrazol (1.26 g, 12.9 mmol) in acetic acid (10 ml) was sealed in microwave process vial (20 ml). The mixture was heated at 130° C. for 30 minutes under microwave irradiation. After removal of acetic acid, the residue was dissolved in 1 ml MeOH, and this solution was added dropwise to 20 ml water. After stirred for half an hour, solid was collected and dried to give product (2 g, 79.7%). LC-MS: m/e 389(MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=CC=2)[CH:3]=[CH:2]1.C([N:17]1[C:29]2[C:28]([OH:30])=[C:27]3[N:31](C(OC(C)(C)C)=O)[C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Cl:46])[CH:22]=2)(OC(C)(C)C)=O.C(N1CCC(CO)CC1)(OC(C)(C)C)=O>>[Cl:38][C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:27]1[C:28]([O:30][CH2:6][CH:5]3[CH2:3][CH2:2][NH:1][CH2:9][CH2:4]3)=[C:29]3[NH:17][C:18]4[CH:19]=[CH:20][C:21]([Cl:46])=[CH:22][C:23]=4[C:24]3=[CH:25][C:26]2=1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Cl)cc2c2cc3c4cc(Cl)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Reactant: c1ccc2[nH]ccc2c1
Agent: CC(C)(C)OC(=O)N1CCC(CO)CC1
Product: Clc1ccc2[nH]c3c(OCC4CCNCC4)c4[nH]c5ccc(Cl)cc5c4cc3c2c1

Procedure:
The title compound was prepared in a manner analogous to Example 28 except the starting indole is 5,7-diBOC-2,10-dichloro-6-hydroxyindolo[2,3-b]carbazole and the reagent is N-Boc-4-piperidinemethanol. 1H-NMR (400 MHz, CD3OD) δ ppm 8.43 (s, 1H), 8.11 (d, J=2.0 Hz, 2H), 7.43 (d, J=8.8 Hz, 2H), 7.29 (dd, J=8.4, 2.0 Hz, 2H), 4.16 (d, J=6.4 Hz, 2H), 3.18-3.08 (m, 2H), 2.70 (td, J=12.4, 2.4 Hz, 2H), 2.22-2.10 (m, 1H), 2.09-1.98 (m, 2H), 1.50-1.38 (m, 2H); MS (ESI) m/z 436.2 (M−H)−; MS (ESI) m/z 438.1 (M+H)+
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[CH3:22][N:23]([CH3:25])[NH2:24]>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].C(Cl)(Cl)Cl>[CH3:22][N:23]([CH3:25])[NH:24][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CN(C)N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CN(C)Nc1c([N+](=O)[O-])cnc2ccccc12
Reaction time: 18 h
Yield: 95.6 %

Procedure:
A solution of 4-chloro-3-nitroquinoline (5.00 g, 24.0 mmol) in 100 mL CH2Cl2 was cooled to 0° C. and treated with triethylamine (8.40 mL, 60.0 mmol) and N,N-dimethylhydrazine (5.65 mL, 74.4 mmol) under an atmosphere of nitrogen. After 18 h, the mixture was diluted with 2% Na2CO3 solution and CHCl3 and separated. The organic portion was washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield 4-(2,2-dimethylhydrazino)-3-nitroquinoline (5.33 g) as a yellow/orange crystalline solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11](OS(C(F)(F)F)(=O)=O)[C:5]=2[C:4](=[O:20])[O:3]1.[CH3:22][O:23][C:24]1[N:29]=[C:28]([Sn](CCCC)(CCCC)CCCC)[CH:27]=[CH:26][CH:25]=1.[Cl-].[Li+]>O1CCOCC1.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.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[CH3:1][C:2]1([CH3:21])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([O:23][CH3:22])[N:29]=3)[C:5]=2[C:4](=[O:20])[O:3]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(OC)n1
Reactant: CC1(C)OC(=O)c2c(cccc2OS(=O)(=O)C(F)(F)F)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Solvent: C1COCCO1
Product: COc1cccc(-c2cccc3c2C(=O)OC(C)(C)O3)n1
Temperature: 140 °C
Reaction time: 4 h
Yield: 95.5 %

Procedure:
10.9 g of 2,2-dimethyl-5-trifluoromethylsulfonyloxy-4H-(1,3)-benzodioxin-4-one, 16.0 g of 6-methoxy-2-tributylstannylpyridine, 4.25 g of lithium chloride, 0.78 g of tetrakistriphenylphosphinepalladium and 40 mg of 2,6-di-t-butyl-4-methylphenol are dissolved in 120 ml of dioxane and the mixture is stirred for 4 h at 140° C. in an autoclave. It is concentrated in vacuo and the product is chromatographed on silica gel 60 using ethyl acetate/toluene. 9.1 g (95%) of a solid of m.p. 130°-132° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7].C(=O)([O-])[O-].[Cs+].[Cs+].C1COCC1.Br[CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36]>CCOC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:6]([N:8]([CH2:36][CH2:35][CH2:34][CH:33]=[CH2:32])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1OC
Reactant: C=CCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCCCN(C(=O)c1ccc(OC)c(OC)c1)c1ccccc1
Temperature: 80 °C
Yield: 61.5 %

Procedure:
To a solution of 3,4-dimethoxybenzanilide 33 (1.28 g, 5 mmol) and anhydrous cesium carbonate (4 equiv) in a mixture of anhydrous THF (14 mL) and DMF (56 mL) was added 5-bromo-pent-1-ene (2.85 g, 4 equiv) at room temperature and the mixture was heated at 80° C. for 72 h. The mixture was cooled, taken up in EtOAc and washed twice with water then brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography on SiO2 (gradient of diethyl ether in petroleum ether) to afford the title compound 37 as a yellow oil (Yield 1.0 g, 62%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)=[O:19])=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:29]2[CH:30]=[N:31][N:32]([CH2:34][C@H:35]3[CH2:39][O:38]C(C)(C)[O:36]3)[CH:33]=2)=[CH:4][N:3]=1.Cl>O1CCCC1>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)=[O:19])=[CH:15][CH:16]=3)=[CH:9][S:10][C:6]=2[C:5]([C:29]2[CH:30]=[N:31][N:32]([CH2:34][C@H:35]([OH:36])[CH2:39][OH:38])[CH:33]=2)=[CH:4][N:3]=1
Reactant: COc1ccc(NC(=O)Nc2ccc(-c3csc4c(-c5cnn(C[C@H]6COC(C)(C)O6)c5)cnc(N)c34)cc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)Nc2ccc(-c3csc4c(-c5cnn(C[C@H](O)CO)c5)cnc(N)c34)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of EXAMPLE 5B (44 mg, 0.077 mL) in tetrahydrofuran (2 mL) was treated with 2N HCl (1 mL), then stirred at room temperature for 18 hours. The resulting suspension was filtered and the solid was collected and dried to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.72 (s, 3H) 3.32-3.45 (m, 4H) 3.84-3.91 (m, 1H) 4.12 (dd, J=13.90, 7.80 Hz, 1H) 4.34 (dd, J=13.90, 3.73 Hz, 1H) 6.89 (d, J=9.15 Hz, 2H) 6.89-6.93 (m, 2H) 7.38 (d, J=9.15 Hz, 2H) 7.45 (d, J=8.81 Hz, 2H) 7.65 (d, J=8.81 Hz, 2H) 7.94 (s, 1H) 7.99 (d, J=0.68 Hz, 1H) 8.06 (s, 1H) 8.28 (d, J=0.68 Hz, 1H) 8.72 (s, 1H) 9.05 (s, 1H); MS (ESI(+)) m/z 531.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[C:7]([C:9]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[N:19]=[CH:18]3)([OH:14])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]1[C:31](O)=[O:32])[CH:2]=[CH2:3].[CH2:34]([N:36](CC)[CH2:37]C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CNC>CN(C=O)C.[Cl-].[Na+].O.O>[CH3:34][N:36]([CH3:37])[C:31]([C:5]1[N:4]([CH2:1][CH:2]=[CH2:3])[CH:8]=[C:7]([C:9]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[N:19]=[CH:18]3)([OH:14])[C:10]([F:11])([F:12])[F:13])[CH:6]=1)=[O:32]
Reactant: CCN(CC)CC
Reactant: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cc1C(=O)O
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cc1C(=O)N(C)C
Reaction time: 18 h
Yield: 83.6 %

Procedure:
To a solution of 1-allyl-4-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-hydroxyethyl}-1H-pyrrole-2-carboxylic acid (400 mg, 0.87 mmol, 1 equiv.) in 10 ml of DMF was added 0.22 mL of triethylamine (1.7 mmol, 2 equiv.) and PyBOP (500 mg, 0.96 mmol, 1.1 equiv.) followed by dimethylamine (2 M in THF, 1.3 mL, 2.6 mmol, 3 equiv.). After 18 hours, the mixture was diluted with 50 mL of brine and 50 mL of water and extracted with ethyl ether. The combined organic layers were dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography using EtOAc-hexanes (10-60% gradient) to afford 354 mg (84%) of the title compound as a white solid. MS m/z 487.29 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[OH-].[Na+].[CH3:16]OS(OC)(=O)=O.S(=O)(=O)(O)O>O.C(OCC)(=O)C.CCCCCC>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:13][CH3:16])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(O)c(O)c(O)c1
Reactant: COS(=O)(=O)OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: COC(=O)c1cc(O)c(O)c(OC)c1
Reaction time: 1 h
Yield: 79.4 %

Procedure:
Methyl 3,4,5-trihydroxybenzoate(50.0 g, 270 mmol) prepared in Step 1 and borax(54.0 g, 140 mmol) were dissoved in distilled water(1) and the mixture was stirred for 1 hour. To this solution was added sodium hydroxide(13 g, 330 mmol) dissoved in distilled water(100 ml), and the resulting mixture was stirred for 10 minutes. Dimethylsulfate(135 ml, 370 mmol) was added and the mixture was stirred again for 15 hours. The reaction solution was neutralized to pH 7-8 using conc. sulfuric acid, extracted with ethyl acetate and then subjected to silica gel column chromatography(eluent: ethyl acetate/n-hexane, 1/2, v/v) to give methyl 3,4-dihydroxy-5-methoxybenzoate(42.5 g, Yield 79%) as a white solid.