Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7](O)=O.OC1C2N=NNC=2C=CC=1.[H-].CN(C)CCCN=C=NCC.[C:32]([C:34]1[CH:59]=[CH:58][CH:57]=[CH:56][C:35]=1[O:36][C:37]1[CH:38]=[C:39]([NH2:55])[C:40]([NH2:54])=[CH:41][C:42]=1[O:43][C:44]1[CH:45]=[N:46][C:47]([S:50]([CH3:53])(=[O:52])=[O:51])=[CH:48][CH:49]=1)#[N:33]>C(OCC)(=O)C.CN(C)C=O>[C:32]([C:34]1[CH:59]=[CH:58][CH:57]=[CH:56][C:35]=1[O:36][C:37]1[C:42]([O:43][C:44]2[CH:45]=[N:46][C:47]([S:50]([CH3:53])(=[O:51])=[O:52])=[CH:48][CH:49]=2)=[CH:41][C:40]2[NH:54][C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[N:55][C:39]=2[CH:38]=1)#[N:33]
Reactant: O=C(O)c1cnccn1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(N)c(N)cc2Oc2ccccc2C#N)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3cc2Oc2ccccc2C#N)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
21 mg of pyrazine-2-carboxylic acid, 52 mg of hydroxybenzotriazole and 52 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydride were added to a dimethylformamide (2 ml) solution of 72 mg of 4-(2-cyano-phenoxy)-5-(6-methanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 196 (step 5), and the reaction liquid was stirred at room temperature for 1 hour. The reaction liquid was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate, water and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was dissolved in 1 ml of N-methylpyrrolidinone, and 20 mg of ytterbium trifluoromethanesulfonate was added to it, and the reaction liquid was stirred at 160° C. for 2 h ours. The reaction liquid was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol=30/1) and through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) to obtain the entitled compound as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][CH3:10].[N+:11]([O-])([O-:13])=[O:12].[K+]>OS(O)(=O)=O>[Cl:8][C:5]1[CH:4]=[C:3]([CH2:9][CH3:10])[C:2]([Cl:1])=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12]
Reactant: CCc1cc(Cl)ccc1Cl
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCc1cc(Cl)c([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a stiffed solution of 2,5-dichloro-1-ethylbenzene (0.795 g, 4.68 mmol) in concd H2SO4 (4.5 mL) at 0° C., KNO3 (0.473 g, 4.68 mmol) was added in one portion. The resulting pale yellow solution was allowed to warm to room temperature and was stirred overnight at room temperature. It was then poured into ice (80 g) and extracted with ether (3×30 mL). The ether was dried over anhydrous Na2SO4, removed under vacuum, and the resulting oil was dried further under vacuum to obtain 0.943 g (92%) title compound as an oil; 1H NMR (CDCl3) δ 1.27 (t, 3H, J=7.5 Hz), 2.80 (q, 2H, J=7.5 Hz), 7.42 (s, 1H), 7.94 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[Cl:14][S:15](O)(=[O:17])=[O:16]>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([S:15]([Cl:14])(=[O:17])=[O:16])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(C(=O)O)c(OC)c1
Product: COc1cc(OC)c(S(=O)(=O)Cl)cc1C(=O)O
Temperature: 10 °C
Reaction time: 8 h

Procedure:
1,800 ml of chlorosulphonic acid is placed in a 4 liter flask fitted with an agitator and a thermometer, and is cooled to 10° C. 328 g of finely powdered 2,4-dimethoxy benzoic acid is added in stages in the course of 45 minutes, between 10° and 15° C. The acid dissolves gradually as it is introduced. When all the acid has been added the solution is gradually heated to 55° C. and that temperature is maintained for 5 hours. The solution is left to stand overnight, then poured little by little into 17 kg of ice, with agitation and with external cooling. The acid which is precipitated is drained, washed with water and dried in air.
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([F:17])[C:15]=1[F:16])[N:12]=[CH:11][C:10]([CH2:18]O)=[C:9]2[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1>C(Cl)Cl>[F:5][C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([F:17])[C:15]=1[F:16])[N:12]=[CH:11][C:10]([CH2:18][Br:2])=[C:9]2[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1
Reactant: BrP(Br)Br
Reactant: OCc1cnc2c(F)c(F)c(F)cc2c1-c1cccs1
Solvent: ClCCl
Product: Fc1cc2c(-c3cccs3)c(CBr)cnc2c(F)c1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.7 %

Procedure:
A solution of PBr3 (8.4 g, 31 mmol) in CH2Cl2 (40 ml) was added to the mixture of F13 (5.0 g, 15.5 mmol) in CH2Cl2 (30 ml) at 0° C. The resulting mixture was stirred for 10 minutes at 0° C. and then for 2 hour at room temperature before quenching with a saturated aqueous NaHCO3 solution to pH 8. The mixture was added to CH2Cl2 and the organic layer was separated, washed with water, dried over Na2SO4, and concentrated to obtain the title compound (5.2 g, 86.8%), mp: 98˜100° C. which was used without further purification.
Reaction SMILES: [SH:1][C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH-].[Na+].CN(C=O)C.[F:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1>C(O)C.O>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32][S:1][C:2]3[N:11]([CH3:12])[C:10](=[O:13])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)=[CH:30][CH:29]=2)=[O:27])=[CH:36][CH:37]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Reactant: Cn1c(S)nc2ccccc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: Cn1c(SCc2ccc(C(=O)c3ccc(F)cc3)cc2)nc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of 2-mercapto-3-methyl-4(3H)-quinazolinone (1.0 g) and sodium hydroxide (250 mg) in 50% ethanol (15 ml)-DMF (15 ml) was added 4-(4-fluorobenzoyl)benzyl bromide (1.55 g) and the mixture was stirred at room temperature for 1 hour. This reaction mixtrue was poured in water and the resulting crystals were collected by filtration, rinsed with water and methanol, and recrystallized from methanol to provide the title compound as colorless solid (1.85 g). 1H-NMR (CDCl3) δ: 3.61(3H,s), 4.62(2H,s), 7.15(2H,t,J=8.6Hz), 7.40(1H,dt,J=8.2&1.4Hz), 7.58-7.90(8H,m), 8.23(1H,dd,J=8.0&1.4Hz).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.F[C:15]1[C:16]([CH3:35])=[N:17][C:18]2[C:23]([N:24]=1)=[C:22]([C:25]1[NH:33][C:32]3[CH2:31][CH2:30][NH:29][C:28](=[O:34])[C:27]=3[CH:26]=1)[CH:21]=[CH:20][CH:19]=2>CS(C)=O>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][C@@H:2]([NH:1][C:15]2[C:16]([CH3:35])=[N:17][C:18]3[C:23](=[C:22]([C:25]4[NH:33][C:32]5[CH2:31][CH2:30][NH:29][C:28](=[O:34])[C:27]=5[CH:26]=4)[CH:21]=[CH:20][CH:19]=3)[N:24]=2)[CH2:3]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 85 °C
Yield: 28.9 %

Procedure:
Prepared according to Example 131, using (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (189 mg, 1.012 mmol, CNH Technologies, Inc., Woburn, Mass.) and 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 100 mg, 0.337 mmol) in DMSO (1.5 mL) and heating at 85° C. for 2 h. Purification by column chromatography (silica gel: 0 to 10% MeOH/DCM) provided (R)-tert-butyl-3-((3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxalin-2-yl)amino)pyrrolidine-1-carboxylate (45 mg, 28.8%). 1H NMR (400 MHz, MeOH-d4) δ ppm 7.90-7.96 (1H, m) 7.63-7.69 (1H, m) 7.42 (1H, t, J=1.00 Hz) 7.11 (1H, s) 4.65-4.80 (1H, m) 3.87-4.03 (1H, m) 3.57-3.68 (3H, m) 3.49-3.55 (1H, m) 3.40-3.49 (1H, m) 2.94-3.03 (1H, m) 2.61 (3H, s) 2.35-2.49 (2H, m) 2.19-2.34 (1H, m) 1.45-1.54 (9H, m). m/z (ESI, +ve) 463.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15](=[O:33])[C:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[CH:31]=O)([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[CH3:13].N1CCCC1>CO>[CH2:12]([O:14][C:15](=[O:33])[C:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1/[CH:31]=[C:6]1\[C:7](=[O:11])[NH:8][C:9]2[C:5]\1=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[CH3:13]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CCCC(CCC)(Oc1ccc(Cl)cc1C=O)C(=O)OCC
Solvent: C1CCNC1
Solvent: CO
Product: CCCC(CCC)(Oc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21)C(=O)OCC
Temperature: 80 °C
Yield: 20.6 %

Procedure:
To the mixture of 6-chlorooxindole (9.3 g, 55.7 mmol) and 2-(4-chloro-2-formyl-phenoxy)-2-propyl-pentanoic acid ethyl ester (14 g, 42.9 mmol) in methanol (100 mL) was added pyrrolidine (3.3 g, 47.2 mmol) dropwise. The mixture was then heated at 80° C. for 2 h. After cooled to room temperature, the mixture was concentrated. The residue was purified by flash column to give the title compound (4.2 g).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([N:12]([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[N+:23]([C:26]1[CH:31]=[CH:30][C:29](F)=[CH:28][CH:27]=1)([O-:25])=[O:24].O>CN(C=O)C>[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([O:1][C@H:2]2[CH2:7][CH2:6][C@H:5]3[C@H:8]4[C@H:18]([CH2:19][CH2:20][C@:3]23[CH3:4])[C@:16]2([CH3:17])[C@H:11]([N:12]([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15]2)[CH2:10][CH2:9]4)=[CH:28][CH:27]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](O)CC[C@H]4[C@@H]3CC[C@@H]12
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](Oc5ccc([N+](=O)[O-])cc5)CC[C@H]4[C@@H]3CC[C@@H]12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 17β-hydroxy4-methyl-5α-4-azaandrostan-3-one (1.07 g, 3.5 mmole) and p-nitrofluorobenzene (2.0 ml, 18 mmole) in DMF (15 ml) under N2 was added 95% Nail (180 mg, 7 mmole) in two portions during 10 mins. The mixture was stirred for 3 hours at room temperature and poured onto ice (50 g) and water (50 ml). The mixture was extracted with CH2Cl2 (30 ml×2). The organic layer was washed with brine and dried (Na2SO4). Removal of solvent gave the crude product which was purified via a flash silica gel column eluting with 1:1 ethyl acetate --CH2Cl2 to give the desired title product. Mp. 183°-184° C. (recrystallized from CH2Cl2 -hexane).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[F:12].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[F:12][C:4]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cccc(CBr)c1F
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc(CN2CCOCC2)c1F
Temperature: 25 °C
Yield: 76.6 %

Procedure:
A stirred solution of 1-(bromomethyl)-2-fluoro-3-nitrobenzene (2.50 g, 10.6 mmol) and morpholine (2.78 g, 32.0 mmol) in toluene (24 mL) was heated at reflux temperature for 2.5 h. The reaction mixture was allowed to cool to room temperature and then washed with 1 N NaOH (2×20 mL). The aqueous layer was extracted with EtOAc (2×25 mL), and the combined toluene solution and EtOAc extracts were dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 4-(2-fluoro-3-nitrobenzyl)morpholine (1.95 g, 89%) as a light yellow solid. 1H NMR (400 MHz, CD3OD): δ 8.02-7.97 (m, 1H), 7.83-7.78 (m, 1H), 7.36 (td, 1H, J=8.0, 1.0 Hz), 3.70-3.67 (m, 6H), 2.51 (br t, 4H, J=4.6 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[CH3:23][C:24]([CH3:28])([CH3:27])[C:25]#[CH:26]>CC1OCCC1.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.[Cu]I>[CH3:23][C:24]([CH3:28])([CH3:27])[C:25]#[C:26][C:2]1[CH:3]=[C:4]2[C@@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:26]#[C:25][C:24]([CH3:28])([CH3:27])[CH3:23])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: C#CC(C)(C)C
Reactant: NC1=N[C@@]2(COC1)c1cc(I)ccc1Oc1ncc(Br)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC1CCCO1
Product: CC(C)(C)C#Cc1ccc2c(c1)[C@@]1(COCC(N)=N1)c1cc(C#CC(C)(C)C)cnc1O2
Temperature: 90 °C
Yield: 51 %

Procedure:
A vial was charged with (S)-3-bromo-7-iodo-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.520 g, 1.102 mmol), DIPA (0.785 mL, 5.51 mmol), Pd(PPh3)4 (0.127 g, 0.110 mmol), copper(I) iodide (0.021 g, 0.110 mmol), and 3,3-dimethyl-1-butyne (0.203 mL, 1.652 mmol) DMF (3 ml) was added, the vial was sealed under argon, and was heated to 90° C. for 60 minutes. The reaction mixture was diluted with 2-MeTHF then washed with water. The organics were dried over MgSO4 and concentrated. Purification of the crude residue by column chromatography gave (S)-3,7-bis(3,3-dimethylbut-1-ynyl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.180 g, 0.421 mmol) as a white solid. [M+H]+=428.0
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]([CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][OH:32])[CH2:26][CH2:25]1)[CH:14]=[C:13]2[C:33]1[N:41](S(C2C=CC(C)=CC=2)(=O)=O)[C:36]2=[N:37][CH:38]=[CH:39][CH:40]=[C:35]2[CH:34]=1.[OH-].[K+]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]([CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][OH:32])[CH2:26][CH2:25]1)[CH:14]=[C:13]2[C:33]1[NH:41][C:36]2=[N:37][CH:38]=[CH:39][CH:40]=[C:35]2[CH:34]=1
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCCN3CCN(CCO)CC3)c2cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(-c3cc4cccnc4[nH]3)cn(CCCN3CCN(CCO)CC3)c2cc1OC
Temperature: 20 °C
Reaction time: 72 h
Yield: 73 %

Procedure:
A solution of 2-[4-(3-{5,6-dimethoxy-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]indol-1-yl}propyl)piperazin-1-yl]ethanol trifluoroacetate (0.038 g; 52.2 μmol) in a methanolic potassium hydroxide solution (3 ml, 0.1 g of potassium hydroxide per ml of methanol) is placed in a hemolysis tube (1.3×10 cm) and is agitated at 20° C. for 72 hours. The solid form is filtered off and then purified by reverse-phase liquid chromatography mass spectrometry (method E). The fractions containing the expected compound are combined and then evaporated under reduced pressure, giving 2-(4-{3-[5,6-dimethoxy-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)indol-1-yl]propyl}piperazin-1-yl)ethanol trifluoroacetate (0.022 g; 90%), the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](=[S:15])[NH2:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)=O>C(O)(C)C>[Br:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2[N:14]=[C:13]([C:12]3[CH:16]=[CH:17][C:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:10][CH:11]=3)[S:15][CH:19]=2)=[CH:23][CH:24]=1
Reactant: CCCCCCCOc1ccc(C(N)=S)cc1
Reactant: O=C(CBr)c1ccc(Br)cc1
Solvent: CC(C)O
Product: CCCCCCCOc1ccc(-c2nc(-c3ccc(Br)cc3)cs2)cc1
Yield: 41.6 %

Procedure:
To a stirring mixture of 4-(heptyloxy)benzothioamide (1.30 g, 5.17 mmol) in isopropanol (20 mL) was added 2-bromo-1-(4-bromophenyl)ethanone (1.44 g, 5.17 mmol). The precipitate was collected by filtration and washed with EtOH (2×5 mL). The filter cake was slurried with NaHCO3 (2×20 mL), water (2×20 mL) then EtOH (2×5 mL) and dried to afford 926 mg (41%) of 4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl)thiazole as a pale yellow powder. LCMS-ESI (m/z) calculated for C22H24BrNOS: 429.1. found 430.0 [M+H]+, tR=3.41 min. (Method 4).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([S:13][C:14]1[S:15][C:16]2[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:17]=2[N:18]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6])[CH3:2].S(OCC)(O[CH2:29][CH3:30])(=O)=O>[OH-].[Na+]>[CH2:1]([O:3][C:4](=[O:24])[C:5]([S:13][C:14]1[S:15][C:16]2[CH:22]=[C:21]([O:23][CH2:29][CH3:30])[CH:20]=[CH:19][C:17]=2[N:18]=1)([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(Sc1nc2ccc(O)cc2s1)c1ccccc1
Reactant: CCOS(=O)(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)C(C)(Sc1nc2ccc(OCC)cc2s1)c1ccccc1

Procedure:
3.59 g. of 2-(6-hydroxybenzothiazol-2-ylthio)-2-phenylpropionic acid ethyl ester is dissolved in 15 ml of 1 N sodium hydroxide solution and 1.6 g of diethyl sulfate is added dropwise, while stirring. After stirring for a total of 1 hour, the mixture is worked up in the customary manner to give 2-(6-ethoxybenzothiazol-2-ylthio)-2-phenylpropionic acid ethyl ester, m.p. 92°-94°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[C:10]2=[N:11][C:12]([CH3:22])=[C:13]([C@H:16]([OH:21])[C:17]([O:19][CH3:20])=[O:18])[C:14]([I:15])=[C:9]2[CH:8]=[CH:7]1.C(O[C:31]([CH3:34])([CH3:33])[CH3:32])(=O)C.Cl(O)(=O)(=O)=O>>[C:31]([O:21][C@@H:16]([C:13]1[C:14]([I:15])=[C:9]2[CH:8]=[CH:7][N:6]([CH2:5][C:4]3[CH:23]=[CH:24][C:25]([F:26])=[C:2]([F:1])[CH:3]=3)[C:10]2=[N:11][C:12]=1[CH3:22])[C:17]([O:19][CH3:20])=[O:18])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H](O)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1I
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
To a solution of (S)-methyl 2-(1-(3,4-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-hydroxyacetate (660 mg, 1.328 mmol) in tert-butyl acetate (15 mL, 111 mmol) was added dropwise in ˜5 min perchloric acid (0.456 mL, 5.31 mmol) (70% reagent) and the mixture was stirred at RT for 1 h. The mixture was carefully quenched with saturated NaHCO3/water and extracted with EtOAc. The organic phase dried (Na2SO4), concentrated, and purified by column chromatography to provide (S)-methyl 2-(tert-butoxy)-2-(1-(3,4-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (551 mg, 1.032 mmol, 78% yield) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.27 (s, 9 H), 2.74 (s, 3 H), 3.70 (s, 3 H), 5.40 (d, J=2.15 Hz, 2 H), 5.76 (s, 1 H), 6.36 (d, J=3.51 Hz, 1 H), 6.92-7.17 (m, 4 H); LCMS (m/z) ES+=529 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:20]N(CCN(C)C)C.[Li]CCCC.CI>>[Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([CH3:20])[N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Cl)ncnc21
Reactant: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CI
Product: Cc1cc2c(Cl)ncnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
To the solution of 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (3 g, 12.6 mmol, 1.0 eq) and TMEDA (3.0 mL, 18.9 mmol, 1.5 eq) THF (120 mL), n-BuLi (7.5 L, 18.9 mmol, 1.5 eq) was added at −78° C. After 3 min, CH3I (3.7 mL, 59.2 mmol, 4.7 eq) was added. After 3 h, the reaction mixture was warmed to RT over 1 h. The reaction was quenched by addition of sat NH4Cl (10 mL) at −78° C. EtOAc (200 mL) and water (100 mL) was added. The organic layer was separated, dried and concentrated to afford 4-chloro-6-methyl-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine as a brown solid (6.7 g, 90% in yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>ClC1C=CC=CC=1Cl.[Cu]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Reactant: Ic1ccccc1
Agent: [Cu]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Solvent: Clc1ccccc1Cl
Product: Brc1ccc2c(c1)c1ccccc1n2-c1ccccc1
Yield: 119.3 %

Procedure:
3Bromo-9H-carbazole (10.0 g, 40.6 mmol), iodobenzene (20.7 g, 101.6 mmol), potassium carbonate (28.1 g, 203.2 mmol), copper (2.58 g, 40.6 mmol), 18-crown-6 (10.7 g, 40.6 mmol) in o-dichlorobenzene (400 mL) were stirred and degassed with nitrogen for 15 minutes. The reaction was refluxed overnight. The reaction mixture was filtered Celite®, washed with toluene and the filtrate was concentrated under vacuum. It was then column chromatographed with 20% DCM/hexane to obtain 15.6 g (81%) of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:23])([CH3:22])[C:9]([CH:11]([C:17](OCC)=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.OS(O)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:17]([OH:18])=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:9](=[O:10])[C:8]2([CH3:22])[CH3:23])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1cccc(Cl)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1=C(O)c2ccc(Cl)cc2C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 50.9 %

Procedure:
Diethyl 2-(2-(3-chlorophenyl)-2-methylpropanoyl)malonate (8.76 g, 26 mmol) was added to H2SO4 (60 mL, 710 mmol), and the mixture was stirred at room temperature for 45 minutes. Ice (H2O) was added, and the aqueous mixture was extracted with EtOAc (2×). The combined organic layers were washed with water (2×) and brine, dried (MgSO4), and concentrated in vacuo to give the crude compound as an orange oil. The crude oil was purified by silica flash chromatography (0-50% DCM/hexane) to give the desired compound as a white solid (3.90 g). MS (m/e)=295.1 (M+H)+.