Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:35])[CH:3]1[CH2:6][N:5]([C:7]2[C:12]([N+:13]([O-])=O)=[CH:11][C:10]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]([CH3:32])[CH:24]=4)[CH:20]=[CH:19][N:18]=3)=[C:9]([O:33][CH3:34])[CH:8]=2)[CH2:4]1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH3:35][N:2]([CH3:1])[CH:3]1[CH2:4][N:5]([C:7]2[CH:8]=[C:9]([O:33][CH3:34])[C:10]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]([CH3:32])[CH:24]=4)[CH:20]=[CH:19][N:18]=3)=[CH:11][C:12]=2[NH2:13])[CH2:6]1
Reactant: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Yield: 79.6 %

Procedure:
A mixture of N-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 117, 160 mg, 0.34 mmol), iron (113 mg, 2.03 mmol) and NH4Cl (13.56 mg, 0.25 mmol) in ethanol (5 mL) and water (1.67 mL) was heated at reflux for 2 h. The cooled mixture was purified by ion exchange chromatography, using an SCX column and eluting with 1:1 7M methanolic ammonia in CH2Cl2. Appropriate fractions were combined and concentrated in vacuo. Further purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (120 mg, 80%) as a brown gum; m/z: ES+ MH+ 444.61.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4([NH:27]C(=O)OC(C)(C)C)[CH2:26][CH2:25][CH2:24]4)=[CH:19][CH:18]=3)=[N:15][C:8]3[O:9][CH2:10][C:11](=[O:14])[N:12]([CH3:13])[C:7]=3[CH:6]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:27][C:23]1([C:20]2[CH:21]=[CH:22][C:17]([C:16]3[C:5]([CH2:4][CH:1]4[CH2:2][CH2:3]4)=[CH:6][C:7]4[N:12]([CH3:13])[C:11](=[O:14])[CH2:10][O:9][C:8]=4[N:15]=3)=[CH:18][CH:19]=2)[CH2:24][CH2:25][CH2:26]1
Reactant: CN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(CC3CC3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(CC3CC3)cc21
Reaction time: 0.01 h
Yield: 46.1 %

Procedure:
Tert-butyl (1-(4-(7-(cyclopropylmethyl)-1-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (0.5 mg, 1.79 μmol) was dissolved in dichloromethane (1 ml). TFA (0.5 ml) was added at room temperature and the reaction mixture was stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜1 ml) and concentrated to dryness under reduced pressure. This was repeated three times. The residue was then slurred in diethyl ether (1 ml) and after settling the supernatant solvent was removed by pipette. This was repeated twice. The residue was then slurred in n-hexane (1 ml) and after settling the supernatant solvent was removed by pipette. This was repeated twice. The residue remaining solvent was dried to give the desired product as an off-white solid as the title compound (0.3 mg, 77% yield). LCMS (Method D) RT=0.77 min, M+1=364. 1H-NMR (500 MHz, CD3OD) δ 7.66-7.50 (4H, m), 7.47 (1H, s), 4.48 (2H, s), 4.15-4.09 (2H,m), 3.06 (3H, s), 2.75-2.65 (2H, m), 2.51-2.42 (2H, m), 2.28-2.20 (1H, m), 1.97-1.90 (1H, m), 1.76-1.71 (1H, m), 1.66-1.55 (2H, m), 1.38-1.31 (2H, m).
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.Cl.[CH3:24][C@@H:25]1[CH2:29][CH2:28][CH2:27][NH:26]1.CCN(C(C)C)C(C)C>CS(C)=O.O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:3]2[C:2]([N:26]3[CH2:27][CH2:28][CH2:29][C@H:25]3[CH3:24])=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)=[CH:17][CH:18]=1
Reactant: C[C@@H]1CCCN1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCC[C@H]3C)nc2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (150 mg, 0.47 mmol) in DMSO (2 mL), was added (R)-2-methylpyrrolidine hydrochloride (61 mg, 0.50 mmol) and DIEA (92 mg, 0.71 mmol). After stirring overnight at 70° C., the reaction mixture was dissolved in water (100 mL), extracted with dichloromethane (3×30 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to afford a residue, which was purified via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford (R)-methyl 2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate as a light yellow solid (95 mg, 55%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[OH:14])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:26](Br)[CH3:27]>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH2:26][CH3:27])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cc1O
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc([N+](=O)[O-])ccc1NC(C)=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To 400 g of 2-acetamido-5-nitrophenol in a 12-L, 4-necked flask equipped with a reflux condenser, nitrogen inlet, thermocouple, addition funnel, and mechanical stirrer was added 790 g of potassium carbonate and 2.0 L of dimethylformamide. The mixture was stirred at 60° C. as 294 g of ethyl bromide was added over 30 minutes. After 1 hour, an additional 27 g of ethyl bromide was added and the mixture was stirred at 60° C. for another hour. The mixture was cooled to room temperature and poured into 4 L of water. After 30 minutes, the product was collected by filtration and washed with water and heptane. The product was dried in a vacuum oven at 60° C. to give 457 g of the title compound.
Reaction SMILES: [CH2:1]([CH:3]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:14])[CH3:2].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26].[S]>N1C=CC=CC=1>[CH2:1]([CH:3]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:14]1[O:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=1)[CH3:2]
Reactant: CCCCC(CC)Cn1c(C)nc2ccccc21
Reactant: Nc1ccccc1O
Agent: [S]
Solvent: c1ccncc1
Product: CCCCC(CC)Cn1c(-c2nc3ccccc3o2)nc2ccccc21
Temperature: 25 °C

Procedure:
24.4 g (0.1 mol) of 1-(2-ethylhexyl)-2-methylbenzimidazole (prepared by heating N-2-ethylhexyl-o-phenylenediamine in acetic acid/hydrochloric acid), 10.9 g (0.1 mol) of o-aminophenol and 9.6 g (0.3 mol) of sulfur in 100 ml of pyridine are heated under reflux for 18 hours. After cooling to room temperature, the crude product is precipitated by addition of water. Multiple recrystallization from n-hexane with addition of active charcoal gives 5.7 g (16% of theory) of product, which according to melting point, HPLC and UV determination is identical to the compound obtained in Example 7.
Reaction SMILES: [CH:1]1[C:2]([CH2:19][C:20]([OH:22])=[O:21])=[CH:3][C:4]([I:18])=[C:5]([O:8][C:9]2[CH:10]=[C:11]([I:17])[C:12]([OH:16])=[C:13]([I:15])[CH:14]=2)[C:6]=1[I:7].O=S(Cl)Cl.O.[CH3:28]O>>[CH3:28][O:21][C:20](=[O:22])[CH2:19][C:2]1[CH:1]=[C:6]([I:7])[C:5]([O:8][C:9]2[CH:10]=[C:11]([I:17])[C:12]([OH:16])=[C:13]([I:15])[CH:14]=2)=[C:4]([I:18])[CH:3]=1
Reactant: O=C(O)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Yield: 61 %

Procedure:
In anhydrous conditions, Tetrac (5.0 g, 6.7 mmol, 1.0 eq.) was dissolved in anhydrous methanol (200 mL). To the solution was then added dropwise SOCl2 (485 μL, 6.7 mmol, 1.0 eq.). The reaction was set to reflux for 2 days. Water was then added to the reaction medium (200 mL) and then the solution was concentrated to yield a precipitate. The precipitate was then collected by vacuum filtration and then recrystallized to give orange crystals (3.10 g, 4.0 mmol) of methyl-2-(4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl)acetate in 61% yield. Method B: In anhydrous conditions, Tetrac (1.0 g, 1.3 mmol, 1.0 eq.) was suspended in MeOH (20 mL). TEA (181.4 μL, 1.3 mmol, 1.0 eq.) was then added dropwise followed by benzylchloroformate (184.8 μL, 1.3 mmol, 1.0 eq.). After stirring for 30 minutes, the solution was filtered, the solvent was removed from the residue and the product was separated by silica gel chromatography (eluent=DCM). The collected fractions were then evaporated to give a white powder which was recrystallized to give orange crystals (990 mg, 1.3 mmol) of methyl-2-(4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl)acetate in a quantitative yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[N:6][CH:7]=1.[CH2:17]([O:19][C:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)=[O:21])[CH3:18].C(=O)([O-])[O-].[K+].[K+].O>COCCOC.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.CN(C=O)C>[C:10]1([C:9]([NH:8][C:4]2[CH:3]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([C:20]([O:19][CH2:17][CH3:18])=[O:21])=[CH:23][CH:24]=3)[CH:7]=[N:6][CH:5]=2)=[O:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Nc1cncc(Br)c1)c1ccccc1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
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: [K+]
Solvent: CN(C)C=O
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1ccc(-c2cncc(NC(=O)c3ccccc3)c2)cc1
Temperature: 85 °C
Reaction time: 12 h

Procedure:
At 50° C., 5.14 g (18.2 mmol) of N-(5-bromopyridin-3-yl)benzamide, 5.40 g (27.8 mmol) of 4-ethoxycarbonylphenylboronic acid and 5.03 g (36.4 mmol) of potassium carbonate were dissolved in 30 ml of 1,2-dimethoxyethane, 9 ml of water and 65 ml of DMF. The mixture was flushed with argon, 105 mg (0.09 mmol) of tetrakis(triphenylphosphine)palladium(0) were added and the mixture was stirred at 85° C. for 12 h. The reaction mixture was concentrated slightly on a rotary evaporator, diluted with water and extracted with dichloromethane. The organic phase was concentrated under reduced pressure and the residue was triturated with methyl tert-butyl ether, the solid was filtered off and the filtrate was purified by column chromatography (cyclohexane/ethyl acetate 2:1→1:1). The separated solid and the appropriate fraction from the chromatography were combined. Yield: 4.6 g (60% of theory)
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].Cl[C:22]1[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([NH:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[N:25]=[CH:24][N:23]=1.C(N(CC)C(C)C)(C)C>C(O)C>[CH3:42][O:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][NH:33][C:26]2[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:22]([NH:1][C@H:2]([C:4]3[N:9]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:8](=[O:16])[C:7]4=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]4[N:5]=3)[CH3:3])[N:23]=[CH:24][N:25]=2)=[CH:40][CH:39]=1
Reactant: CCOC(=O)c1c(Cl)ncnc1NCc1ccc(OC)cc1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1c(NCc2ccc(OC)cc2)ncnc1N[C@@H](C)c1nn2ccc(C)c2c(=O)n1-c1ccccc1
Yield: 82 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one was treated with ethyl 4-chloro-6-((4-methoxybenzyl)amino)pyrimidine-5-carboxylate (6 mg, 0.02 mmol), N,N-diisopropylethylamine (16 μl, 0.09 mmol) and ethanol as a solvent according to the method described in Example 17. The solvent was concentrated and the solid was suspended in ethanol and filtered. The white solid obtained was washed with ether and dried in the oven to give 281 mg (82% yield) of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:8]=1)=[O:6].[H-].[Na+].[CH2:27]([C:31]1[CH:36]=[CH:35][C:34]([CH:37]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45][CH:46]([CH3:48])[CH3:47])=[CH:41][CH:40]=2)Br)=[CH:33][CH:32]=1)[CH:28]([CH3:30])[CH3:29].Cl>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[CH2:45]([C:42]1[CH:43]=[CH:44][C:39]([CH:37]([C:34]2[CH:35]=[CH:36][C:31]([CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:32][CH:33]=2)[O:1][C:2]2[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=2)[C:5]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:8]=2)=[O:6])=[CH:40][CH:41]=1)[CH:46]([CH3:48])[CH3:47]
Reactant: CC(C)Cc1ccc(C(Br)c2ccc(CC(C)C)cc2)cc1
Reactant: O=C(O)CCCn1cc(C(=O)c2cccc(O)c2)c2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(C(Oc2cccc(C(=O)c3cn(CCCC(=O)O)c4ccccc34)c2)c2ccc(CC(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.9 %

Procedure:
A solution of 4-[3-(3-hydroxybenzoyl)indol-1-yl]butyric acid (500 mg) in N,N-dimethylformamide (5 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 136 mg) in N,N-dimethylformamide (10 ml) at 25° . The mixture was stirred at 25° C. for 1 hour, and a solution of bis (4-isobutylphenyl)bromomethane (1.11 g) in tetrahydrofuran (10 ml) was added at 0° C. After stirred at 25° C. overnight, the mixture was poured into a mixture of ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (20 g) eluting with 2% methanol in chloroform to give 4-[3-[3-[bis(4-isobutylphenyl)methoxy]benzoyl]indol-1-yl]butyric acid (120 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:19]=[C:20]([C:23]([OH:25])=O)[S:21][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[Na+].[Na+].[C:32](Cl)([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33].S(Cl)([Cl:45])=O>C1(C)C=CC=CC=1.O.C(Cl)(Cl)Cl>[C:32]([N:17]([C:18]1[CH:19]=[C:20]([C:23]([Cl:45])=[O:25])[S:21][CH:22]=1)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCCCCCNc1csc(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCCCCCCN(C(=O)OCc1ccccc1)c1csc(C(=O)Cl)c1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To 15 g. 4-(hexadecylamino)-2-thiophenecarboxylic acid in 200 ml. warm chloroform is added a solution of 15 g. of sodium carbonate in 150 ml. water. To the vigorously stirred solution is added 10 g. carbobenzyloxy chloride. After 2 hours stirring at 40° C., the organic layer is separated, washed three times with 1 N hydrochloric acid, dried, and evaporated to yield an oil. The oil is dissolved in 300 ml. toluene, treated with 15 ml. thionyl chloride and the solution is refluxed for 5 hours. The solvents are evaporated and the residue is dissolved three times in toluene, evaporating each time, ultimately to yield 4-[N-(carbobenzyloxy)-N-(hexadecyl)amino]-2-thiophenecarbonyl chloride as a viscous, orange oil.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]2[NH2:24])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[C:3]([NH:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[NH:24][S:35]([CH3:34])(=[O:37])=[O:36])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC1CCCCC1Nc1nc(-c2c[nH]c3ncccc23)ncc1F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N[C@@H]1CCCC[C@@H]1Nc1nc(-c2c[nH]c3ncccc23)ncc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N1-(5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)cyclohexane-1,2-diamine, 16b, (0.009 g, 0.027 mmol) was dissolved in an 8:2 mixture of CH2Cl2/DMF (1 mL) and treated with iPr2NEt (0.019 mL, 0.110 mmol) and methanesulfonyl chloride (0.006 mL, 0.083 mmol). The reaction was stirred at room temperature overnight, concentrated in vacuo and the residue was purified by HPLC with 10%-90% acetonitrile/water with 0.03% TFA to provide compound 337.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[NH:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([SH:19])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=c1[nH]n(-c2ccccc2)c2cc(Br)ccc12
Solvent: Cc1ccccc1C
Product: Sc1nn(-c2ccccc2)c2cc(Br)ccc12
Temperature: 130 °C
Reaction time: 1 h

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed a solution of 6-bromo-1-phenyl-1,2-dihydroindazol-3-one (7 g, 24.22 mmol, 1.00 equiv) in xylene (50 mL) and P2S5 (21.5 g, 96.85 mmol, 4.00 equiv). The resulting solution was stirred for 1 h at 130° C. in an oil bath. The solids were collected by filtration, washed with ethyl acetate (2×50 mL). The organic layer was washed with water (2×50 mL). The resulting mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to yield 6-bromo-1-phenyl-1H-indazole-3-thiol as a brown solid. MS: 304 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:11](=[O:12])[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(Cl)Oc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(F)cc1F)Oc1ccccc1

Procedure:
The intermediate is then reacted with a secondary amine in an aprotic solvent such as toluene at temperatures from room temperature or below up to the boiling point of the solvent. An example of this process is the reaction of 2,4-difluoroaniline with phenyl chloroformate to yield the intermediate phenyl N-(2,4-difluorophenyl)carbamate which is then reacted with N-(4-butylphenyl)-N-(6-hydroxyhexyl)amine to yield 1-(4-n-butylphenyl)-3-(2,4-difluorophenyl)-1-(6-hydroxyhexyl)urea.
Reaction SMILES: I[C:2]1[S:6][C:5]([C:7]2([O:11][CH2:12][C:13]([O:15][CH2:16]C)=[O:14])[CH2:10][CH2:9][CH2:8]2)=[N:4][CH:3]=1.[F-].[Cs+].CC1(C)C(C)(C)OB([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)O1.C(COC)OC>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.CO>[NH2:32][C:31]1[CH:33]=[CH:34][C:28]([C:2]2[S:6][C:5]([C:7]3([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:8][CH2:9][CH2:10]3)=[N:4][CH:3]=2)=[CH:29][CH:30]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CCOC(=O)COC1(c2ncc(I)s2)CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Product: COC(=O)COC1(c2ncc(-c3ccc(N)cc3)s2)CCC1
Temperature: 90 °C

Procedure:
A solution of Example 24A (0.750 g, 2/04 mmol), CsF (0.930 g, 6.12 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.447 g, 2.04 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.231 g, 0.200 mmol) in a solvent mixture of dimethoxyethane (5 mL) and methanol (5 mL) was heated to 90° C. for 16 h. The reaction was cooled to room temperature and partitioned between H2O (10 mL) and ethyl acetate (10 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×10 mL). The combined organics were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 gel, eluting with a gradient of 10% ethyl acetate in hexane to 50% ethyl acetate in hexane, to give the title compound. MS (ESI) m/z 319 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[F:18][C:19]([F:35])([F:34])[C:20]1[CH:21]=[C:22]([CH2:30][C:31](O)=[O:32])[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1>>[F:18][C:19]([F:34])([F:35])[C:20]1[CH:21]=[C:22]([CH2:30][C:31]([NH:13][CH2:12][CH:8]2[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([Cl:17])=[C:2]([Cl:1])[CH:3]=3)[CH2:7]2)=[O:32])[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1
Reactant: O=C(O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 38.1 %

Procedure:
Example 17 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.055 g) and [3,5-bis(trifluoromethyl)phenyl]acetic acid (0.054 g) to give the title compound (0.04 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][C:23](F)=[CH:22][C:21]=2[O:27][CH2:28][CH2:29][OH:30])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].[CH3:32][N:33]1[CH2:39][CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][C:23]([N:36]3[CH2:37][CH2:38][CH2:39][N:33]([CH3:32])[CH2:34][CH2:35]3)=[CH:22][C:21]=2[O:27][CH2:28][CH2:29][OH:30])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: CN1CCCNCC1
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(F)ccc1NC(=O)c1ccc(F)cc1OCCO
Product: CN1CCCN(c2ccc(C(=O)Nc3ccc(F)cc3C(=O)Nc3ccc(Cl)cn3)c(OCCO)c2)CC1

Procedure:
Prepared from 5-fluoro-2-[4-fluoro-2-(2-hydroxyethoxy)-benzoylamino]-N-(5-chloropyridin-2-yl)-benzamide and 1-methyl-hexahydro-1,4-diazepine to afford 25 mg (24%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:20]([OH:22])=O)=[CH:11][C:12]3[N:16]([CH3:17])[CH:15]=[N:14][C:13]=3[C:18]=2[F:19])=[C:4]([Cl:23])[CH:3]=1.[CH:24]([O:26][CH2:27][CH2:28][O:29][NH2:30])=[CH2:25].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.C(OCC)(=O)C>[CH:24]([O:26][CH2:27][CH2:28][O:29][NH:30][C:20]([C:10]1[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[Cl:23])=[C:18]([F:19])[C:13]2[N:14]=[CH:15][N:16]([CH3:17])[C:12]=2[CH:11]=1)=[O:22])=[CH2:25]
Reactant: C=COCCON
Reactant: Cn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)O)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=COCCONC(=O)c1cc2c(ncn2C)c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 90.1 %

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid 10c (2.00 g, 5.0 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (0.776 g, 7.5 mmol), HOBt (0.88 g, 6.5 mmol), triethylamine (1.61 mL, 2.3 mmol) and EDCl (1.3 g, 6.5 mmol) are dissolved in dimethylformamide (52 mL) and stirred at room temperature for 48 hours. The reaction mixture is diluted with ethyl acetate, washed with water (3×), saturated potassium carbonate (2×), saturated ammonium chloride (2×), brine, dried (Na2SO4) and concentrated under reduced pressure to an off-white solid. Trituration of the solid with diethyl ether provides 2.18 g (90%) desired product as an off-white solid. MS ESI (+) m/z 483, 485 (M+Br pattern) detected.