Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=CC(C)C)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([NH:19][CH2:14][CH2:13][CH:12]([CH3:17])[CH3:4])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CCNn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.083 g, 0.19 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.150 mL, 0.3 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 1% methanol in chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.62 Hz, 6 H) 1.44 (q, J=7.11 Hz, 2 H) 1.70 (m, 1 H) 3.03 (t, J=6.99 Hz, 2 H) 6.61 (s, 1 H) 7.43 (d, J=5.15 Hz, 1 H) 7.55 (t, J=7.54 Hz, 1 H) 7.65 (d, J=8.09 Hz, 1 H) 7.77 (t, J=7.72 Hz, 1 H) 7.92 (d, J=7.72 Hz, 1 H) 8.35 (d, J=5.52 Hz, 1 H) 14.20 (s, 1 H) 14.81 (s, 1 H). MS (ESI−) m/z 431 (M−H)−.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[C:11](OC)=[O:12].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[CH2:11][OH:12]
Reactant: COC(=O)C1Cc2ccccc2N1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1c2ccccc2CC1CO
Yield: 100.3 %

Procedure:
A procedure similar to that described in Preparation 2 was repeated, except that 8.0 g of methyl 1-methyl-indoline-2-carboxylate (prepared as described in Preparation 5), 1.91 g of lithium aluminum hydride and 250 ml of tetrahydrofuran were used, to give 6.85 g of the title compound having Rf=0.35 (on silica gel thin layer chromatography using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:37]1[S:41][C:40]([C:42]23[CH2:49][N:46]([CH2:47][CH2:48]2)[CH2:45][CH2:44][O:43]3)=[N:39][CH:38]=1)CCC>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:46]12[CH2:49][C:42]([C:40]3[S:41][C:37]([C:9]4[N:8]([S:12]([C:15]5[CH:16]=[CH:17][C:18]([CH3:19])=[CH:20][CH:21]=5)(=[O:14])=[O:13])[C:5]5=[N:6][CH:7]=[C:2]([F:1])[C:3]([C:22]6[S:26][C:25]([C:27]7([OH:31])[CH2:28][CH2:29][CH2:30]7)=[N:24][CH:23]=6)=[C:4]5[CH:10]=4)=[CH:38][N:39]=3)([CH2:48][CH2:47]1)[O:43][CH2:44][CH2:45]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(C23CCN(CCO2)C3)s1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(-c3cnc(C45CCN(CCO4)C5)s3)cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc32)cc1
Reaction time: 8 h

Procedure:
A solution of 1-(5-(5-fluoro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (150 mg, 0.263 mmol), 5-(5-(tributylstannyl)thiazol-2-yl)-4-oxa-1-azabicyclo[3.2.1]octane (192 mg, 0.395 mmol), and bis(triphenylphosphine)palladium dichloride (0.013 g, 0.025 mmol) in N,N-dimethylformamide (1.8 mL) was heated to 70° C. for 2 hours. The reaction was quenched by the addition of an aqueous potassium fluoride solution (1.0 g in 2.5 mL water) and ethyl acetate (5 mL). The mixture was stirred vigorously overnight and was then filtered through diatomaceous earth, eluting with ethyl acetate. The layers were separated, and the organic layer was washed with aqueous saturated sodium bicarbonate and water. The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used without further purification. MS ESI(+) m/z 638.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([NH:12][C:13](=O)[CH2:14][CH3:15])[CH:3]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[CH2:39]([NH2:47])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:8])[N:47]([CH2:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:13]([CH2:14][CH3:15])=[N:12]2)=[CH:9][C:10]=1[F:11]
Reactant: CCC(=O)Nc1cc(Cl)c(F)cc1C(=O)O
Reactant: NCCc1ccccc1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCc1nc2cc(Cl)c(F)cc2c(=O)n1CCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 27.3 %

Procedure:
The crude solid (3 g) from step 3 above mixed with triphenyl phosphite (4 mL, 14.81 mmol) in pyridine (15 mL) was stirred at rt for 4 h. The mixture was added with phenethylamine (1.55 mL, 12.18 mmol), irradiated with microwave 250 W to refluxing for 15 min. The mixture was diluted with ethyl acetate (50 mL), washed with water (2×50 mL). The ethyl acetated solution was mixed with water (50 mL) and kept at rt to give solid form. The solution was filtered to give yellow solid title compound (1.1 g, 27.2%). mp=150-152° C. (recrystallized from ethyl acetate); 1H NMR (400 MHz, DMSO-d6) δ 1.19 (t, J=7.2 Hz, 3H, CH3), 2.76 (q, J=7.2 Hz, 2H, CH2), 2.93 (br t, J=7.6 Hz, 2H, CH2), 4.19 (br t, J=7.6 Hz, 2H, CH2), 7.20-7.31 (m, 5H, ArH), 7.80 (d, J=6.4 Hz, 1H, ArH), 7.91 (d, J=8.8 Hz, 1H, ArH); 13C NMR (100 MHz, DMSO-d6) δ 10.6, 26.9, 33.5, 44.8, 112.2, 112.4, 119.8, 119.9, 126.6, 126.8, 127.0, 128.5, 128.7, 128.8, 138.0, 144.1, 153.6, 156.1, 158.9, 160.0; Anal. (C18H16ClFN2O) C, H, N. Calcd: 65.36, 4.88, 8.47. Found: 65.09, 4.77, 8.50.
Reaction SMILES: O1CCOC[CH2:2]1.Cl.[C:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([F:19])[CH:11]=1)#[N:9]>CO>[C:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([O:16][CH3:2])=[O:15])=[C:12]([F:19])[CH:11]=1)#[N:9]
Reactant: C1COCCO1
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(C#N)cc1F
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A 4 M hydrochloric acid dioxane solution (70.0 mL, 280 mmol) was added to a methanol (70.0 mL) solution of 4-cyano-2-fluorobenzoic acid (10.0 g, 60.6 mmol), and the mixture was stirred for one hour at 70° C. The reaction mixture was cooled to room temperature, and then the solvent was distilled off under reduced pressure. Thus, a crude product of the title compound was obtained.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl.F[B-](F)(F)F.[Ag+]>[NH:30]([CH2:2][C:3]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1ccccc1
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CC1(CNc2ccccc2)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Temperature: -10 °C
Yield: 74.7 %

Procedure:
2,2,2-Trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (1.10 g) dissolved in methylene chloride (15 ml). To this solution was added aniline (0.28 g) under cooling at -10°C and then silver fluoroborate (0.43 g), after which the mixture was stirred for 2 hours. After the reaction was completed, the reaction mixture was washed with a dilute phosphoric acid aqueous solution and then with water, dried over magnesium sulfate, after which the solvent was distilled off. The residue was subjected to column chromatography on silica gel (20 g) and eluted with chloroform. The eluate was separated into fractions of each about 20 ml. The second to seventh fractions were collected and the solvent was distilled off to give 2,2,2-trichloroethyl 2-anilinomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate (0.84 g), mp 148° to 149°C. Infrared Absorption Spectrum (CHCl3) 3400, 1780, 1765, 1680 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.O=[C:18]1[CH2:24][O:23][CH2:22][CH2:21][N:20]([CH2:25][CH2:26][CH2:27][CH:28]=O)[CH2:19]1.C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=[O:41])C.[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH2:14][CH2:15][CH3:16])[CH2:28][CH2:27][CH2:26][CH2:25][N:20]3[C:19](=[O:41])[CH2:18][CH2:24][O:23][CH2:22][CH2:21]3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CCCNC1CCc2ccc(OC)cc2C1
Reactant: O=CCCCN1CCOCC(=O)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CCCCN1CCOCCC1=O)C1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine (ca. 13 mg 50 μmole) prepared as described in Example 1, was added 440 μL solution of 4-(6-oxo-[1,4]oxazepan-4-yl)-butyraldehyde (0.125 M in 1,2 dichloroethane), 30 μL diisopropylethylamine (DIEA) and 300 μL of 0.25 M slurry of sodium triacetoxyborohydride in 1,2 dichloroethane. The reaction was shaken at room temperature for 48 h. After quenching with 2 mL 2% NaOH, the reaction mixture was transferred along with 0.5 mL water and ethyl acetate to workup flasks. The organic phase was washed, dried and concentrated. Purification by chromatography yielded 3-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazinan-2-one 18, MS: 375 ([M+H]+).
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:27]2[C:18](=[CH:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[CH:15]2.[CH3:29][Mg]Br.C([O:34][CH2:35][CH3:36])C>C1COCC1>[CH:15]1[C:16]2[C:11](=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:35]([OH:34])([CH3:36])[CH3:29])[C:27]3[C:18]([CH:17]=2)=[CH:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=3)[CH:12]=[CH:13][CH:14]=1
Reactant: C[Mg]Br
Reactant: COC(=O)c1ccccc1-c1c2ccccc2cc2cc3ccccc3cc12
Reactant: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)c1ccccc1-c1c2ccccc2cc2cc3ccccc3cc12
Yield: 81 %

Procedure:
The methyl-2-(tetracen-5-yl)benzoate (2.58 g, 7.13 mmol) was dissolved in 200 mL of THF. A 3M methyl magnesium bromide-diethyl ether solution (7.84 mL, 23.5 mmol) was added dropwise in a nitrogen atmosphere under reflux at the boiling point and the mixture was reacted for 2 hours to obtain 2-(2-(tetracen-5-yl)phenyl)propan-2-ol at a yield of 81%. The 2-(2-(tetracen-5-yl)phenyl)propan-2-ol (2.09 g, 5.78 mmol) was added to a solvent mixture containing 100 mL of acetic acid and 20 mL of 37% hydrochloric acid and the mixture was reacted for 5 hours under reflux at the boiling point to synthesize Illustrative Compound A-8 at a yield of 36%.
Reaction SMILES: [Si:1]([O:18][C:19]1[C:24]([CH3:25])=[C:23]([CH:26]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:22]([OH:42])=[C:21]([CH3:43])[C:20]=1[CH3:44])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:45](Cl)(=[O:47])[CH3:46].O>ClCCl.C(N(CC)CC)C>[C:45]([O:42][C:22]1[C:23]([CH:26]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[C:24]([CH3:25])[C:19]([O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:20]([CH3:44])[C:21]=1[CH3:43])(=[O:47])[CH3:46]
Reactant: COC(=O)CCCCCC(c1ccccc1)c1c(C)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(C)c(C)c1O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)CCCCCC(c1ccccc1)c1c(C)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(C)c(C)c1OC(C)=O
Reaction time: 2 h

Procedure:
4-tert-Butyldiphenylsilyloxy-1-hydroxy-6-(6-methoxycarbonyl-1-phenylhexyl)-2,3,5-trimethylbenzene (22.2 g, 36.46 mM) was dissolved in dichloromethane (200 ml) and triethylamine (8.3 ml, 59.9 mM). Acetyl chloride (4.1 ml, 57.7 mM) was added under ice-cooling, and the mixture was stirred for 2 hours. The reaction mixture was poured into ice-cooled water (100 ml) and stirred for 20 minutes. Then the organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to obtain 1-acetoxy-4-tert-butyldiphenylsilyloxy-6-(6-methoxycarbonyl-1-phenylhexyl)-2,3,5-trimethylbenzene as a pale yellow oil. This oil was dissolved in tetrahydrofuran (70 ml). 1M tetra-n-butylammonium fluoride trihydrate/tetrahydrofuran solution (73 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice-cooled water (150 ml) and extracted with ethyl acetate (150 ml). The organic layer was washed with water followed by saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from hexane to obtain the desired compound as pale yellow prisms (9.03 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]([OH:18])=O)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[N:19]1([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.ClCCl.CO.N>>[N:19]1([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([NH:32][C:16](=[O:18])[C:15]#[C:14][C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[CH:13][N:12]=3)=[CH:30][CH:31]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(O)C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: O=C(C#Cc1ccc(-c2ccc(Cl)cc2)cn1)Nc1ccc(CN2CCCCC2)cc1

Procedure:
Prepared analogously to Example 2.3.f. from [5-(4-chlorophenyl)pyridin-2-yl]propynoic acid and 4-piperidin-1-ylmethylphenylamine. Yield: 0.2 g (48% of theory); C26H24ClN3O (M=429.95); calc.: molecular ion peak (M+H)+: 430/432; found: molecular ion peak (M+H)+: 430/432; Rf value: 0.4 (silica gel, dichloromethane/methanol/ammonia (90:10:0.1)).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])(=[O:29])=[O:28].[CH3:38][Zn]C.C1(C)C=CC=CC=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:38])[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])(=[O:29])=[O:28]
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1cc(F)ccc1F
Reactant: C[Zn]C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2Cl)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 13.1 %

Procedure:
A solution of N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide (0.15 g, 0.26 mmol) in 1,4-dioxane (3 mL) with PdCl2(dppf) (0.047 g, 0.064 mmol) was degassed for 5 min. To this mixture was added 2.0 M dimethylzinc in toluene (0.39 mL, 0.77 mmol). The reaction mixture was heated to 80° C. After 2 h, the reaction was quenched slowly with MeOH (15 mL) and then was further diluted with DCM (50 mL), filtered through a nylon membrane and evaporated to a crude yellow residue. The residue was purified by silica gel chromatography eluting 0-100% EtOAC/hexanes, followed by 10% EtOH/EtOAc. The resulting solid was dissolved in DCM (10 mL) and hexanes (20 mL) added to afford the title compound as a yellow solid (0.02 g; 13.1% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.72 (s, 1H), 8.26 (d, J=5.6 Hz, 1H), 7.51-7.60 (m, 2H), 7.40-7.50 (m, 3H), 7.32-7.39 (m, 1H), 6.07 (d, J=5.5 Hz, 1H), 3.71 (t, J=4.8 Hz, 4H), 3.48-3.53 (m, 4H) Note: The 2-Me group is submerged under the water peak at 2.5 ppm. MS (ESI) 564.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH2:34]([O:36][C:37]1[CH:43]=[C:42]([N:44]2[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH2:46][CH2:45]2)[CH:41]=[CH:40][C:38]=1[NH2:39])[CH3:35].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:39][C:38]3[CH:40]=[CH:41][C:42]([N:44]4[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH2:46][CH2:45]4)=[CH:43][C:37]=3[O:36][CH2:34][CH3:35])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1N
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 130 °C
Yield: 67 %

Procedure:
3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (100 mg, 0.22 mmol), 2-(ethyloxy)-4-{4-[2-(methylsulfonyl)-ethyl]-1-piperazinyl}aniline (Example 143, step C) (64 mg, 0.194 mmol), and p-toluenesulfonic acid (99 mg, 0.52 mmol) were weighed into a 20 mL vial. 10 mL of iPrOH was added and the mixture was heated to 130° C. for 72 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (98 mg, 0.13 mmol, 61%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.22 (s, 1H), 9.36 (s, 1H), 8.34 (d, J=13.00 Hz, 2H), 8.21 (d, J=4.94 Hz, 1H), 8.02 (s, 1H), 7.79 (s, 1H), 7.72 (d, J=8.97 Hz, 1H), 7.59 (s, 1H), 7.36-7.48 (m, 3H), 7.19 (t, J=7.97 Hz, 2H), 6.96 (s, 1H), 6.66 (s, 1H), 6.41-6.52 (m, 2H), 4.05 (q, J=6.59 Hz, 2H), 3.30-3.37 (m, 2H), 3.07-3.14 (m, 4H), 3.02 (s, 3H), 2.74 (t, J=6.32 Hz, 2H), 2.54-2.61 (m, 4H), 1.22 (t, J=6.68 Hz, 3H). MS (ESI): 753 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:13])=[C:6]([CH:9]=[CH:10][C:11]=1[CH3:12])[CH2:7][NH2:8])([O-:3])=[O:2].[CH3:14][C:15]([CH3:20])([CH3:19])[C:16](Cl)=[O:17]>C1COCC1>[N+:1]([C:4]1[C:5]([CH3:13])=[C:6]([CH:9]=[CH:10][C:11]=1[CH3:12])[CH2:7][NH:8][C:16](=[O:17])[C:15]([CH3:20])([CH3:19])[CH3:14])([O-:3])=[O:2]
Reactant: Cc1ccc(CN)c(C)c1[N+](=O)[O-]
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: Cc1ccc(CNC(=O)C(C)(C)C)c(C)c1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
3-Nitro-2,4-dimethyl-benzylamine (1.40 g, crude) is added to a mixture of 2,2-dimethyl-propionic acid chloride (0.682 mL, 5.5 mmol) and TEA (1.92 mL, 13.8 mmol) in THF (30 mL) and it is stirred overnight. The reaction mixture is concentrated, diluted with EtOAc, washed successively with 2 M HCl-solution, 5% aq. NaHCO3 solution and water, dried with Na2SO4 filtered and concentrated.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH3:16][S:17][CH2:18][C:19]([NH:21][CH3:22])=[O:20].C(OCl)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:4](=[O:5])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:12][CH:13]=[CH:14][C:15]=1[CH:18]([S:17][CH3:16])[C:19]([NH:21][CH3:22])=[O:20]
Reactant: CNC(=O)CSC
Reactant: Nc1ccccc1C(=O)c1ccccc1
Agent: CC(C)(C)OCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)C(SC)c1cccc(C(=O)c2ccccc2)c1N
Temperature: 25 °C
Yield: 65.7 %

Procedure:
A solution of 29.6 g (0.15 mole) of 2-aminobenzophenone in 350 ml of methylene chloride was cooled to -70° C. and 17.9 g (0.15 mol) of 2-methylthio-N-methylacetamide in 20 ml of methylene chloride was added. To the (-70° C.) mixture was added dropwise a solution of 17.2 g (0.15 mole) of 95% t-butylhypochlorite in 30 ml of methylene chloride. The temperature was maintained at or below -65° C. for 1.5 hr, then 15.1 g (0.15 mole) of triethylamine was added rapidly. The solution was allowed to warm to room temperature and was washed with water. The organic solution was concentrated and the residue crystallized when mixed with isopropyl ether. The solid was recrystallized from isopropyl alcohol to give 31 g (65%) of yellow needles, m.p. 149.0°-150.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:9])[CH:3]=1.[I:10]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([NH2:8])=[C:6]([I:10])[CH:7]=1
Reactant: Cc1cc(Cl)ccc1N
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: Cc1cc(Cl)cc(I)c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.4 %

Procedure:
To a solution of 4-chloro-2-methyl-phenylamine (1 g, 7.06 mmol) in acetic acid (20 ml) was added N-iodo succinimide (2.38 g, 10.59 mmol) portion wise at 25° C. under nitrogen. The reaction mixture was stirred at 25° C. for 16 h. The volatiles were removed in vacuo and the resultant crude residue was diluted with EtOAc (40 ml). The organic layer was washed with aqueous 1N NaOH solution (2×15 ml), followed by aqueous Na2S2O3 solution (2×15 ml), and brine (20 ml). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (5-10% EtOAc in hexane) to yield 4-chloro-2-iodo-6-methyl-phenylamine (1.5 g, 79%) as brown solid. GC-MS: 267 (M).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:12][C:13]2[C:14]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-])=O)[CH:28]=3)(=[O:26])=[O:25])=[N:15][C:16]3[C:21]([N:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:6]=[C:7]([N+:9]([O-])=O)[CH:8]=1.CCO.C(O)=O.C([O-])=O.[K+]>C1COCC1>[NH2:33][C:29]1[CH:28]=[C:27]([S:24]([NH:23][C:14]2[C:13]([NH:12][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([NH2:9])[CH:6]=3)=[N:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)(=[O:26])=[O:25])[CH:32]=[CH:31][CH:30]=1
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc([N+](=O)[O-])c1
Agent: O=C[O-]
Agent: [K+]
Solvent: O=CO
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(N)cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(N)c2)c1
Temperature: 60 °C
Yield: 93.3 %

Procedure:
N-(3-(3-Methoxy-5-nitrophenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide (400 mg, 0.81 mmol), prepared as described above in Example 115, was dissolved in 1:1 THF:EtOH (4 mL), to which was added formic acid (938 μl, 2.42 mmol) and potassium formate (203 mg, 2.42 mmol). The system was flushed with nitrogen, and then 10% wt Pd/C (50 mg) was added. The reaction was then heated to 60° C. Once the reaction was determined complete by LC-MS, it was allowed to cool, and DMF was added for solubility. The solution was then filtered through a nylon fit to remove the catalyst. The filtrate was diluted water and the pH adjusted to 7 and extracted with DCM (2×) and EtOAc (2×). All organic layers were combined and evaporated to dryness to give 3-amino-N-(3-(3-amino-5-methoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide (330 mg, 93%). MS (EI) m/z for C21H20N6O3S: 437.06 (MH+)