Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]([NH:21][CH2:22][CH2:23][OH:24])[N:18]=[C:17]([O:25][CH3:26])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:26][O:25][C:17]1[N:16]=[C:15]([NH:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[N:20]=[C:19]([NH:21][CH2:22][CH2:23][OH:24])[N:18]=1
Reactant: COc1nc(NCCO)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCO
Product: COc1nc(NCCO)nc(NC2CCNCC2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
To a stirred solution of 4-[4-(2-hydroxy-ethylamino)-6-methoxy-[1,3,5]triazin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 2.7 mmol, 1.0 equiv) in ethanol (30 mL) was added 4 M HCl in dioxane (3.40 mL, 13.6 mmol, 5.0 equiv) drop by drop. The reaction mixture was subsequently stirred at rt for 72 h and at 80° C. for 2 h. It was then cooled down to rt, poured into ice water and the pH was adjusted to 9-10 by addition of a sat. solution of potassium carbonate. The solution was extracted six times with a mixture of dichloromethane/isopropanol (4:1). The combined organic layers were concentrated by evaporation under reduced pressure to yield 0.60 g (83%) of the title compound as light yellow oil. MS (ISP): 269.2 [M+H]+.
Reaction SMILES: C(O)C.[NH2:4][C@@H:5]1[C:11](=[O:12])[N:10]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]=2[S:7][CH2:6]1.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34](=O)[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:28][CH:27]=1>[C].[Pd].C(O)(=O)C>[CH2:38]([O:37][C:35]([CH:34]([NH:4][C@@H:5]1[C:11](=[O:12])[N:10]([CH2:13][C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]=2[S:7][CH2:6]1)[CH2:33][CH2:32][C:29]1[CH:28]=[CH:27][C:26]([CH3:25])=[CH:31][CH:30]=1)=[O:36])[CH3:39]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSc2ccccc21
Reactant: CCOC(=O)C(=O)CCc1ccc(C)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(CCc1ccc(C)cc1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
A mixture of 50 ml of ethanol, 1 g of tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, 0.4 g of acetic acid, 3.6 g of ethyl 4-(p-methylphenyl)-2-oxobutyrate and 5 g of molecular sieve 4A is stirred at room temperature for 1 hour, and the mixture is subjected to catalytic reduction over 0.5 g of 5% palladium carbon, at ordinary temperature and at atmospheric pressure. After 7 hours, the catalyst is filtered off and the mixture is concentrated. The residue is treated with oxalic acid in a manner similar to that described in Example 1. The resulting oil is purified by silica gel column chromatography to give 0.3 g of tert-butyl 3(R)-[1-ethoxycarbonyl-3-(p-tolyl)propyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as colorless oil. This product is a mixture of two diastereomers (about 1:1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([OH:18])=O)[CH2:14][O:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O.FC(F)(F)C(O)=O.[NH2:51][C:52]1[S:53][CH:54]=[C:55]([C:57]2[CH:68]=[CH:67][C:60]([C:61]([NH:63][CH:64]3[CH2:66][CH2:65]3)=[O:62])=[CH:59][CH:58]=2)[N:56]=1>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16](=[O:18])[NH:51][C:52]2[S:53][CH:54]=[C:55]([C:57]3[CH:58]=[CH:59][C:60]([C:61](=[O:62])[NH:63][CH:64]4[CH2:66][CH2:65]4)=[CH:67][CH:68]=3)[N:56]=2)[CH2:14][O:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1COCN1C(=O)OCc1ccccc1
Reactant: Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Agent: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CC1)c1ccc(-c2csc(NC(=O)[C@@H]3COCN3C(=O)OCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
(S)-Oxazolidine-3,4-dicarboxylic acid 3-benzyl ester (51.3 mg, 0.20 mmol) was dissolved in DMF (1.5 mL). Triethylamine (56 μL, 0.40 mmol) and pentafluorophenyl trifluoroacetate (35 μL, 0.20 mmol) were added, and the reaction was allowed to stir at ambient temperature for 25 minutes. Then 4-(2-Amino-thiazol-4-yl)-N-cyclopropyl-benzamide trifluoroacetic acid salt (148.8 mg, 0.40 mmol) was added, and the reaction was stirred at ambient temperature overnight. The reaction was filtered and purified by reverse phase HPLC to give the desired product. Yield 10.2 mg. MS: 493.1 (M+H+); H1 NMR (DMSO-d6): δ(ppm) 0.52-0.74 (m, 4H), 4.05-4.37 (m, 2H), 4.58-4.69 (m, 1H), 4.90-5.17 (m, 4H), 7.00-7.45 (m, 4H), 7.72-7.98 (m, 5H), 8.37-8.48 (m, 1H), 12.48-12.51 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[NH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C.Cl>CN(C=O)C>[CH:20]1([CH2:19][NH:18][C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][C:3]=2[N+:15]([O-:17])=[O:16])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NCC1CCCCC1
Reactant: O=[N+]([O-])c1cc(Oc2ccccc2)ccc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Oc2ccccc2)ccc1NCC1CCCCC1
Yield: 65.3 %

Procedure:
A solution of 1-chloro-2-nitro-4-phenoxy-benzene (0.60 g, 2.58 mmol), (aminomethyl)cyclohexane (1.0 mL, 7.76 mmol) and N,N′-diisopropylethylamine (1.36, 7.76 mmol) in DMF (20.00 mL) was stirred at 100° C. under an inert atmosphere for 18.5 h. The reaction mixture was transferred to a separatory funnel containing HCl (2.0 N). The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water, brine and dried over MgSO4. The solution was filtered through diatomaceous earth and the solvent was evaporated. The resulting dark red residue was flash chromatographed (10% EtOAc/hexane) to give cyclohexylmethyl-(2-nitro-4-phenoxy-phenyl)-amine as a dark red solid (0.55 g, 65.6% yield).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.[CH2:20]1[C:23]2([CH2:26][NH:25][CH2:24]2)[CH2:22][O:21]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:25]3[CH2:26][C:23]4([CH2:20][O:21][CH2:22]4)[CH2:24]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:2][CH2:3]1
Reactant: C1NCC12COC2
Reactant: O=C(O)c1ccc(N2CCCC2)c(OCC2CC2)n1
Product: O=C(c1ccc(N2CCCC2)c(OCC2CC2)n1)N1CC2(COC2)C1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid (Example 14 a) and 2-oxa-6-azaspiro[3.3]heptane (CAN 174-78-7) as starting materials, MS (EI): m/e=344.3 [M+H]+.
Reaction SMILES: Br[C:2]([CH3:12])=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[CH3:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.[CH3:29][N:30]1[CH2:43][CH2:42][C:33]2[NH:34][C:35]3[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][C:40]=3[C:32]=2[CH2:31]1>CN(C=O)C.[Cu]I>[F:11][C:8]1[CH:9]=[CH:10][C:5](/[C:3](/[CH3:4])=[C:2](/[N:34]2[C:35]3[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][C:40]=3[C:32]3[CH2:31][N:30]([CH3:29])[CH2:43][CH2:42][C:33]2=3)\[CH3:12])=[CH:6][CH:7]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC(Br)=C(C)c1ccc(F)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C(/C)n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(F)cc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
1-(3-Bromobut-2-en-2-yl)-4-fluorobenzene (250 mg, 1.2 mmol) was dissolved in DMF (5 mL). potassium phosphate (424 mg, 2 mmol) was added followed by copper (I) iodide (19 mg, 0.1 mmol) and L-proline (23 mg, 0.2 mmol). 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was added and nitrogen gas was purged into the reaction mixture for 2 min. The contents were stirred at 85° C. overnight. Water (5 mL) was added and the solid mass was filtered under vacuum to obtain crude compound which was purified on silica gel (100-200 mesh) using 0-3% MeOH:DCM as eluent. The compound was further purified through reverse phase chromatography. Yield: 6 mg. 1H NMR (CD3OD, HCl salt) δ (ppm): 7.42 (m, 2H), 7.30 (s, 1H), 7.20 (m, 3H), 7.10 (d, 1H), 4.70 (d, 1H), 4.40 (d, 1H), 3.90 (m, 1H), 3.62 (m, 1H), 3.25 (m, 1H), 3.16 (s, 3H), 3.10 (m, 1H), 2.42 (s, 3H), 1.94 (d, 3H), 1.64 (d, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[O:11][CH3:12].Cl[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([S:30]([NH:33][C:34]4[CH:39]=[CH:38][N:37]=[CH:36][N:35]=4)(=[O:32])=[O:31])=[CH:27][CH:28]=3)[CH:23]=[CH:22][N:21]=2)=[C:16]([O:40][CH3:41])[CH:15]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:29]4[C:24](=[CH:25][C:26]([S:30]([NH:33][C:34]5[CH:39]=[CH:38][N:37]=[CH:36][N:35]=5)(=[O:31])=[O:32])=[CH:27][CH:28]=4)[CH:23]=[CH:22][N:21]=3)=[C:16]([O:40][CH3:41])[CH:15]=2)=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(B(O)O)ccc1F
Reactant: COc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2ccc(-c3nccc4cc(S(=O)(=O)Nc5ccncn5)ccc34)c(OC)c2)ccc1F
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 16.5 %

Procedure:
A microwave vial charged with PdCl2(Amphos)2 (0.025 g, 0.035 mmol), 4-fluoro-3-methoxyphenylboronic acid (0.119 g, 0.703 mmol), 1-(4-chloro-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (0.150 g, 0.351 mmol), potassium phosphate (0.298 g, 1.406 mmol), 1.5 mL dioxane, and 0.5 mL water was heated to 150° C. in the microwave for 40 minutes. LC/MS showed product, so the aqueous layer was removed. The reaction mixture was treated with excess HCl (4N in dioxane) and was allowed to stir for 10 minutes. The reaction mixture was then concentrated. Purification of the crude residue by reverse phase column chromatography [Puriflash C18, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 1-(4′-fluoro-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (0.030 g, 0.058 mmol, 16.5%). 1H NMR (MeCN-d3) δ: 8.69 (d, J=5.7 Hz, 1H), 8.62 (s, 1H), 8.48 (s, 1H), 8.20 (d, J=6.4 Hz, 1H), 7.89-7.98 (m, 2H), 7.80 (d, J=9.0 Hz, 1H), 7.34-7.47 (m, 4H), 7.19-7.33 (m, 2H), 7.06 (d, J=6.3 Hz, 1H), 3.98 (s, 3H), 3.71-3.75 (m, 3H) (M+H)+=517.1.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[CH:15]=[N:16][CH:17]=[N:18][CH:19]=3)[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[S:27]1[CH:31]=[C:30]([CH:32]=O)[N:29]=[CH:28]1.C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([BH3-])#N.[Na+]>ClCCCl.C1COCC1.ClCCl.C(=O)(O)[O-].[Na+]>[C:21]1([CH2:20][C@H:2]([NH:1][CH2:32][C:30]2[N:29]=[CH:28][S:27][CH:31]=2)[C:3]([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:14]4[CH:19]=[N:18][CH:17]=[N:16][CH:15]=4)[CH:12]=3)[CH2:7][CH2:6]2)=[O:4])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1cscn1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCc2ccc(-c3cncnc3)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C([C@H](Cc1ccccc1)NCc1cscn1)N1CCc2ccc(-c3cncnc3)cc21
Temperature: 70 °C
Reaction time: 3 h
Yield: 34.2 %

Procedure:
The (S)-2-amino-3-phenyl-1-(6-(pyrimidin-5-yl)indolin-1-yl)propan-1-one (39.0 mg, 110 μmol) was dissolved in a DCE/THF mixture 1.5 mL. Thiazole-4-carbaldehyde (13 mg, 110 μmol), diisopropylethyl amine (20 μl, 110 μmol), and sodium triacetoxyborohydride (48 mg, 230 μmol) was added to the reaction mixture. The resulting solution was heated to 70° C. and stirred for three hours. LCMS indicated starting material was still present. 24 mg of sodium cyanoborohydride was added and the solution was stirred at 70° C. overnight to completion. The reaction mixture was diluted with dichloromethane and basified with saturated sodium bicarbonate. The layers were separated and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was then purified on an SCX column eluting with 0 to 2M ammonia in methanol solution to give impure product. This material was then purified by medium pressure chromatography (silica gel, 0 to 6.5% 2M ammonia in methanol: dichloromethane) to give the desired product (S)-3-phenyl-1-(6-(pyrimidin-5-yl)indolin-1-yl)-2-(thiazol-4-ylmethylamino)propan-1-one (16.6 mg, 33% yield). MS ESI (pos.) m/e: 442.1 (M+H).
Reaction SMILES: Br[C:2]1[N:3]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][C@H:12]1[CH3:17])[N:7]=[C:6]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][C@H:19]1[CH3:24])[N:5]=2.C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)CCC>C1(C)C=CC=CC=1.CCOC(C)=O.[Cl-].[Na+].O.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>[CH3:24][C@@H:19]1[CH2:20][O:21][CH2:22][CH2:23][N:18]1[C:6]1[N:5]=[C:4]2[C:9]([N:10]=[C:2]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[N:3]2[CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@H:12]2[CH3:17])[N:7]=1
Reactant: C[C@@H]1COCCN1c1nc(N2CCOC[C@H]2C)c2nc(Br)n(C3CCCCO3)c2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H]1COCCN1c1nc(N2CCOC[C@H]2C)c2nc(-c3ccccn3)n(C3CCCCO3)c2n1
Temperature: 120 °C
Reaction time: 3 h
Yield: 87.9 %

Procedure:
8-Bromo-2,6-bis-((R)-3-methyl-morpholin-4-yl)-9-(tetrahydro-pyran-2-yl)-9H-purine (40 mg, 83 μmol) was dissolved in 2 mL of toluene under argon in a microwave vial, and 2-(tributylstannyl)-pyridine (36 mg, 83 μmol) and Pd(PPh3)4 (4.8 mg, 4.2 μmol) were added. The microwave vial was capped, and the reaction mixture was stirred for 3 hours at 120° C. The vial was cooled to room temperature and opened. The mixture was diluted with EtOAc (20 mL) and brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (12 g SiO2, heptane/TBME in a gradient from 4/1 to 2/3) to give the product as a solid (35 mg, 88%).
Reaction SMILES: O.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:9]1[CH:10]=[CH:11][C:12](=[O:30])[N:13]([CH2:15][CH2:16][O:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)[N:14]=1.[S:31]1[C:35](B(O)O)=[CH:34][C:33]2[CH:39]=[CH:40][CH:41]=[CH:42][C:32]1=2>COCCOC.O.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].C(Cl)Cl>[S:31]1[C:35]([C:9]2[CH:10]=[CH:11][C:12](=[O:30])[N:13]([CH2:15][CH2:16][O:17][C:18]3[C:27]4[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=4)[N:21]=[CH:20][CH:19]=3)[N:14]=2)=[CH:34][C:33]2[CH:39]=[CH:40][CH:41]=[CH:42][C:32]1=2
Reactant: COc1ccc2c(OCCn3nc(Cl)ccc3=O)ccnc2c1
Reactant: OB(O)c1cc2ccccc2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: COc1ccc2c(OCCn3nc(-c4cc5ccccc5s4)ccc3=O)ccnc2c1
Temperature: 80 °C
Yield: 56.2 %

Procedure:
A mixture of sodium carbonate hydrate (250 mg, 2016 μmol), PdCl2(dppf)-CH2Cl2 adduct (30 mg, 37 μmol), 6-chloro-2-(2-(7-methoxyquinolin-4-yloxy)ethyl)pyridazin-3(2 H)-one (220 mg, 663 μmol), and benzo[b]thiophen-2-ylboronic acid (290 mg, 1629 μmol) in DME (5 mL) and H2O (2 mL) was heated to 80° C. under nitrogen for 18 h. The mixture was cooled to room temperature and partitioned between EtOAc (50 mL) and H2O (20 mL). The organic phase was washed with H2O (2×), NH4Cl (aq), dried over Na2SO4, and concentrated to a brown solid. The solid was triturated with hot hexane-EtOAc-MeOH (2:1:0.1) twice and the solid was further washed with MeOH in EtOAc (1%), CH2Cl2 (de-colorization), and ether to give the product as an off-white solid (160 mg). MS (ESI pos. ion) calc'd for C24H19N3O3S: 429.11; found 430.2 (MH+). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.65 (s, 3 H) 5.46 (s, 4 H) 7.76 (d, J=4.11 Hz, 1 H) 7.81 (d, J=9.19 Hz, 1 H) 7.95 (d, J=9.39 Hz, 1 H) 8.08 (s, 1 H) 8.24 (d, J=3.33 Hz, 2 H) 8.67 (d, J=5.09 Hz, 1 H) 8.81 (d, J=8.41 Hz, 2 H) 8.88 (s, 1 H) 9.00 (d, J=9.78 Hz, 1 H) 9.44 (d, J=4.30 Hz, 1 H)
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[C:22]1(=[O:28])[CH2:26][CH2:25][C:24](=[O:27])[CH2:23]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl[C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[F:44][C:41]1[CH:42]=[CH:43][C:38]([CH:23]2[C:24](=[O:27])[CH2:25][CH2:26][C:22]2=[O:28])=[CH:39][CH:40]=1
Reactant: Fc1ccc(Cl)cc1
Reactant: O=C1CCC(=O)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1COCCO1
Product: O=C1CCC(=O)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The title compound was also prepared as follows. To a 100 L flask was charged sequentially 113.3 g (0.50 mol) of Pd(OAc)2, 331.4 g (1.11 mol) of 2-(di-t-butylphosphino)biphenyl, 2.476 kg (25.24 mol) of 1,3-cyclopentanedione, and 10.72 kg (50.5 mol) of powdered K3PO4. The resulting mixture was degassed (3×) by vacuum/N2 back fills. The vessel was then charged with 26 L of 1,4-dioxane and 4.28 kg (32.78 mol) of 1-chloro-4-fluorbenzene and the vessel degassed (3×) with vacuum/N2 back fills. The resulting slurry was heated to reflux for 12 h, cooled to rt, and water (23 L) was added. The vessel was rinsed with an additional 6 L of water and the reaction mixture further diluted with an additional 46 L of water. To the homogeneous solution was added 9 L of conc. HCl to adjust the pH to 1 and the solution aged for 2.5 h. The slurry was then filtered and the cake washed with 17 L of water and 17 L of toluene. The solid was then dried at 60° C. for 48 h, providing 2-(4-fluoro -phenyl)-1,3-cyclopentanedione as a light tan solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH2:9]([CH:11]([NH2:14])[CH2:12][CH3:13])[CH3:10]>CCO>[CH3:10][CH2:9][CH:11]([NH:14][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1)[CH2:12][CH3:13]
Reactant: Clc1cncc(Cl)n1
Reactant: CCC(N)CC
Solvent: CCO
Product: CCC(CC)Nc1cncc(Cl)n1

Procedure:
A solution of 2,6-dichloropyrazine (2.2 g) and 1-ethylpropylamine (5 mL) in EtOH (10 mL) is heated at 140° C. in a Teflon-sealed tube. Resulting solution is concentrated in vacuo, diluted by water, and extracted twice with hexane-ethyl ether. Combined extracts are dried (sodium sulfate), filtered, concentrated in vacuo, and the residue is filtered through a short pad of silica gel. The filtrate is concentrated to give 2-(3-pentylamino)-6-chloropyrazine as brownish oil that solidifies on standing (3.0 g).
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[CH3:31][N:32]1[C:40]2[C:35](=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:37]=[CH:38][CH:39]=2)[CH:34]=[N:33]1>>[CH3:31][N:32]1[C:40]2[C:35](=[C:36]([C:18]3[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=3)[CH:37]=[CH:38][CH:39]=2)[CH:34]=[N:33]1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: Cn1ncc2c(B3OC(C)(C)C(C)(C)O3)cccc21
Product: Cn1ncc2c(C3=COCCN3C(=O)OC(C)(C)C)cccc21
Yield: 45 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as a brown solid (45% yield); 1H-NMR (d6-DMSO) 0.80 (9H, s), 3.81 (2H, m), 4.02 (3H, s), 4.18 (2H, m), 6.50 (1H, s), 6.94 (1H, d), 7.31 (1H, t), 7.47 (1H, m), 7.90 (1H, s); 13C-NMR (CDCl3) 27.4, 35.4, 41.3, 66.8, 107.0, 116.5, 126.2, 131.8; MS ES(+) 316.0 (M++1); HRMS m/z calcd for C17H21N3O3+H+ 316.1661 [M+H+]. Found 316.1664. IR λmax=1692, 1638 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[CH3:22][C:23](=O)CC(=O)C.C([O-])(O)=O.[Na+]>C(O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]([NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:6]([F:12])[C:7]2[N:11]=[C:22]([CH3:23])[NH:10][C:8]=2[CH:9]=1)=[O:20]
Reactant: CC(=O)CC(C)=O
Reactant: COC(=O)c1cc(N)c(N)c(F)c1Nc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1cc2[nH]c(C)nc2c(F)c1Nc1ccccc1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
4,5-Diamino-3-fluoro-2-phenylamino-benzoic acid methyl ester 6c (0.20 g, 0.73 mmol) is suspended in ethanol (3 mL) and 5 M aqueous HCl (1 mL., 5.00 mmol) is added. The reaction mixture is brought to reflux under N2 and then 2,4-pentanedione (0.150 mL, 1.45 mmol) is added. The reaction mixture is stirred at reflux for 60 minutes. The reaction mixture is cooled to room temperature and treated with saturated aqueous NaHCO3 until the pH of the reaction mixture is pH 7 and is then concentrated under reduced pressure to dryness. The residue is diluted with ethyl acetate and water, poured into a separatory funnel and the layers separated. The ethyl acetate layer is washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The red solid residue is triturated with diethyl ether to yield a light brown solid and a red filtrate. The solid is collected and washed with diethyl ether to yield 0.20 g (91%) of the pure desired product as a light brown solid. MS ESI (+) m/z 300 (M+1) detected.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:15]=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:18][C:19]=1[F:20].CC(C)=O.[C:29](=[O:31])=[O:30].C(=O)=O.Cl.CC1CCCCC1>C1COCC1>[Cl:13][C:14]1[C:19]([F:20])=[C:18]([CH:17]=[C:16]([C:21]([F:24])([F:22])[F:23])[CH:15]=1)[C:29]([OH:31])=[O:30]
Reactant: O=C=O
Reactant: Fc1ccc(C(F)(F)F)cc1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: CC1CCCCC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cc(C(F)(F)F)cc(Cl)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a solution of diisopropyl amine (19.79 ml, 140 mmol, 1.4 equiv.) in 100 ml THF was added at −78° C. n-BuLi (1.6 M in hexane, 81.25 ml, 130 mmol, 1.3 equiv.) within 25 min, the light yellow solution was stirred for 30 min at −78° C. and a solution of 3-chloro-4-fluoro benzotrifluoride (19.86 g, 100 mmol, 1 equiv.) in 100 ml of THF was added dropwise within 25 min keeping the temperature between −73 and −76° C. The resulting yellow solution was stirred for 1 h at −78° C., transferred into an addition funnel which was cooled with an acetone/dry ice mixture and added to a cold (−78° C.) mixture of CO2 (44.0 g, 1000 mmol, 10 equiv.) in 100 ml of THF within 1 h keeping the temperature between −75 and −78° C. Afterwards the reaction mixture was transferred into an addition funnel and added to a solution of HCl (aq., 2M, 163 ml) within 15 min at −4° C., stirred for 15 min and transferred into a separation funnel. After separation of the phases, the aqueous phase was extracted with TBME (300 ml), the combined organic phases were dried over sodium sulfate (370 g), filtered with suction on funnel with a fritted disk, washed with TBME (100 ml in total) and the TBME was removed under vacuum to yield a light yellow solid (23.48 g of crude product, 96.8% yield). The crude product was treated with methyl cyclohexane (117 ml) and heated in a pre-heated oil bath to reflux. After 5 min, a brown clear solution was obtained, the oil bath was removed, the reaction mixture was cooled to ambient temperature, seeding crystals (2 mg) were added and the mixture was stirred overnight at ambient temperature. After 17 h the off-white suspension was stirred in an ice bath (0-5° C.) for two hours, the obtained crystals were filtered off, the crystals were washed with cold methyl cyclohexane (39 ml) and the crystals were dried until weight constancy to yield the product as white crystals (18.75 g, 77.3% yield).