Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([NH:8][C:9](=[O:22])[C:10]1[CH:15]=[C:14]([N:16]2[CH:20]=[N:19][N:18]=[N:17]2)[CH:13]=[C:12](I)[CH:11]=1)[CH3:7].[F:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1COCC1.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>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([NH:8][C:9]([C:10]1[CH:11]=[C:12]([C:25]2[CH:26]=[CH:27][C:28]([CH3:30])=[CH:29][C:24]=2[F:23])[CH:13]=[C:14]([N:16]2[CH:20]=[N:19][N:18]=[N:17]2)[CH:15]=1)=[O:22])[CH3:7]
Reactant: Cc1ccc(B(O)O)c(F)c1
Reactant: CC(NC(=O)c1cc(I)cc(-n2cnnn2)c1)c1ccco1
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: [Cs+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C(=O)NC(C)c3ccco3)cc(-n3cnnn3)c2)c(F)c1
Temperature: 130 °C
Yield: 99.7 %

Procedure:
A mixture of N-(1-Furan-2-yl-ethyl)-3-iodo-5-tetrazol-1-yl-benzamide (60 mg, 0.146 mmol), 2-fluoro-4-methyl-phenylboronic acid (27.1 mg, 0.176 mmol), Cs2CO3 (0.35 mL, 0.5 N, 0.176 mmol) and Pd(Ph3P)4 (8.5 mg, 0.00735 mmol) in toluene (1.5 mL) and THF (1.5 mL) was stirred under microwave heating for 30 minutes at 130° C. After reaction mixture was cooled down, the solvent was removed under vacuum and the residue was purified by column chromatography (hexane/EtOAc=1:2) to afford 2′-Fluoro-4′-methyl-5-tetrazol-1-yl-biphenyl-3-carboxylic acid (1-furan-2-yl-ethyl)-amide as a white solid (57 mg, 98%). MS (M+H)=392.
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.[CH2:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26](=O)[CH2:27]C)=[CH:22][CH:21]=1)[CH:17]([CH3:19])[CH3:18].[C:30]([O:33][C:34](=O)C)(=[O:32])C.S(=O)(=O)(O)O.COC(OC)OC>O>[CH3:34][O:33][C:30]([CH:26]([C:23]1[CH:22]=[CH:21][C:20]([CH2:16][CH:17]([CH3:18])[CH3:19])=[CH:25][CH:24]=1)[CH3:27])=[O:32]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(=O)c1ccc(CC(C)C)cc1
Agent: O=S(=O)(O)O
Solvent: Ic1ccccc1
Solvent: COC(OC)OC
Solvent: O
Product: COC(=O)C(C)c1ccc(CC(C)C)cc1
Temperature: 0 °C

Procedure:
Oven-dried iodobenzene diacetate (86.4 grams(g), 0.25 mol), which experience has shown is essentially free of water, was added with stirring to p-isobutylpropiophenone (47.5 g, 0.25 mol) at room temperature (about 22°-25° C.), which temperature was maintained throughout the procedure of this example unless indicated otherwise. To the resulting mixture was added water (approximately 15.8 g, 0.88 mol) with stirring to provide a mixture containing a known amount of water. To the resulting aqueous mixture were added sequentially, with stirring, acetic anhydride (75 ml, 0.88 mol) and, dropwise, concentrated sulfuric acid (about 96% H2SO4, 0.14 ml, 3 mmol). The resulting mixture was stirred 2 hours to ensure substantially complete reaction of the anhydride with the water and then cooled to 0° C. Trimethylorthoformate (24.6 ml, 0.225 mol) was then added with stirring, followed by dropwise addition, with stirring, of concentrated sulfuric acid (about 96% H2SO4 2.5 ml, 0.05 mol) over 30 minutes. The ensuing reaction mixture was stirred an additional 2 hours at 0° C. to 20° C. The resulting ibuprofen-methyl-ester-forming reaction was quenched by adding 50 ml deionized water. HPLC (high performance liquid chromatography) analysis of the resulting reaction product comparing to an external standard, demonstrated 75% yield of ibuprofen methylester. The mixture obtained can be separated into an aqueous phase and an organic phase, followed by isolation of purified ibuprofen methyl ester from the organic phase by column chromatography or distillation. Alternatively, the crude ester can be hydrolyzed by treating with 50% aqueous sodium hydroxide, followed by extraction of the resulting aqueous phase with heptane. Acidification of the aqueous phase and recrystallation of the solid precipitate yields high-purity ibuprofen.
Reaction SMILES: [O:1]([CH3:3])[K].CO.C1(C)C=CC=CC=1.F[C:14]1[CH:19]=[C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[CH:27]=3)[N:22]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:21]=2)[CH:17]=[CH:16][N:15]=1>>[CH3:3][O:1][C:14]1[CH:19]=[C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[CH:27]=3)[N:22]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:21]=2)[CH:17]=[CH:16][N:15]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)c(-c1ccnc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CO[K]
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc([N+](=O)[O-])cc23)ccn1
Temperature: 70 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
In a 250 ml pressure vessel, 3-(2-Fluoro-pyridin-4-yl)-5-nitro-1-trityl-1H-indazole 3BV (5.005 g, 10.0 mmole) was dissolved in 0.1N KOCH3/MeOH/Toluene (Acros, 150 mL, 15.0 mmole) under dry N2 gas. The pressure vessel was tightly sealed and heated under stirring at 70° C. for 24 hours. The pressure vessel was cooled to 0° C. in ice-bath before opening. The contents of the pressure vessel were transferred to 500 ml RBF and evaporated to dryness. The resulting solid was dissolved in CH2Cl2 and washed with saturated NaCl solution and dried over MgSO4. The solvent was evaporated to dryness and dried under high vacuum to yield 4BV as a brown solid (5.12 g, 100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]([C:11]2[N:12](COCC[Si](C)(C)C)[C:13]([CH3:31])=[C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([C:25]3[O:29][N:28]=[C:27]([CH3:30])[N:26]=3)=[CH:19]4)[N:15]=2)=[O:10])=[CH:3][CH:2]=1.Cl.C([O-])(O)=O.[Na+].[OH-].[Na+]>C(O)C.C(OCC)C.O>[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][NH:8][C:9]([C:11]2[NH:12][C:13]([CH3:31])=[C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([C:25]3[O:29][N:28]=[C:27]([CH3:30])[N:26]=3)=[CH:19]4)[N:15]=2)=[O:10])=[CH:5][CH:6]=1
Reactant: Cc1noc(-c2cc3cc(-c4nc(C(=O)NCc5ccncc5)n(COCC[Si](C)(C)C)c4C)ccc3[nH]2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: Cc1noc(-c2cc3cc(-c4nc(C(=O)NCc5ccncc5)[nH]c4C)ccc3[nH]2)n1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of 5-Methyl-4-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-indol-5-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid 4-pyridylmethyl amide (12.6 g, 19 6 mmoL) in ethanol (70 ml) is added aqueous HCl (6N 50 ml, 300 mmol). The mixture is heated at 100° C. for 7 hours. After cooling to room temperature, the resulting suspension is diluted with ice-cooled water (500 ml), basified with saturated aqueous NaHCO3 (50 ml) and aqueous sodium hydroxide (5N, 46.5 ml) to pH 7-8. Diethylether is added, (50 ml) and suspension stirred for 30 minutes. The resulting suspension is filtered and the solids are washed with water (2×50 ml), ether (2×25 ml), dried at 60° C. in vacuo for 14 hours to give a solid that is triturated with 1:1 acetonitrile-ethanol (40 ml) to give the product 5.75 g, 80%, LC/MS ESI m/z (M+H)+=414.5.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@H:30]([CH3:35])[C:31]([O:33][CH3:34])=[O:32].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][C@@H:30]([CH3:35])[C:31]([O:33][CH3:34])=[O:32])[CH3:2]
Reactant: CCc1cccc(O)c1
Reactant: COC(=O)[C@@H](C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1cccc(O[C@@H](C)C(=O)OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-ethylphenol (3.42 g, 28 mmol) in THF (20 mL) at ice bath was added triphenylphosphine (9.5 g, 36.4 mmol) and then (R)-methyl 2-hydroxypropanoate (2.94 mL, 31 mmol). And then DIAD (8.2 mL, 42 mmol) was added dropwise to the above cole solution. The mixture was stirred at room temperature for 16 hr. The solvent was removed and the residue was purified by silica gel to obtain the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:28])[CH2:14][CH2:13][N:12]([CH:15](F)[CH2:16][CH:17]([F:26])[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:29][NH:30][CH3:31].CS(C)=O>O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:28])[CH2:14][CH2:13][N:12]([CH:15]([N:30]([CH3:31])[CH3:29])[CH2:16][CH:17]([F:26])[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=C(c1ccccc1)C(F)CC(F)N1CCC(O)(c2ccc(Cl)cc2)CC1
Reactant: CNC
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: CN(C)C(CC(F)C(=O)c1ccccc1)N1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of γ-[4-(p-chlorophenyl)-4-hydroxypiperidin-1-yl]-2,4-difluorobutyrophenone hydrochloride (2.0 g), 40 % aqueous solution of dimethylamine (10.0 g) and dimethylsulfoxide (30 ml) was stirred at room temperature for 1 hour. The reaction mixture was poured into cold water (200 ml). The precipitate was filtered and recrystallized from aqueous ethanol to yield γ-[4-(p-chlorophenyl)-4-hydroxypiperidin-1-yl]-4-dimethylamino-2-fluorobutyrophenone. M.P. 160° to 163°C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6]Cl.[Cl:8][C:9]1[NH:18][C:17](=[O:19])[C:16]2[C:11](=[CH:12][C:13]([Cl:20])=[CH:14][CH:15]=2)[N:10]=1.CCN(C(C)C)C(C)C.C1COCC1>CCOC(C)=O>[Cl:8][C:9]1[N:18]=[C:17]([O:19][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:16]2[C:11](=[CH:12][C:13]([Cl:20])=[CH:14][CH:15]=2)[N:10]=1
Reactant: COCCOCCl
Reactant: O=c1[nH]c(Cl)nc2cc(Cl)ccc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COCCOCOc1nc(Cl)nc2cc(Cl)ccc12
Reaction time: 16 h
Yield: 84.6 %

Procedure:
2-methoxyethoxymethyl chloride (1.0 mL, 8.8 mmol) was added dropwise to a solution of 2,7-dichloro-4-oxoquinazoline (1.7 g, 7.8 mmol), DIEA (2.1 mL, 12 mmol), and THF (20 mL). The reaction was allowed to proceed at rt for 16 h, and then EtOAc was added (250 mL). The solution was washed with water (2×100 mL) and brine (100 mL). The organic layer was then dried and concentrated, and the resulting residue was triturated with EtOH to provide the titled compound (2.0 g, 83%). This material was used directly without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6](B(O)O)=[CH:5][N:4]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][N:16]=1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(O)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:14][C:15]1[N:16]=[CH:17][C:18]([C:6]2[C:7]([O:9][CH3:10])=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=2)=[CH:19][CH:20]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: Clc1ccc(I)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Product: COc1ncc(-c2ccc(Cl)nc2)c(OC)n1

Procedure:
2,4-Dimethoxy-pyrimidine-5-boronic acid (1.14 g, 6.26 mmol) was dissolved in degassed n-PrOH (20 ml) and then 2-chloro-5-iodopyridine (1 g, 4.2 mmol), Na2CO3 (884 mg, 15.8 mmol), PPh3 (109 mg, 0.42 mmol) and Pd(OAc)2 (46 mg) were added. The suspension was stirred at reflux for 2.5 hours. The solvent was evaporated under vacuum and the crude was partitioned between water and DCM. The organic phase was dried (Na2SO4) and evaporated to give the title compound that was used in the next step without further purification (quantitative yield).
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[C:19]1([C:25]2[N:26]=[C:27]3[N:32]=[C:31]([NH2:33])[CH:30]=[CH:29][N:28]3[CH:34]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:35]([O:37][C:38]([C:40]1[C:44]([C:45](O)=[O:46])=[CH:43][N:42]([CH3:48])[N:41]=1)=[O:39])[CH3:36].C(C(N(C(C)C)C(C)C)C)C>C(OCC)(=O)C>[CH2:35]([O:37][C:38]([C:40]1[C:44]([C:45](=[O:46])[NH:33][C:31]2[CH:30]=[CH:29][N:28]3[CH:34]=[C:25]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:26]=[C:27]3[N:32]=2)=[CH:43][N:42]([CH3:48])[N:41]=1)=[O:39])[CH3:36]
Reactant: Nc1ccn2cc(-c3ccccc3)nc2n1
Reactant: CCOC(=O)c1nn(C)cc1C(=O)O
Agent: CCC(C)N(C(C)C)C(C)C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(C)cc1C(=O)Nc1ccn2cc(-c3ccccc3)nc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
At 0° C., propylphosphonic acid anhydride (1-propanephosphonic acid cyclic anhydride, 50% in ethyl acetate, 7.4 ml, 2.5 eq.) was added slowly to a solution of 2-phenylimidazo[1,2-a]pyrimidin-7-amine (example 1, step 1, 1.27 g, 6 mmol), 1-methyl-1H-pyrazole-3,4-dicarboxylic acid 3-ethyl ester (1.00 g, 5 mmol), and ethyldiisopropylethylamine (2.0 ml, 15 mmol) in ethyl acetate (20 ml). The mixture was stirred for 30 min at 0° C., and subsequently at RT for 48 h. The mixture was taken up in ethyl acetate, and washed with water. The combined water layers were adjusted to pH=9 (NaOH), and extracted with dichloromethane. All organic layers were combined, dried (Na2SO4), and evaporated. The title compound (580 mg, 29%) was obtained from the residue by column chromatography (silica gel, heptane:ethyl acetate=100:0-80:20). (1-Methyl-1H-pyrazole-3,4-dicarboxylic acid 3-ethyl ester was obtained by the method of Pérez et al., Spanish patent appl. ES 493459.)
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]4)[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[CH3:27][C:28]1[CH2:29][C:30](=[O:33])[NH:31][N:32]=1>>[CH3:27][C:28]1[CH2:29][C:30](=[O:33])[N:31]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][N:10]3[CH2:15][CH2:14][N:13]([C:16]4[CH:25]=[CH:24][CH:23]=[C:22]5[C:17]=4[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]5)[CH2:12][CH2:11]3)[CH:3]=2)[N:32]=1
Reactant: CC1=NNC(=O)C1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(I)c4)CC3)cccc2n1
Product: CC1=NN(c2cccc(CCN3CCN(c4cccc5nc(C)ccc45)CC3)c2)C(=O)C1
Yield: 58 %

Procedure:
The title compound was prepared in 58% yield according to the general procedure for the preparation of amides, ureas and carbamates (Method A) starting from 5-{4-[2-(3-iodophenyl)ethyl]-1-piperazinyl}-2-methylquinoline and 5-methyl-2,4-dihydro-3H-pyrazol-3-one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([CH2:10][CH3:11])[C:3]=1[CH:12]=O.[OH-].[Na+].[C:16]1([CH2:22][C:23]#[N:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[NH2:24][C:23]1[C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][C:3]2[C:2](=[CH:7][C:6]([CH2:8][CH3:9])=[N:5][C:4]=2[CH2:10][CH3:11])[N:1]=1
Reactant: N#CCc1ccccc1
Reactant: CCc1cc(N)c(C=O)c(CC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc2nc(N)c(-c3ccccc3)cc2c(CC)n1

Procedure:
A mixture of 4-amino-2,6-diethylpyridine-3-carbaldehyde (2.2 g), ethanol (26 ml), aqueous sodium hydroxide solution (10% w/v; 2.2 ml) and phenylacetonitrile (3.8 ml) was heated at reflux for 2 hours. Volatile material was removed by evaporation and the residue was partitioned between ethyl acetate and 2M hydrochloric acid. The organic phase was separated and discarded. The aqueous phase was adjusted to pH 6 with solid sodium carbonate and then extracted twice with dichloromethane. The combined extracts were dried (MgSO4) and solvent was removed by evaporation to give 2-amino-5,7-diethyl-3-phenyl-1,6-naphthyridin (B) as a pale yellow solid (3.2 g); m.p. 109.5°-112° C.; NMR (d6 -DMSO): 1.27(t, 3H), 1.28(t, 3H), 2.77(q, 2H), 3.09(q, 2H), 6.41(broad, 2H), 7.05(s, 1H), 7.4-7.6(m, 5H), 7.96(s, 1H); mass spectrum (+ve FAB, methanol/NBA): 278 (M+H)+ ; microanalysis, found: C, 68.1; H, 6.5; N, 13.1%; C18H19N3.HCl.0.25H2O requires: C, 68.0; H, 6.5; N, 13.2%.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@H:12]([B:29]1[O:37]C2C(C)(C3CC(C2)C3(C)C)[O:30]1)[CH2:13][C:14]1[C:15](OC)=[C:16]([CH:24]=[CH:25][CH:26]=1)[C:17]([O:19]C(C)(C)C)=[O:18].B(Cl)(Cl)Cl>>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[C@H:12]1[CH2:13][C:14]2[CH:26]=[CH:25][CH:24]=[C:16]([C:17]([OH:19])=[O:18])[C:15]=2[O:37][B:29]1[OH:30]
Reactant: COc1c(C[C@@H](B2OC3CC4CC(C4(C)C)C3(C)O2)N2C(=O)c3ccccc3C2=O)cccc1C(=O)OC(C)(C)C
Agent: ClB(Cl)Cl
Product: O=C(O)c1cccc2c1OB(O)[C@@H](N1C(=O)c3ccccc3C1=O)C2

Procedure:
Prepared from tert-butyl 3-((2R)-2-(1,3-dioxoisoindolin-2-yl)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoate and BCl3 following the procedure described in Step 2 of Example 3. ESI-MS m/z 338 (MH)+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:30]([CH3:31])=[CH:29][C:15]2[N:16]=[C:17]([C:19]3[C:24]([CH:25]([F:27])[F:26])=[CH:23][N:22]=[C:21](Cl)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:39][N:40]1[C:48]2[C:43](=[CH:44][C:45](B(O)O)=[CH:46][CH:47]=2)[CH:42]=[N:41]1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=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>[C:1]([O:5][C@@H:6]([C:12]1[C:30]([CH3:31])=[CH:29][C:15]2[N:16]=[C:17]([C:19]3[C:24]([CH:25]([F:26])[F:27])=[CH:23][N:22]=[C:21]([C:45]4[CH:44]=[C:43]5[C:48](=[CH:47][CH:46]=4)[N:40]([CH3:39])[N:41]=[CH:42]5)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cc(Cl)ncc3C(F)F)sc2c1-c1ccc(Cl)cc1
Reactant: Cn1ncc2cc(B(O)O)ccc21
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: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cc(-c4ccc5c(cnn5C)c4)ncc3C(F)F)sc2c1-c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
A microwave vial containing (S)-ethyl 2-(tert-butoxy)-2-(2-(2-chloro-5-(difluoromethyl)pyridin-4-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)acetate (44 mg, 0.076 mmol) was charged with (1-methyl-1H-indazol-5-yl)boronic acid (26 mg, 0.15 mmol), then Pd(PPh3)4 (18 mg, 0.02 mmol). The vial was flushed with argon, diluted with dioxane (1.0 mL) and to this was added 2M aqueous K2CO3 (0.15 mL, 0.30 mmol). The vial was sealed, heated to 120° C. for 3 hours, and then allowed to cool to room temperature. The mixture was diluted with EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (10-40% EtOAc/Hex gradient) to afford the desired product. LCMS-ESI+: calc'd for C36H34ClF2N4O3S: 675.2 (M+H+); Found: 675.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][SH:7])=[CH:4][CH:3]=1.CO.Cl[C:13]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)=[CH:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16]>C[O-].[Na+].CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][S:7][C:13]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)=[CH:14][C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])=[CH:4][CH:3]=1
Reactant: SCc1ccc(Cl)cc1
Reactant: COc1ccc(C(Cl)=CC(=O)N2CCOCC2)cc1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(C(=CC(=O)N2CCOCC2)SCc2ccc(Cl)cc2)cc1OC
Temperature: 50 °C
Reaction time: 1 h

Procedure:
3.17 g (20 mmol) of 4-chlorobenzylmercaptan are dissolved in 20 ml of methanol containing 3.60 g (20 mmol) of sodium methylate (30%), warmed to 50° C. and then evaporated. A solution of 4.68 g (15 mmol) of 3-chloro-3-(3,4-dimethoxyphenyl)-1-morpholin-4-ylprop-2-en-1-one in 20 ml of dimethylformamide is added. At the end of the exothermic reaction the solution is stirred at 100° C. for 1 hour and the solvent is evaporated. The residue is shaken with toluene/water, the organic phase is washed with water, dried and the reaction product is purified by flash column (150 g of silicagel) chromatography; elution with 1000 ml of toluene containing 10 and 20% of acetone. The fractions with TLC Rf-values 0.45 and 0.38 (toluene/acetone 7:3) are collected and evaporated.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][CH:3]=1.O.[NH2:11][NH2:12]>C(O)(C)C>[F:9][C:5]1[C:6]([CH3:8])=[N:7][C:2]([NH:11][NH2:12])=[CH:3][CH:4]=1
Reactant: NN
Reactant: Cc1nc(Cl)ccc1F
Solvent: CC(C)O
Solvent: O
Product: Cc1nc(NN)ccc1F

Procedure:
To a mixture of 6-chloro-3-fluoro-2-methylpyridine (4.7 g, 32.3 mmol) in isopropanol (100 mL) was added hydrazine hydrate (5 g, 100 mmol). After the mixture was refluxed for 5 hrs, additional hydrazine hydrate (5 g, 100 mmol) was added, and the reaction was refluxed for 3 days. The mixture was then concentrated to dryness and stored under high vacuum overnight. This material was used without further purification.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1CCCCC1>[O:11]=[C:1]1[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:6])[N:12]1[CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOC(=O)C(C)N
Solvent: C1CCCCC1
Product: CCOC(=O)C(C)N1C(=O)c2ccccc2C1=O
Yield: 89 %

Procedure:
20.87 g (0.141 mol) of phthalic anhydride together with 16.5 g (0.141 mol) of ethyl aminopropionate in an open round-bottom flask at 120° C. for 5 h. 300 ml of cyclohexane are added, and the mixture is heated to reflux. The hot cyclohexane solution is decanted off from the remaining oil and completely concentrated. A slowly solidifying viscous oil is obtained (31 g, 89% yield).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)=[CH:5][NH:6]2.[NH:18]1[C:26]2[C:21](=[C:22]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([N:30]3[CH2:31][CH2:32][N:27]([C:22]4[CH:23]=[CH:24][CH:25]=[C:26]5[C:21]=4[CH:20]=[CH:19][NH:18]5)[CH2:28][CH2:29]3)[CH2:13][CH2:12]1)=[CH:5][NH:6]2
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Reactant: O=C1CCC(c2c[nH]c3cccc(F)c23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Fc1cccc2[nH]cc([C@H]3CC[C@@H](N4CCN(c5cccc6[nH]ccc56)CC4)CC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
A solution of 4-(4-fluoro-1H-indol-3-yl)-cyclohexanone (0.88 g, 3.8 mmol), 1-(indol-4-yl)piperazine (0.7 g, 3.5 mmol), sodium triacetoxyborohydride (1.1 g, 5.2 mmol) and acetic acid (0.4 ml, 7 mmol) in 1,2-dichloroethane (20 ml) was allowed to stir at room temperature overnight. The reaction was quenched with 1N sodium hydroxide (10 ml), extracted with methylene chloride (3×60 ml), and washed with brine (3×60 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (5-7% methanol-ethyl acetate) afforded 1.14 g (79%) of product as a white foam.