Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22].[CH3:24][C:25]([CH3:27])=O>>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([O:8][CH2:27][CH:25]=[CH2:24])[CH:7]=1)[CH:21]=[CH2:22]
Reactant: COC(=O)Cc1cc(O)cc(O)c1
Reactant: CC(C)=O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1cc(CC(=O)OC)cc(OCC=C)c1
Reaction time: 8 h
Yield: 93 %

Procedure:
Methyl 3,5-dihydroxyphenylacetate (30 g, 0.17 mol) was dissolved in acetone (0.50 L), and potassium carbonate (91 g, 0.66 mol) and allyl bromide (0.11 L, 1.3 mol) were added thereto at room temperature. The mixture was stirred for 8 hours under heating and reflux, and then stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/15-1/3) to obtain methyl 3,5-diallyloxyphenylacetate (40 g, 93%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Br.[Br:42][CH2:43][CH2:44][NH2:45]>ClCCl.O>[Br:42][CH2:43][CH2:44][NH:45][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: NCCBr
Reactant: O=C(O)c1ccccn1
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCBr)c1ccccn1
Reaction time: 0.17 h
Yield: 52.5 %

Procedure:
Picolinic acid (0.99 g) in dichloromethane (30 mL) was treated with triethylamine (1.27 mL) and HATU (3.6 g). The mixture was stirred for 10 minutes then a solution of 2-bromoethylamine hydrobromide (1.5 g) and triethylamine (1.27 mL) in dichloromethane (20 mL) was added. The reaction mixture was stirred for 3h. Water (50 mL) was added and the layers were separated. The organic layer was washed with water (3×50 mL), dried over magnesium sulphate and evaporated to afford the crude product which was purified by silica gel chromatography eluting with 0-100% EtOAc/dichloromethane. The relevant fractions were combined and evaporated, dissolved up in EtOAc (40 mL) and washed with saturated sodium hydrogen carbonate solution, ensuring the aqueous layer remained basic. The organic layer was dried over magnesium sulphate and evaporated to give the sub-titled compound (0.88 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][C:12](Br)=[CH:13][C:14]=3[C:15]=1[F:16])=[CH:7][CH:6]=[C:5]([CH2:18][CH2:19][CH2:20][CH3:21])[CH:4]=2.[CH2:22]([O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>[Pd]>[CH2:22]([O:32][C:33]1[CH:34]=[CH:35][C:36]([C:12]2[CH:11]=[CH:10][C:9]3[C:8]4[C:3](=[CH:4][C:5]([CH2:18][CH2:19][CH2:20][CH3:21])=[CH:6][CH:7]=4)[C:2]([F:1])=[C:15]([F:16])[C:14]=3[CH:13]=2)=[CH:37][CH:38]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCOc1ccc(B(O)O)cc1
Reactant: CCCCc1ccc2c(c1)c(F)c(F)c1cc(Br)ccc12
Agent: [Pd]
Product: CCCCCCCCCCOc1ccc(-c2ccc3c(c2)c(F)c(F)c2cc(CCCC)ccc23)cc1

Procedure:
From 9,1 0-difluoro-2-bromo-7-butylphenanthrene and 4-decyloxyphenyl-boronic acid by means of palladium-catalyzed Suzuki coupling (in analogy to Acc. Chem. Res. 1982, 15, 178). The crude product is purified by column chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7](=[O:12])[NH:8][S:9](=[O:11])(=[O:10])[C:5]=2[CH:4]=1.[H-].[Na+].Cl[CH2:18][C:19](=[O:21])[CH3:20]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7](=[O:12])[N:8]([CH2:18][C:19](=[O:21])[CH3:20])[S:9](=[O:11])(=[O:10])[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)S(=O)(=O)NC2=O
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)S(=O)(=O)N(CC(C)=O)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
360 mg of 6-methoxy-1,1-dioxo-1,2-dihydro-benzo[d]isothiazol-3-one are added in small portions to a suspension of 72 mg of 60% NaH in mineral oil in 1.6 ml of anhydrous dimethylformamide. After stirring for 30 min. at ambient temperature, the reaction mixture becomes homogeneous and 162 μl of chloroacetone are added thereto. The reaction mixture is heated at 110° C. for 30 min. It is allowed to return to ambient temperature, and then the mixture is precipitated by addition of water. The precipitate is filtered off, rinsed several times with water, suction-filtered off and dried in vacuo.
Reaction SMILES: C[C:2]1[C:3](C)=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[C:12]#[C:13]CO.[OH-].[Na+].C1(C)C=CC=CC=1>C(OCC)C>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[C:12]#[CH:13])[CH:11]=[CH:2][CH:3]=1
Reactant: Cc1cc2cccc(C#CCO)c2nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C#Cc1cccc2cccnc12
Temperature: 120 °C
Yield: 80 %

Procedure:
8.5 g (40 mmol) of Dimethylhydroxymethyl-8-quinolylacetylene and 1. g (45 mmol) of sodium hydroxide (manufactured by KISHIDA CHEMICAL CO., Ltd., 0.7 mm granular, 98%) were placed in a 300 mL two-neck flask equipped with a reflux condenser and the air inside the flask was replaced with argon gas. 200 mL of toluene was added thereto and the mixture was refluxed at 120° C. for 0.5 hours. Diethyl ether was added to the reaction mixture, the mixture was washed with a saturated aqueous ammonium chloride solution and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure by an evaporator. Hexane (250 ml) was added to the residue and the mixture was heated to 70° C. After filtering out the insolubles, the desired compound precipitated by cooling it to −78° C. was filtered and washed with cold hexane (−78° C., 100 ml) and then dried under reduced pressure to give 4.9 g of the desired compound as a yellowish white solid (yield: 80%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[N:16]1([C:26]2[C:27](=O)[NH:28][C:29]3[C:34]([N:35]=2)=[CH:33][C:32]([C:36]([O:38][CH3:39])=[O:37])=[CH:31][CH:30]=3)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1.N1C=CC=CC=1>ClCCl>[N:16]1([C:26]2[C:27]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[N:28][C:29]3[C:34]([N:35]=2)=[CH:33][C:32]([C:36]([O:38][CH3:39])=[O:37])=[CH:31][CH:30]=3)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4ccccc43)nc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCc4ccccc43)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoromethanesulfonic anhydride (315.6 mg, 1.12 mmol) was added to a solution of methyl 3-(3, 4-dihydroquinolin-1(2H)-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (200.0 mg, crude) and pyridine (176.8 mg, 2.24 mmol) in dichloromethane (50 ml). After stirring overnight at room temperature, the reaction was quenched with water (50 ml) and extracted with dichloromethane (3×80 ml). Then the organic layers were combined dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford methyl 3-(3,4-dihydroquinolin-1(2H)-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (300 mg, crude), which was used directly in the next step.
Reaction SMILES: C([O:3][C:4](=[O:43])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C@H:15]2[C@H:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[F:27])[C@:18]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[F:37])([C:28]#[N:29])[C@H:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]2)=[O:14])=[N:7][CH:6]=1)C.O.[OH-].[Li+]>C1COCC1.O>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C@@:18]2([C:28]#[N:29])[C@H:17]([CH2:38][C:39]([CH3:41])([CH3:40])[CH3:42])[NH:16][C@@H:15]([C:13]([NH:12][CH2:11][C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:43])=[O:3])=[CH:6][N:7]=3)=[O:14])[C@@H:19]2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=2[F:27])=[C:31]([F:37])[CH:32]=1
Reactant: CCOC(=O)c1ccc(CNC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NCc2ccc(C(=O)O)cn2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Yield: 101.3 %

Procedure:
In a manner similar to the method described in Example 380, chiral 6-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-nicotinic acid ethyl ester (73.8 mg, 0.117 mmol) in THF (8 ml) was combined with lithium hydroxide hydrate (35.9 mg, 0.855 mmol) in water (4 mL). It was stirred at room temperature to give chiral 6-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-nicotinic acid as a white lyophilized solid (71.3 mg, 100%). HRMS (ES+) m/z Calcd C30H28Cl2F2N4O3+H [(M+H): 601.1580. Found: 601.1581.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[CH3:10][O:11][CH2:12][C:13]([O:15]C)=O>C1COCC1.C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=2)([OH:15])[CH2:12][O:11][CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc([Mg]Br)c1
Reactant: COCC(=O)OC
Solvent: C1CCOC1
Solvent: O=CO
Product: COCC(O)(c1cccc(Cl)c1)c1cccc(Cl)c1

Procedure:
A solution of 1,1-bis(3-chlorophenyl)-2-methoxyethanol (47 g) (obtained by the reaction of 3-chlorophenylmagnesium bromide with methyl 2-methoxyacetate in THF) in formic acid (44 cc) is heated to reflux for 5 hours, cooled and poured into a mixture of saturated sodium carbonate solution (500 cc) and ethyl acetate (300 cc). The organic phase is washed with water (3×250 cc) and with saturated sodium chloride solution (200 cc), then dried and concentrated to dryness under reduced pressure (2.7 kPa) to give bis(3-chlorophenyl)acetaldehyde (36.9 g) in the form of a yellow oil.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@H:10]1[C:11]([O:13]CC1C=CC=CC=1)=[O:12])=[O:8]>[Pd].CO>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: O=C1CC[C@@H](C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)N1
Agent: [Pd]
Solvent: CO
Product: O=C1CC[C@@H](C(=O)N2CCC[C@H]2C(=O)O)N1
Temperature: 23 °C
Reaction time: 4.5 h
Yield: 65.4 %

Procedure:
A solution of F2 (8.63 g, 31.34 mmol) and palladium on activated charcoal (10%, 86 mg, 10% w/w) in degassed MeOH (125 mL) was placed in a high pressure Parr reactor and purged with nitrogen gas (2×30 psi). The reaction mixture was sealed under hydrogen (30 psi) and stirred at 23° C. for 4.5 h. The mixture was filtered through a 0.45 □m teflon filter and concentrated at reduced pressure. The residue (6.29 g) was coated in SiO2 and loaded onto the top of a column (LC 5.5×10.0 cm) and eluted with hex:EtOAc 1:2 to yield F1 (4.64 g, 80%) as a white solid. Rf=0.22 (hex:EtOAc 1:1). [α]D20 −92.4 (c 0.12, CHCl3). M.p. 67-69° C.
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C@@H:19]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)=[O:24])[CH2:18][C@@H:17]1[C:34](O)=[O:35])=[O:15])([CH3:12])([CH3:11])[CH3:10].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][C:34]([C@H:17]1[CH2:18][C@H:19]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)=[O:24])[CH2:20][CH2:21][N:16]1[C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])=[O:35]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)Nc2ccc(C#N)cc2)C[C@@H]1C(=O)O
Reactant: Nc1ccccc1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)Nc2ccc(C#N)cc2)C[C@@H]1C(=O)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
Benzene-1,2-diamine (365 mg, 3.38 mmol) was added to a mixture of (2R,4R)-1-(tert-butoxycarbonyl)-4-(3-(4-cyanophenyl)ureido)piperidine-2-carboxylic acid (1400 mg, 3.60 mmol), BOP (1600 mg, 3.6 mmol) and DIEA (1.2 mL, 6.9 mmol) in DMF (20 mL), and the resulting solution was stirred at room temperature for 8 hours. Water (100 mL) was added to the reaction mixture and it was then extracted with ethyl acetate (2×200 mL). The organic layers were dried over MgSO4 and concentrated to give a red solid. Further purification by Companion (ReadySep, 80 g, silica gel packed) using ethyl acetate/heptane from 50-80% as eluent provided the title compound as a white solid 1600 mg (93%). LC-MS: 479.1, 477.2 (t=2.3 min).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([S:17][CH2:18][CH2:19][CH3:20])=[C:15]([C:21]([O:23]C(C)(C)C)=[O:22])[CH:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:16]([S:17][CH2:18][CH2:19][CH3:20])=[C:15]([C:21]([OH:23])=[O:22])[CH:14]=[N:13]2)=[CH:10][CH:11]=1)=[O:4]
Reactant: CCCSc1c(C(=O)OC(C)(C)C)cnn1-c1ccc(CC(=O)OC)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCSc1c(C(=O)O)cnn1-c1ccc(CC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
tert-butyl 1-[4-(methoxycarbonylmethyl)phenyl]-5-propylsulfanyl-pyrazole-4-carboxylate (Intermediate #36) was dissolved in DCM (10 mL). TFA (2 mL) was added and the mixture was stirred at ambient temperature for 5 h. Volatiles were then evaporated under reduced pressure and the residue dried under vacuum to afford 1-[4-(methoxycarbonylmethyl)phenyl]-5-propylsulfanyl-pyrazole-4-carboxylic acid as a light brown oil. (440 mg, 98%)
Reaction SMILES: NC1N=[C:7]([C:9]2C(OC)=CC(C)=C[C:10]=2[O:18]C)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2N(C)C1=O.C([NH:33][C@@H](C(O)=O)CC1C=CC=CC=1)(OC(C)(C)C)=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.O>[C:6]1([CH2:7][CH2:9][C:10]([NH2:33])=[O:18])[CH:20]=[CH:21][CH:22]=[CH:23][CH:5]=1
Reactant: COc1cc(C)cc(OC)c1C1=NC(N)C(=O)N(C)c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)CCc1ccccc1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
1.73 g of 3-amino-1,3-dihydro-5-(2,6-dimethoxy-4-methylphenyl)-1-methyl-1,4-benzodiazepin-2-one are dissolved in 30 ml of dimethylformamide in the presence of 1.42 g of BOC-D-phenylalanine, followed by cooling to 5° C. and addition of 1.07 ml of triethylamine and then 2.4 g of BOP. The reaction mixture is allowed to return to room temperature and is left stirring overnight. It is then poured into water and extracted with ethyl acetate. The organic phase is washed with water, separated out after settling of the phases, dried over Na2SO4, filtered and concentrated under vacuum. An oily residue of 2-tertbutoxycarbonylamino-N-]2,3-dihydro-5-(2,6-dimethoxy-4-methylphenyl)-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl!-3-phenylpropionamide, obtained in quantitative yield, is used as it is for the following step (Compound 16).
Reaction SMILES: N12CCCN=C1CCCC[CH2:2]2.[CH3:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:15]=1[C:16]([OH:18])=[O:17]>C(=O)(OC)OC.CCOC(C)=O.O>[CH3:24][O:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:14]([O:13][CH3:12])[C:15]=1[C:16]([O:18][CH3:2])=[O:17]
Reactant: C1CCC2=NCCCN2CC1
Reactant: COc1cccc(OC)c1C(=O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: COC(=O)OC
Product: COC(=O)c1c(OC)cccc1OC
Temperature: 90 °C

Procedure:
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), (836 mg, 5.49 mmol), was added to a mixture of 2,6-dimethoxybenzoic acid (1), (1.0 g, 5.49 mmol), in dimethyl carbonate (DMC) (10 mL) and the resulting mixture was heated to reflux at 90° C. for 4 hours. The reaction mixture was cooled to 25° C. and diluted with EtOAc (30 mL) and water (30 mL). The organic layer was separated and washed in sequence with 10 mL of water, 2 M HCl (2×30 mL), saturated aqueous NaHCO3 (2×30 mL) and water (2×25 mL). The organic layer was dried over Na2SO4, filtered and concentrated under vacuum to give methyl 2,6-dimethoxybenzoate (2) as a white solid. The yield of the 2,6-dimethoxybenzoate as determined by HPLC was 97-98% conversion.
Reaction SMILES: O=[C:2]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:10]=1[F:17])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[CH:22][CH:21]=1)=O.[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[C:44]1[CH:48]=[C:47]([NH2:49])[NH:46][N:45]=1.C([O-])(=O)C.[NH4+]>O.C(OCC)(=O)C>[C:35]([O:34][C:32]([N:29]1[CH2:30][CH2:31][N:26]([C:23]2[CH:24]=[CH:25][C:20]([CH:18]3[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([C:9]4[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:10]=4[F:17])[NH:49][C:47]4[NH:46][N:45]=[C:44]([C:40]5[S:39][CH:43]=[CH:42][CH:41]=5)[C:48]3=4)=[CH:21][CH:22]=2)[CH2:27][CH2:28]1)=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: CCOC(=O)CC(=O)c1c(F)ccc(F)c1F
Reactant: Nc1cc(-c2cccs2)n[nH]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(c2c(F)ccc(F)c2F)Nc2[nH]nc(-c3cccs3)c2C1c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 1 h
Yield: 44.2 %

Procedure:
250 mg (1.02 mmol) of ethyl 3-oxo-3-(2,3,6-trifluorophenyl)propanoate, 295 mg (1.02 mmol) of tert-butyl 4-(4-formylphenyl)piperazine-1-carboxylate, 168 mg (1.02 mmol) of 3-(thiophen-2-yl)-1H-pyrazol-5-amine and 196 mg (2.54 mmol) of ammonium acetate are added to a test tube which is then sealed. The mixture is carried without solvent at 120° C. for 1 hour. After returning to room temperature, the solid is dissolved in a water/ethyl acetate mixture. The phases are separated and the aqueous phase is extracted several times with ethyl acetate. The organic phases are combined, dried on magnesium sulfate and concentrated. The residue is purified by silica gel chromatography (eluent: 6:4 cyclohexane/ethyl acetate) to yield 300 mg (44%) of ethyl 4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)-3-(thiophen-2-yl)-6-(2,3,6-trifluorophenyl)-4,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylate in the form of a light yellow powder.
Reaction SMILES: B(Cl)(Cl)Cl.[Cl:5][CH2:6][CH2:7][CH2:8][C:9]#N.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Al+3].[Cl-].[Cl-].[Cl-].[OH2:22]>ClCCCl>[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:9](=[O:22])[CH2:8][CH2:7][CH2:6][Cl:5]
Reactant: O
Reactant: N#CCCCCl
Reactant: Nc1ccccc1
Agent: ClB(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Nc1ccccc1C(=O)CCCCl
Temperature: 35 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
A mixture of BCl3 (59.2 g, 0.50 mole) in 1,2-dichloroethane is treated with 4-chlorobutyronitrile (62.5 g, 0.604 mole) over a 1 hour period at -8° to 0° C., stirred for 1 hour at 0° to 5° C., treated with aniline (45.1 g, 0.485 mole) over a 1 hour period at 2° to 9° C., stirred for 1 hour, and treated with AlCl3 (68.8 g, 0.515 mole) in a single portion at ambient temperatures. The reaction mixture is sparged with nitrogen at reflux temperature for about 17 hours. The heated and sparged reaction mixture is cooled to 35° C. and added to approximately a 2-fold volume of water (based upon initial reaction volume) and stirred for 0.5 hour at 33° to 35° C. The phases are separated and the aqueous phase is washed with 1,2-dichloroethane. The organic phases are combined and concentrated in vacuo to give a solution of the title product containing, 85.9 g of the desired o-aminophenyl ketone, 89.7% yield, identified by HPLC analysis.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:10]([O-:13])(=O)[CH3:11].[K+].C(OC(=O)C)(=O)C.C1OCCOCCOCCOCCOCCOC1.[N:40](OCCC(C)C)=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]2[C:3]=1[CH:9]=[N:40][N:5]2[C:10](=[O:13])[CH3:11].[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]2[C:3]=1[CH:9]=[N:40][NH:5]2
Reactant: CC(=O)[O-]
Reactant: Cc1c(N)cccc1Br
Reactant: CC(C)CCON=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: Brc1cccc2[nH]ncc12
Product: CC(=O)n1ncc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-bromo-2-methyl aniline (5.0 g, 26.9 mmol) in chloroform (50 mL) was added potassium acetate (1.05 eq., 28.2 mmol, 2.77 g). Acetic anhydride (2.0 eq., 53.7 mmol, 5.07 mL) was added with concurrent cooling in ice-water. The mixture was then stirred at room temperature for 10 minutes after which time a white gelatinous solid formed. 18-Crown-6 (0.2 eq., 5.37 mmol, 1.42 g) was added followed by iso-amyl nitrite (2.2 eq., 59.1 mmol, 7.94 mL) and the mixture was heated under reflux for 18 h. The reaction mixture was allowed to cool, and was partitioned between chloroform (3×100 mL) and saturated aqueous sodium hydrogen carbonate (100 mL). The combined organic extracts were washed with brine (100 mL), separated and dried (MgSO4). The crude product was evaporated onto silica and purified by chromatography eluting with 20% to 40% EtOAc-petrol to give 1-(4-bromo-indazol-1-yl)-ethanone A (3.14 g, 49%) as an orange solid, and 4-bromo-1H-indazole B (2.13 g, 40%) as a pale orange solid. A: 1H NMR (400 MHz, CDCl3) 2.80 (3H, s), 7.41 (1H, t, J=7.8 Hz), 7.50 (1H, d, J=7.8 Hz), 8.15 (1H, s), 8.40 (1H, d, J=7.8 Hz). B: 1H NMR (400 MHz, CDCl3) 7.25 (1H, t, J=7.3 Hz), 7.33 (1H, d, J=7.3 Hz), 7.46 (1H, d, J=7.3 Hz), 8.11 (1H, s), 10.20 (1H, br s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[CH3:10])[NH2:6].[N+]([C:14]1[CH:15]=C(S([O-])(=O)=O)C=C[CH:19]=1)([O-])=O.[Na+].S(O)(C)(=O)=O.OCC(CO)O.[OH-].[Na+]>O1CCOCC1>[CH3:10][C:9]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[N:6]=[CH:15][CH:14]=[CH:19]2
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Reactant: COc1cc(N)ccc1C
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: OCC(O)CO
Solvent: C1COCCO1
Product: COc1cc2ncccc2cc1C
Temperature: 150 °C
Yield: 98.2 %

Procedure:
Using a minimal amount of dioxane, 3-methoxy-4-methylaniline (5.00 g, 36.5 mmol) was slowly added to a mixture of sodium m-nitrobenzenesulfonate (6.62 g, 29.4 mmol), MsOH (20 mL), and FeSO4.7H2O (0.39 g, 1.4 mmol) in a 100 mL round bottom flask heated to an internal temperature of 145-155° C. Glycerol (10.75 g, 116.8 mmol) was then added dropwise via addition funnel while keeping the internal temperature at 145-155° C. After addition, the reaction was stirred in a 150° C. oil bath until LCMS indicated completion (4-6 h). After being cooled to rt, ice (20 g) was added, then the solution was neutralized with 10 N NaOH (calculated to same eq of MsOH) at a speed to keep the internal temperature below 40° C. A thick suspension appeared after addition, and this was extracted with EtOAc (50 mL×3). The organic layer was filtered through a Celite pad to remove insoluble black particles and then purified by flash column chromatography on silica gel to give the desired product (5.0 g, 79%). MS (ES) m/z 174.1 (M+H+).