Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:8]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH:18]=[C:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21][CH2:20]1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([C:3]1[C:8]([B:9]2[O:13][C:12]([CH3:14])([CH3:15])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:23][CH2:24]1)[CH3:2]
Reactant: CCOC(=O)CN1CCC(=Cc2cccc(B3OC(C)(C)C(C)(C)O3)c2CC)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CN1CCC(Cc2cccc(B3OC(C)(C)C(C)(C)O3)c2CC)CC1
Reaction time: 4 h
Yield: 80.7 %

Procedure:
To a solution of ethyl (4-{[2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methylidene}-1-piperidinyl)acetate (D143) (0.37 g, 0.895 mmol) in Ethanol (10 mL) was added Pd/C (0.191 g, 0.179 mmol). The reaction solution was stirred under hydrogen atmosphere for 4 hours. After filtration, the filtrate was concentrated to afford ethyl (4-{[2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperidinyl)acetate (D144) (300 mg). MS (ES): C24H38BNO4 requires 415.3. found 416.3 (M+H+).
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:13][C:8]=2[N:7]=[C:6]1[C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=1[N:31]1[CH:35]=[CH:34][CH:33]=[N:32]1)([CH3:4])([CH3:3])[CH3:2].Br[C:37]1[CH:38]=[C:39]2[CH2:45][CH2:44][NH:43][C:40]2=[N:41][CH:42]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.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>[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:37]3[CH:38]=[C:39]4[CH2:45][CH2:44][NH:43][C:40]4=[N:41][CH:42]=3)=[CH:13][C:8]=2[N:7]=[C:6]1[C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=1[N:31]1[CH:35]=[CH:34][CH:33]=[N:32]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Brc1cnc2c(c1)CCN2
Reactant: COc1ccc(-n2cccn2)c(-c2nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3n2C(C)(C)C)c1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-n2cccn2)c(-c2nc3cc(-c4cnc5c(c4)CCN5)ccc3n2C(C)(C)C)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 17.2 %

Procedure:
In a microwave vial are combined 1-tert-butyl-2-(5-methoxy-2-pyrazol-1-yl-phenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole (285 mg, 0.60 mmol), 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.50 mmol), potassium carbonate (140 mg, 1.0 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (53 mg, 0.08 mmol) in toluene (3.0 mL) and water (0.30 mL). The reaction vial is sealed and stirred at 100° C. for 4 hours in an oil bath. After this time the reaction is cooled and poured into water. The product is extracted into EtOAc (2×). The combined organics are dried (MgSO4), filtered and concentrated. Purification via flash chromatography (12 g silica gel, 0-5% MeOH/CH2Cl2) affords the title compound (40 mg, 17%). LCMS (ESMS): m/z 465.20 (M++1)
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([CH3:13])[CH:5]=1>CO>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([N:2]([CH3:15])[CH3:1])=[O:14])=[CH:5][C:6]=1[CH3:13]
Reactant: Cc1cc(C(=O)N(C)C)ccc1[N+](=O)[O-]
Solvent: CO
Product: Cc1cc(C(=O)N(C)C)ccc1N
Reaction time: 0.75 h

Procedure:
N,N,3-trimethyl-4-nitrobenzamide (0.6 g, 2.88 mmol) in methanol was hydrogenated using the H-cube apparatus (1.2 mL/min, RT, atmospheric pressure). After 45 minutes the reaction was complete. Removal of the solvent in vacuo gave 4-amino-N,N,3-trimethylbenzamide as a colourless solid (quantitative); MS (ES+) 179.
Reaction SMILES: [O:1]1CCCC(=O)[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.Br[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[O:1]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:3]=1
Reactant: O=C1CCCOc2ccccc21
Reactant: CCOC(=O)CCCBr
Product: CCOC(=O)CCCOc1ccccc1

Procedure:
Scheme 1 shows a general method for preparation of 3,4-dihydrobenzo[b]oxepin-5(2H)-one intermediates 66 by O-alkylation of a phenolic compound with ethyl 4-bromobutanoate to give a ethyl 4-phenoxybutanoate intermediate 67, followed by saponification to the carboxylic acid 68 and intramolecular cyclization under acidic conditions.
Reaction SMILES: Cl[C:2]1[C:11]([NH:12][C:13](=O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25].N1C=CC=CC=1>CC1C=CC(C)=CC=1>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]1[S:25][C:2]2[C:11]([N:12]=1)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)([O-:22])=[O:21]
Reactant: COC(=O)c1cnc(Cl)c(NC(=O)c2ccccc2[N+](=O)[O-])c1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: Cc1ccc(C)cc1
Product: COC(=O)c1cnc2sc(-c3ccccc3[N+](=O)[O-])nc2c1
Temperature: 130 °C
Yield: 57 %

Procedure:
A mixture of methyl 6-chloro-5-(2-nitrobenzamido)nicotinate (1 eq), P2S5 (2.1 eq), and pyridine (7.6 eq) in p-xylene was heated at 130° C. for 2 h. The clear liquid was decanted and allowed to cool to room temperature. The resultant precipitate was collected by filtration and dried to give methyl 2-(2-nitrophenyl)thiazolo[5,4-b]pyridine-6-carboxylate (57% yield).
Reaction SMILES: [O:1]=[C:2]1[C:7](=O)[CH:6]([C:9]#[N:10])[CH2:5][CH2:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.Cl.[NH2:19][NH2:20].C(O)(=O)C>C(O)C>[NH2:10][C:9]1[C:6]2[CH2:5][CH2:4][N:3]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[C:2](=[O:1])[C:7]=2[NH:20][N:19]=1
Reactant: Cc1ccc(N2CCC(C#N)C(=O)C2=O)cc1
Reactant: NN
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(N2CCc3c(N)n[nH]c3C2=O)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 86 %

Procedure:
2,3-Dioxo-1-p-tolylpiperidine-4-carbonitrile (3.56 g, 15.597 mmol) was added to anhydrous ethanol (52.0 mL) and dissolved by heating to 60° C. After adding hydrazine hydrochloride (1.06 mL, 21.836 mmol) and glacial acetic acid (1.34 mL, 23.396 mmol) room temperature, reaction was carried out for 2 days. After removing ethanol by distillation, the produced solid was filtered and then acetic acid was completely removed by washing with NaHCO3 twice or more times. A target compound (3.25 g, 13.414 mmol, 86.0%) was yielded as white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([CH2:12][CH2:13][CH3:14])[C:5](=[O:11])[N:6]([CH2:8][CH2:9][CH3:10])[CH:7]=1.[N:16]([O-])=O.[Na+].Cl.S(S([O-])=O)([O-])=O.[Na+].[Na+].[OH-].[Na+]>O>[NH2:1][C:2]1[C:3](=[O:15])[N:4]([CH2:12][CH2:13][CH3:14])[C:5](=[O:11])[N:6]([CH2:8][CH2:9][CH3:10])[C:7]=1[NH2:16]
Reactant: O=N[O-]
Reactant: CCCn1cc(N)c(=O)n(CCC)c1=O
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Yield: 60.8 %

Procedure:
A mixture of 5-amino-1,3-dipropyl-2,4-(1H,3H)-pyrimidinedione (52.8 g, 0.25 moles), sodium nitrite (20.7 g, 0.30 moles) and water (1000 ml) is prepared and treated with hydrochloric acid (12 N, 30 ml, 0.35 moles) after the method of Blicke (J. Am. Chem. Soc., 76, 2798 (1954)]. 6-Amino-1,3-dipropyl-5-nitroso-2,4-(1H,3H)pyrmidinedione is collected as described and is used as obtained in the next step. The nitroso compound is suspended in water (500 ml) and treated with sodium dithionite, added portionwise in a quantity sufficient to effect decolorization of the purple nitroso compound. The resulting slurry is treated with sodium hydroxide (100 ml 50%), chilled, and filtered. The solids thus obtained are dried at 78° in a vacuum oven to yield 34.4 g of 5,6-diamino-1,3-dipropyl-2,4-(1H,3H)pyrimidinedione.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][CH:11]([C:14](O)=[O:15])[CH2:10]2)=[CH:5][C:4]=1[C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:19]=2[N:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:52][N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1.C([O-])(O)=O.[Na+]>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][CH:11]([C:14]([N:56]3[CH2:57][CH2:58][N:53]([CH3:52])[CH2:54][CH2:55]3)=[O:15])[CH2:10]2)=[CH:5][C:4]=1[C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:19]=2[N:18]=1
Reactant: COc1ccc2[nH]c(-c3cc(N4CCC(C(=O)O)C4)ccc3Cl)nc2c1
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COc1ccc2[nH]c(-c3cc(N4CCC(C(=O)N5CCN(C)CC5)C4)ccc3Cl)nc2c1
Temperature: 35 °C
Yield: 35.2 %

Procedure:
Method P—Step a To a vial with 1-[4-Chloro-3-(5-methoxy-1H-benzoimidazol-2-yl)-phenyl]-pyrrolidine-3-carboxylic acid hydrochloride (obtained as described in general method 3,4, step e) (0.10 g, 0.25 mmol), HATU (0.10 g, 0.26 mmol), TEA (0.07 mL, 0.53 mmol) and 1-methyl-piperazine (0.04 mL, 0.33 mmol), dichloromethane (2 mL) was added and the reaction mixture was heated at 35° C. overnight. Reaction was cooled to room temperature, saturated NaHCO3 solution (2 mL) was added with stirring, the organic layer recovered by filtration through phase separator, and the solvent removed under reduced pressure. The crude was purified by SCX, trituration from diethyl ether and finally by preparative HPLC to obtain 0.04 g of the title compound (34%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[CH:11][C:10]=2[F:32])[CH:5]=[CH:4][N:3]=1.[C:33]1([O:39][C:40](Cl)=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl.N1C=CC=CC=1.C(Cl)Cl>[CH3:24][N:21]1[C:22]([CH3:23])=[C:18]([C:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:40](=[O:41])[O:39][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:7]=3)=[C:10]([F:32])[CH:11]=2)=[O:17])[C:19](=[O:31])[N:20]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
A suspension of N-(4-((2-aminopyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (500 mg, 1.10 mmol) in DCM/pyridine (50 mL/25 mL) was cooled to 0° C., then a solution of phenylcarbonochloridate (450 mg, 2.90 mmol) in DCM (5 mL) was added to the mixture slowly over 0.5 hour. The reaction was stirred at rt for 2 hours, then diluted with DCM (250 mL). The mixture was washed with water (150 mL×3), followed by washing with brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v)=150/1) to give the title compound as a white solid (352 mg, 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[NH:12][N:11]=[CH:10][C:9]=2[NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]=23)=[O:15])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:34][CH:35]=[C:36]([CH3:38])[CH3:37].CCOC(C)=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[C:9]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:10][N:11]([CH2:34][CH:35]=[C:36]([CH3:38])[CH3:37])[N:12]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1[nH]ncc1NC(=O)c1cnn2cccnc12
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1-c1nn(CC=C(C)C)cc1NC(=O)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.4 %

Procedure:
To a suspension of N-(5-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (114.0 mg, 0.31 mmol) and cesium carbonate (201.4 mg, 0.62 mmol) in N,N-dimethylformamide (2 mL), was added 4-bromo-2-methyl-2-butene (53 μL, 0.46 mmol). The reaction mixture was stirred for 3 hours at room temperature, then EtOAc was added. The organic layer was washed 1× each with water and saturated brine solution. The organic layer was separated, then dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (20-100% EtOAc:Hex) to afford N-(3-(5-chloro-2-methoxyphenyl)-1-(3-methylbut-2-enyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow foam (67 mg, 0.15 mmol). Acetone and water (1 mL each) were then added, followed by osmium tetraoxide (1.89 mg, 0.0074 mmol), and N-methylmorpholine-N-oxide in water (1:1, N-methylmorpholine-N-oxide:Water, 37 mg). The reaction mixture was stirred for 3 hours at room temperature. Celite was added and the mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (50-100% EtOAc*:Hex, *EtOAc also contained 10% MeOH), and then by chiral SFC to separate enantiomers to give 11.2 mg and 15.8 mg of the title compounds as white solids. LCMS (ESI) m+H=471.1; 1H NMR (500 MHz, DMSO) δ 9.69 (s, 1H), 9.34 (d, J=6.9, 1H), 8.78 (d, J=4.0, 1H), 8.66 (s, 1H), 8.30 (s, 1H), 7.49 (dd, J=8.8, 2.6, 1H), 7.42 (d, J=2.6, 1H), 7.29 (dd, J=10.0, 4.6, 2H), 5.05 (d, J=6.3, 1H), 4.53 (s, 1H), 4.43 (d, J=13.5, 1H), 3.95 (dd, J=13.5, 10.1, 1H), 3.85 (s, 3H), 3.60 (s, 1H), 1.16 (s, 3H), 1.10 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]3[C:14]([O:23]C)=[C:15]4[C:20](=[O:21])[N:19]([CH3:22])[CH2:18][CH2:17][N:16]4[C:10]=3[C:9]([CH2:25][OH:26])=[N:8]2)=[CH:4][CH:3]=1.B(Br)(Br)Br.CO>ClCCl>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]3[C:14]([OH:23])=[C:15]4[C:20](=[O:21])[N:19]([CH3:22])[CH2:18][CH2:17][N:16]4[C:10]=3[C:9]([CH2:25][OH:26])=[N:8]2)=[CH:4][CH:3]=1
Reactant: COc1c2n(c3c(CO)nn(Cc4ccc(F)cc4)c(=O)c13)CCN(C)C2=O
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CN1CCn2c(c(O)c3c(=O)n(Cc4ccc(F)cc4)nc(CO)c32)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-fluorobenzyl)-4-(hydroxymethyl)-10-methoxy-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (27 mg g, 70 μmol) in anhydrous dichloromethane (1 mL), a solution of boron tribromide in dichloromethane (90 μL, 90 μmol; 1 M) was added. After stirring at room temperature for one hour, the reaction mixture was treated with anhydrous methanol (2 mL), stirred for 30 minutes, and concentrated under vacuum. The procedure was repeated twice. The residue was subjected to purification on preparative reverse phase high pressure column chromatography. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: ClC(Cl)=[C:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[N+]([O-])(O)=[O:20]>O>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[O:20])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])O
Reactant: ClC(Cl)=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: O
Product: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 20 °C

Procedure:
A 200 ml flask equipped with a stirrer was charged with 3.3 g of 1,1-dichloro-2,2-bis(4-chlorophenyl)ethylene and then with 50 ml of an aqueous nitric acid solution having a specific gravity of 1.52. The weight ratio of the reaction material to the aqueous solution of nitric acid was 0.043. While vigorously stirring the resulting mixture at room temperature of about 20° C. in a nitrogen atmosphere, they were reacted for 1 hour. The reaction mixture was thereafter added with water, followed by extraction with dichloromethane. After sufficient washing of the dichloromethane layer with water, the extract was analyzed by gas chromatography. As a result, it was found that 1,1-dichloro-2,2-bis(4-chlorophenyl)ethylene was converted in its entirety to 4,4'-dichloro-3,3'-dinitrobenzophenone, but no 4,4'-dichlorobenzophenone was formed at all.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[O:9]1[CH2:15][CH2:14][C:13](=[O:16])[NH:12][CH2:11][CH2:10]1.I[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[CH3:27].CN(C)CCN>[Cu]I.O1CCOCC1>[CH3:27][C:19]1[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:18]=1[N:12]1[C:13](=[O:16])[CH2:14][CH2:15][O:9][CH2:10][CH2:11]1
Reactant: Cc1cc([N+](=O)[O-])ccc1I
Reactant: O=C1CCOCCN1
Agent: [Cu]I
Agent: CN(C)CCN
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc([N+](=O)[O-])ccc1N1CCOCCC1=O
Temperature: 110 °C

Procedure:
3.32 g (15.6 mmol) of potassium phosphate are mixed with 0.5 g (2.6 mmol) of copper(I) iodide in a round-bottom flask, and baked out and filled with argon in repeated alternation. Subsequently, 10 ml of anhydrous dioxane, 1.5 g (13.0 mmol) of 1,4-oxazepan-5-one, 3.43 g (13.0 mmol) of 1-iodo-2-methyl-4-nitrobenzene and 0.46 g (5.21 mmol) of N,N-dimethylethylenediamine are added, and the mixture is heated to 110° C. for 15 h. The mixture is allowed to cool and filtered through silica gel, and the silica gel is washed with dioxane. The combined filtrates are concentrated to dryness under reduced pressure. The residue is dissolved in acetonitrile and purified by preparative HPLC with a gradient of water and acetonitrile. The product fractions are combined and concentrated to dryness under reduced pressure. This affords 430 mg (13% of theory) of the desired product.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[C:8]([O:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[C:6]=2[CH:7]=1.CS(C)=[O:30]>>[CH:2]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[C:8]([O:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[C:6]=2[CH:7]=1)=[O:30]
Reactant: CS(C)=O
Reactant: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(CBr)oc2c1
Product: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(C=O)oc2c1
Yield: 84 %

Procedure:
A solution of ethyl 2-(bromomethyl)-4-(4-(methylsulfonyl)phenoxy)benzofuran-6-carboxylate (320 mg, 0.706 mmol) and IBX (395 mg, 1.41 mmol) in DMSO (2 mL) was heated at 65° C. for 3 h. The reaction was quenched with water and the product was extracted with CHCl3. The combined organic layers were washed with water (2×), dried over MgSO4, and concentrated. The product was purified by gradient chromatography on silica gel using hexanes/EtOAc (100/0 to 40/60) to give the title compound (230 mg, 84%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.40 (t, J=7.16 Hz, 3 H) 3.09 (s, 3H) 4.41 (q, J=7.16 Hz, 2 H) 7.14-7.23 (m, 2 H) 7.46 (d, J=0.94 Hz, 1 H) 7.62 (d, J=0.94 Hz, 1 H) 7.89-8.02 (m, 2 H) 8.15 (t, J=0.94 Hz, 1 H) 9.89 (s, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:14])[C:7]([NH2:13])=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2].[F:15][C:16]([F:23])([F:22])[CH:17]([OH:21])[C:18](O)=O.Cl.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[N+:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]2[NH:13][C:18]([CH:17]([OH:21])[C:16]([F:23])([F:22])[F:15])=[N:14][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)C(O)C(F)(F)F
Reactant: Nc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc2nc(C(O)C(F)(F)F)[nH]c2cc1[N+](=O)[O-]
Temperature: 108 °C

Procedure:
4,5-Dinitro-benzene-1,2-diamine (2.01 g; 10.2 mmoles) and 3,3,3-trifluoro-2-hydroxy-propionic acid (2.22 g; 15.4 mmoles) were suspended in 6N HCl (5 mL; 30 mmoles) and water (4 mL) under a nitrogen atmosphere. The reaction was stirred vigorously and heated to 108° C. for 18 hrs, then cooled to room temperature. The reaction was diluted with water (40 mL) and with ethyl acetate (40 mL), then sodium bicarbonate (3.79 g; 45.0 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×30 mL). The extracts were combined, washed with water (30 mL) and brine (40 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude brown solid which was then purified by column chromatography (SiO2; 30% ethyl acetate/CH2Cl2) to yield the title compound as a brown solid.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][CH:42]([O:45][C:46](=[O:60])[NH:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH2:41][CH2:40]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([NH:36][CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([O:45][C:46](=[O:60])[NH:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH2:41][CH2:40]2)=[O:3])=[CH:5][CH:6]=1)=[O:9]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: NCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=Cc1ccc(C(=O)NCCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
A mixture of 4-carboxybenzaldehyde (0.95 g, 6.35 mmol) and HATU (3.02 g, 7.94 mmol) in 55 mL of DCM was stirred at room temperature for 1 hour and then biphenyl-2-ylcarbamic acid 1-(2-aminoethyl)piperidin-4-yl ester (3 g, 5.29 mmol; prepared as described in Preparation 7) and DIPEA (4.6 mL, 26.45 mmol) were added. The resulting mixture was stirred at room temperature for 2 hours and then diluted with 100 mL of DCM and washed with saturated sodium bicarbonate (150 mL) and brine (150 mL). The organic layer was dried over MgSO4, filtered and concentrated to provide 2.3 g of the title intermediate (92% yield), which was suitable for use without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C(S)CC.[Br:21][C:22]([F:28])([F:27])[C:23]([F:26])([F:25])Br>CN(C)C=O>[Br:21][C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[O:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=1[Cl:10]
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: FC(F)(Br)C(F)(F)Br
Agent: CCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(Cl)c(OC(F)(F)C(F)(F)Br)c(Cl)c1

Procedure:
In a manner similar to Step A of Example 1, the reaction of 12.5 g 0.07 mole) 4-amino-2,6-dichlorophenol, 7.3 g (0.053 mole) potassium carbonate, 1.0 g (0.013 mole) propanethiol, 36.5 g (0.14 mole) 1,2-dibromotetrafluoroethane and 125 ml of N,N-dimethylformamide produced 3.7 g of 4-(2-bromo-1,1,2,2-tetrafluoroethoxy)-3,5-dichloroaniline as an oil.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH:13]([C:16]2[NH:20][N:19]=[N:18][N:17]=2)[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[Pd].CO>[NH:11]1[CH2:15][CH2:14][CH:13]([C:16]2[NH:20][N:19]=[N:18][N:17]=2)[CH2:12]1
Reactant: O=C(OCc1ccccc1)N1CCC(c2nnn[nH]2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C1CC(c2nnn[nH]2)CN1

Procedure:
A mixture of 662 mg (2.4 mmol) of (R/S)-5-[1-benzyloxycarbonyl-pyrrolidin-3-yl]-1H-tetrazole (from Step B) and 220 mg of 10% palladium on charcoal in 5 mL of MeOH was hydrogenated at atmospheric pressure using a balloon of hydrogen for 3 h. The reaction was filtered through a pad of Celite and concentrated to afford the title compound as a white solid: 1H-NMR (500 MHz, CD3OD) δ 2.27 (m, 1H), 2.49 (m, 1H), 3.39-3.51 (m, 3H), 3.70 (m, 1H), 3.85 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>>[Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: O=C(O)c1ccc(O)cc1Cl
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution 2-chloro-4-hydroxybenzoic acid in anhydrous methanol was added thionyl chloride (1.5 eq). After stirring the solution at room temperature for 16 hours, the solvent was evaporated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate, water, brine, and dried over MgSO4 and concentrated in vacuo to give methyl 2-chloro-4-hydroxybenzoate.