Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]([CH3:12])[CH3:11])=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:15][C:16]([CH:18]1[CH2:20][CH:19]1[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([F:28])[CH:22]=1)=[O:17])C>>[F:28][C:23]1[CH:22]=[C:21]([CH:19]2[CH2:20][CH:18]2[C:16]([OH:17])=[O:15])[CH:26]=[CH:25][C:24]=1[O:27][CH2:2][C:3]1[C:4]([S:9][CH:10]([CH3:12])[CH3:11])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)Sc1ncccc1CCl
Reactant: CCOC(=O)C1CC1c1ccc(O)c(F)c1
Product: CC(C)Sc1ncccc1COc1ccc(C2CC2C(=O)O)cc1F
Yield: 83 %

Procedure:
3-Chloromethyl-2-isopropylsulfanyl-pyridine (0.040 g, 0.20 mmol) obtained in Step C of Preparation Example 1 and 2-[3-fluoro-4-hydroxy-phenyl]-cyclopropane carboxylic acid ethyl ester (0.044 g, 0.20 mmol) obtained in Step C of Preparation Example 44 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.060 g, 84%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][C@@:9]2([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:14][C:13](=[O:15])[N:12]([C@H:16]([C:18]3[CH:23]=[CH:22][C:21](B4OC(C)(C)C(C)(C)O4)=[CH:20][CH:19]=3)[CH3:17])[CH2:11][CH2:10]2)=[N:4][N:3]=1.Cl[C:40]1[N:41]=[N:42][C:43]([CH3:46])=[CH:44][CH:45]=1>>[CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][C@@:9]2([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[O:14][C:13](=[O:15])[N:12]([C@H:16]([C:18]3[CH:19]=[CH:20][C:21]([C:40]4[N:41]=[N:42][C:43]([CH3:46])=[CH:44][CH:45]=4)=[CH:22][CH:23]=3)[CH3:17])[CH2:11][CH2:10]2)=[N:4][N:3]=1
Reactant: Cc1nnc(CC[C@]2(c3ccccc3)CCN([C@@H](C)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)C(=O)O2)o1
Reactant: Cc1ccc(Cl)nn1
Product: Cc1ccc(-c2ccc([C@H](C)N3CC[C@](CCc4nnc(C)o4)(c4ccccc4)OC3=O)cc2)nn1

Procedure:
(R)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 3-chloro-6-methylpyridazine were reacted following a procedure analogous to that described in Example 1 Step 2 to afford (R)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-3-((S)-1-(4-(6-methylpyridazin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one. LC-MS Method 2 tR=0.984 min, m/z=499.1; 1H NMR (CD3OD) 1.50 (m, 3H), 2.25 (m, 2H), 2.42 (m, 1H), 2.35 (s, 3H), 2.38 (m, 1H), 2.42 (m, 1H), 2.49-2.55 (m, 1H), 2.65 (s, 3H), 2.90 (m, 1H), 3.05 (m, 1H), 5.52 (m, 1H), 7.07 (m, 2H), 7.25 (m, 3H), 7.32 (m, 2H), 7.69-7.76 (m, 3H), 8.06 (m, 1H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[CH3:2].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:15])=[C:9]([OH:13])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cccc(O)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCc1ccc(Br)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
To a −10° C. solution of 3-(3-hydroxy-phenyl)-propionic acid ethyl ester (2.0 g, 10.31 mmol) in chloroform (0.2 M, 51 mL) was added N-bromosuccinimide (1.93 g, 10.83 mmol). After stirring at RT overnight, the solution was concentrated in vacuo and purified by flash column chromatography (SiO2, 5% to 15% ethyl acetate/hexanes) to give the product as a colorless oil (0.45 g, 16%).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[CH3:17][C:18]1([CH3:39])[C:22]([CH3:24])([CH3:23])[O:21][B:20](C2C=CC(OC3C=CC=CC=3)=CC=2C)[O:19]1>>[C:9]1([N:6]2[C:5]3[CH:15]=[CH:16][C:2]([B:20]4[O:21][C:22]([CH3:24])([CH3:23])[C:18]([CH3:39])([CH3:17])[O:19]4)=[CH:3][C:4]=3[N:8]=[CH:7]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cc(Oc2ccccc2)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccc2c(c1)ncn2-c1ccccc1
Product: CC1(C)OB(c2ccc3c(c2)ncn3-c2ccccc2)OC1(C)C

Procedure:
Prepared from 5-bromo-1-phenyl-1H-benzoimidazole according to general Method I for borylation described above for preparation of 4,4,5,5-tetramethyl-2-(2-methyl-4-phenoxy-phenyl)-[1,3,2]dioxaborolane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.C(O)C.[CH3:29][C:30]1[CH:31]=[C:32]([C:36]([N:38]=[C:39]=[S:40])=[O:37])[CH:33]=[CH:34][CH:35]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:39]([NH:38][C:36](=[O:37])[C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([CH3:29])[CH:31]=2)=[S:40])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1
Reactant: Cc1cccc(C(=O)N=C=S)c1
Reactant: COc1cc2nccc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(C)c4)c([N+](=O)[O-])c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-nitroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 3-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (69 mg, yield 91%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]([NH:14]C(=O)C)=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-:3])=[O:2].Cl>O1CCCC1>[N+:1]([C:4]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-:3])=[O:2]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])c2cccnc12
Agent: Cl
Solvent: C1CCOC1
Product: Nc1ccc([N+](=O)[O-])c2cccnc12
Reaction time: 3.5 h

Procedure:
5-Nitro-8-acetamidoquinoline prepared as above, (15 g, 64.9 mmol) was dissolved in tetrahydrofuran (75 ml) and treated with 40% hydrochloric acid (300 ml). The mixture was held at 80° C. for 3.5 hours and then allowed to cool. Tetrahydrofuran was removed under reduced pressure and the residual liquid was treated with saturated sodium bicarbonate solution until a neutral solution was obtained. The precipitate was removed by filtration to give 5-nitro-8-aminoquinoline (10 g).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[NH:7][C:8]2=[O:13].Br[CH2:21][CH2:22][CH2:23][CH2:24][OH:25]>>[CH3:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[CH2:16][CH2:15]1)[NH:7][C:8]2=[O:13]
Reactant: OCCCCBr
Reactant: Cc1cccc2c(=O)[nH]c(C3CCNCC3)cc12
Agent: Cl
Product: Cc1cccc2c(=O)[nH]c(C3CCN(CCCCO)CC3)cc12
Yield: 22.6 %

Procedure:
By the reaction in the same manner as in Example 2a, using 5-methyl-3-(piperidin-4-yl)-2H-isoquinolin-1-one hydrochloride (1 g) and 4-bromo-1-butanol (433 mg), 5-methyl-3-[1-(4-hydroxybutyl)piperidin-4-yl]-2H-isoquinolin-1-one (201 mg) was obtained.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[CH3:22][C:23]1([NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])[CH2:26][NH:25][CH2:24]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:25]4[CH2:26][C:23]([CH3:22])([NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])[CH2:24]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC1(NC(=O)C(F)(F)F)CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC1(NC(=O)C(F)(F)F)CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1

Procedure:
A solution of 1 g (3.5 mmoles) of 1-cyclopropyl-6,7,8-trifluoro-4-oxo-3-quinolinecarboxylic acid, 1.15 g (5.3 mmoles) of 3-methyl-3-trifluoroacetamidoazetidine hydrochloride, 2 ml of triethylamine in 10 ml of pyridine is refluxed for 3 hours.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][NH:23][C:22](=[O:26])[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][N:23]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=2)[C:22](=[O:26])[CH:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-n2ccc(OCc3ccccc3)cc2=O)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 56 h
Yield: 50.4 %

Procedure:
To a solution of 5-fluoro-2-nitrotoluene (1.00 g, 6.44 mmol) in DMF (6.5 mL) was added 4-benzyloxy-pyridin-2(1H)-one (1.11 g, 5.55 mmol) and Na2CO3 (0.588 g, 5.55 mmol). After stirring at 120° C. for 56 hours, the reaction mixture was cooled, and the solids were collected by filtration and washed with EtOAc (100 ml) and H2O (100 mL). The solids were triturated with hot H2O (50 mL) and then washed with Et2O (50 mL) to yield the title compound (0.94 g, 50%) as a light yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 8.08 (d, J=8.5 Hz, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.50 (dd, J=9.0, 2.5 Hz, 1H), 7.47-7.37 (m, 5H), 6.16 (dd, J=8.0, 3.0 Hz, 1H), 6.01 (d, J=2.5 Hz, 1H), 5.15 (s, 2H), 2.55 (s, 3H); ESI MS m/z 337 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1B(O)O>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9]
Reactant: Nc1ccc(Br)c(F)c1
Reactant: COc1ccc(Cl)c(B(O)O)c1
Product: COc1ccc(Cl)c(-c2ccc(N)cc2F)c1
Yield: 92.7 %

Procedure:
The title compound (280 mg) was prepared from 4-bromo-3-fluoroaniline (227 mg, 1.2 mmol) and 2-chloro-5-methoxyphenylboronic acid (290 mg, 1.6 mmol) as a pale-yellow liquid.
Reaction SMILES: [CH:1]([N:3]1[CH2:6][CH2:5][C:4]1([CH3:8])[CH3:7])=[O:2].[CH:9](N1CCC1(OC)OC)=[O:10]>F[B-](F)(F)F.C[N+](C)(C)C.CO>[CH:1]([N:3]1[CH:6]([O:10][CH3:9])[CH2:5][C:4]1([CH3:8])[CH3:7])=[O:2]
Reactant: CC1(C)CCN1C=O
Reactant: COC1(OC)CCN1C=O
Agent: C[N+](C)(C)C
Agent: F[B-](F)(F)F
Solvent: CO
Product: COC1CC(C)(C)N1C=O

Procedure:
In the same manner as indicated in Example 6 there are electrolyzed 19.3 g of 1-formyl-2,2-dimethylazetidine and 54.7 g of methanol in the presence of 0.27 g of tetramethylammonium tetrafluoroborate as conducting salt. After throughput of 2.5 Faraday per mol of 1-formyl-2,2-dimethoxyazetidine the current is switched off. The calculated mean cell voltage is 32.6 volts. Work-up of the electrolysis solution gives 12.2 g of 1-formyl-4-methoxy-2,2-dimethylazetidine (boiling point 52° C./0.26 mbar; nD25 =1.4496), which corresponds to a product yield of 49.9% and a current efficiency of 39.9%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][S:10][C:11]#[N:12])=[CH:4][CH:3]=1.[BrH:14].C(O)(=O)C.O>C(O)(=O)C>[Br:14][C:11]1[S:10][CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:12]=1
Reactant: N#CSCC(=O)c1ccc(F)cc1
Reactant: Br
Solvent: CC(=O)O
Solvent: O
Product: Fc1ccc(-c2csc(Br)n2)cc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a solution of 2-(4-fluorophenyl)-2-oxoethyl thiocyanate (3.70 g, 19.0 mmol) in acetic acid (35 ml) was added a 25% hydrogen bromide/acetic acid (35 ml) solution, and the mixture was stirred at 130° C. for 2 hours and at room temperature for 2 hours. Water was poured into the reaction solution, and the mixture was extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of ethanol and water to give the desired product (4.50 g, 91.9%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[C@@H:10](O)([CH2:12][CH3:13])[CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][C@H:10]([CH3:11])[CH2:12][CH3:13])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Oc1ccc(F)c(Cl)c1
Reactant: CC[C@H](C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC[C@@H](C)Oc1ccc(F)c(Cl)c1
Temperature: 25 °C

Procedure:
To a 0° C. solution of 3-chloro-4-fluorophenol (2.10 g, 14.3 mmol) in toluene (14.3 ml) was added (S)-(+)-sec-butanol (1.39 ml, 15.0 mmol), triphenylphosphine (3.76 g, 14.3 mmol), and DIAD (3.06 ml, 15.76 mmol). The reaction warmed to rt overnight. The reaction mixture was filtered through a fritted funnel and washed with toluene. The filtrate was concentrated. The residue was diluted with EtOAc and washed with 1N NaOH. The aqueous phase was extracted with EtOAc (2 times). The combined organics were dried with MgSO4, filtered, and concentrated. The residue was purified on a silica gel cartridge (0% EtOAc/hexanes to 4% EtOAc/hexanes) to give the desired product.
Reaction SMILES: [CH2:1]([C:3]([CH3:32])([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[C:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:15]=1)[C:4]([O:6]CC)=[O:5])[CH3:2].[OH-].[K+]>O.C(O)C>[CH2:1]([C:3]([CH3:32])([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[C:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:15]=1)[C:4]([OH:6])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(C)(CC)CCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(C)(CCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1)C(=O)O

Procedure:
The procedure in Example 6 is followed but using ethyl 2-ethyl-2-methyl-6-[(4,6-diphenyl-2-pyridyl)oxy]hexanoate (3.6 g), potassium hydroxide pellets (0.95 g) dissolved in distilled water (20 cc) and ethanol (50 cc). The reaction mixture is refluxed for 120 hours. The product is purified by chromatography under pressure on silica gel (30-60 mm; eluent: n-hexane-ethyl acetate 75-25) and then by recrystallisation in an n-hexane-ethyl acetate (2-1) mixture (40 cc), white crystals (m.p.=119°-120° C.)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].O>C(#N)C>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][N:7]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2]
Reactant: CCOC(=O)CCNCC(=O)OCC
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CCN(CC(=O)OCC)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of diester 58 (3.88 g, 20.2 mmol) in dry acetonitrile (40 mL) at 0° C., under Argon, was added slowly benzyl chloroformate (3.17 mL, 1.1 equiv.). The solution was stirred at 0° C. for 1 h after which it was poured into water (50 mL) The phases were separated and the aqueous layer was extracted with dichloromethane (3×50 mL) the combined organic extracts were washed with 5% HCl, water, brine and dried over anhydrous sodium sulfate. Evaporation of the solvents was followed by distillation to afford compound 70 as a colorless oil (5.4 g, 80%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25]Br)[C:20]=2[F:27])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[NH3:29]>CO>[NH2:29][CH2:25][C:21]1[C:20]([F:27])=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][N:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[C:2]([Br:1])[C:3]1=[O:28]
Reactant: O=c1c(Br)c(OCc2ccc(F)cc2F)ccn1Cc1cccc(CBr)c1F
Reactant: N
Solvent: CO
Product: NCc1cccc(Cn2ccc(OCc3ccc(F)cc3F)c(Br)c2=O)c1F
Temperature: 80 °C
Yield: 60 %

Procedure:
A sealed tube containing a solution of 3-bromo-1-(3-bromomethyl-2-fluorobenzyl)-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one (0.24 g, 0.45 mmol) and NH3 (24 mL of a 7 N solution in MeOH, 168 mmol) was heated at 80° C. for 1 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. Purification by flash column chromatography (silica, eluent 99.5:0.5 to 96:4 methylene chloride/methanol) afforded a white solid (0.12 g, 60%): mp 160-163° C.; 1H NMR (300 MHz, CDCl3) δ 7.46-7.45 (m, 1H), 7.44-7.35 (m, 2H), 7.34-7.26 (m, 1H), 7.15-7.05 (m, 1H), 6.95-6.80 (m, 2H), 6.11 (d, J=9 Hz, 1H), 5.21 (s, 2H), 5.19 (s, 2H), 3.90 (s, 2H). ESHRMS m/z 453.0442 (M+H C20H17BrF3N2O2 requires 453.0420).
Reaction SMILES: Cl[O-].[F:3][C:4]([F:16])([F:15])[CH2:5][N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][C:9](=[O:14])[CH2:10]2.[C-:17]#[N:18].[Na+].Cl>C(OCC)C>[C:17]([C:9]1([OH:14])[CH2:8][CH:7]2[N:6]([CH2:5][C:4]([F:3])([F:15])[F:16])[CH:11]([CH2:12][CH2:13]2)[CH2:10]1)#[N:18]
Reactant: O=C1CC2CCC(C1)N2CC(F)(F)F
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCOCC
Product: N#CC1(O)CC2CCC(C1)N2CC(F)(F)F

Procedure:
A split-neck jacketed reactor was equipped with a stirrer bar, thermometer, hypochlorite scrubber and pressure equalised dropping funnel. To this was charged 8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octan-3-one (3.04 g, 14.5 mmol) and diethyl ether (7 ml). The reaction mixture was agitated and cooled to 0+ C. (recirculating glycol), then around sodium cyanide (1 .07 g, 21.7 mmol) was added via a powder funnel. Hydrochloric acid (5M, 4.0 ml, 20.3 mmol) was added to the reaction mixture via a dropping funnel over 5 minutes and the reaction mixture was then stirred for 24 hours. The pH of the mixture was adjusted from 9 to 5.5 using hydrochloric acid (5M), and the organic layer was separated. The aqueous phase was extracted with diethyl ether (2×30 ml) and the combined organic extracts were washed with dilute hydrochloric acid (30 ml, pH 6). Sulphuric acid (98%, 2 drops) was added to the extracts before drying (MgSO4) and filtering. A further 2 drops of sulphuric acid were added then the ether extracts were concentrated in vacuo to give 3-cyano-3-hydroxy-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane ( 72:28 exo:endo cyano) as a pale yellow solution in diethyl ether. (Reaction conversion 83% by 1H NMR analysis.)
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:24]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25]1.C(O)(C(F)(F)F)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([NH:23][S:27]([CH:24]3[CH2:26][CH2:25]3)(=[O:29])=[O:28])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc2cc(N)ccc2n1CC1CCC(F)(F)CC1
Reactant: O=S(=O)(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1nc2cc(NS(=O)(=O)C3CC3)ccc2n1CC1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-amine (300 mg, 0.934 mmol) and DMAP (115 mg, 0.934 mmol) were dissolved in 10 mL of DCM. Cyclopropanesulfonyl chloride (170 mg, 1.21 mmol) was added and the solution was stirred at rt for 2 h. The solution was washed with saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The product was purified by silica gel flash chromatography using EtOAc as eluent. The fractions were concentrated and the residue was dissolved in 25 mL of MeOH. TFA (0.143 mL, 1.86 mmol) was added dropwise and the solution was stirred at rt for 30 min. The solvent was evaporated and the product was precipitated in ether affording the title compound as its corresponding TFA salt. Yield: 390 mg (77%). 1H NMR (400 MHz, METHANOL-D4) δ 0.91-0.97 (m, 2 H), 1.02-1.08 (m, 2 H), 1.48-1.60 (m, 2 H), 1.65 (s, 9 H), 1.67-1.75 (m, 3 H), 1.75-1.82 (m, 1 H), 2.00-2.10 (m, 2 H), 2.18-2.28 (m, 1 H), 2.53-2.61 (m, 1 H), 4.50 (d, J=7.42 Hz, 2 H), 7.42 (dd, J=8.98, 2.15 Hz, 1 H), 7.74 (d, J=1.56 Hz, 1 H), 7.85 (d, J=8.79 Hz, 1 H); MS (ESI) (M+H)+ 426.0; Anal. Calcd (%) for C21H29N3O2SF2+1.0 TFA; C, 51.20; H, 5.60; N, 7.79. Found: C, 51.38; H, 5.66; N, 7.56.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]([O:24]C(C)C)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.ClB(Cl)Cl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]([OH:24])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(OC(C)C)cc12
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(O)cc12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a mixture of 2-(4-fluorophenyl)-5-isopropoxy-N-methyl-6-nitrobenzofuran-3-carboxamide (210.5 mg, 0.565 mmol) in CH2Cl2 (14 mL) at 0° C. under N2 was added trichloroborane (1.70 mL, 1.7 mmol) (1M solution in CH2Cl2). The mixture was then stirred at r.t. for 17 hr. The mixture was evaporated. The reddish orange residue was added 7 ml H2O, and then 3.5 ml 1N HCl, and left standing until the solid turned yellow. The yellow solid product was then filtered and washed with 3×3 ml H2O and dried (182 mg, 93%). 1H NMR (500 MHz, DMSO-d6) δ 10.18 (broad s, 1H), 8.53 (m, 1H), 8.31 (s, 1H), 7.98 (apparent dd, J=8.85, 5.49, 2H), 7.43 (apparent t, J=8.85, 2H), 7.28 (s, 1H,), 2.84 (appeared as d, J=4.58, 3H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters MICROMASS®. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: XTERRA® MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)+=331.21, HPLC Rt=1.442 min.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:11]=2[O:19][CH3:20])[CH:7]=[CH:8][CH:9]=1>CO.O1CCCC1.[Pd]>[ClH:1].[ClH:1].[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[C:14]([CH:13]=[CH:12][C:11]=2[O:19][CH3:20])[NH2:16])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1cccc(CN)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(N)cc1-c1cccc(CN)c1
Reaction time: 24 h
Yield: 149.7 %

Procedure:
To a solution of 2-(3-aminomethylphenyl)-4-nitroanisole hydrochloride (1.26 g, 4.2 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL) under nitrogen was added palladium on carbon (10% by weight, 200 mgs, 15 wt. %). The solution was purged with hydrogen and stirred under hydrogen for 24 hours. The reaction was purged with nitrogen and the catalyst was removed by filtration. Solvent was removed in vacuo and the residue was redissolved in dichloromethane (10 mL) and hydrochloride acid was added (4.0 M solution in dioxane, 1.5 equiv., 1.57 mL). The solution was stirred for 1 hour while a solid precipitated. The solid was collected on a Buchner funnel and dried under vacuum to afford 3-(3-aminomethylphenyl)-4-methoxyaniline dihydrochloride (947 mgs, 73% yield).
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)([O-:15])=[O:14]>C(OC(=O)C)(=O)C>[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH:12][C:11]2[C:2]([CH:1]=[CH:20][C:19]3[CH:22]=[CH:23][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=3)=[N:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:10]=2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: Cc1nc2ccccc2nc1C
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1ccc(C=Cc2nc3ccccc3nc2C=Cc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
In 200 ml of acetic anhydride, 16 g of 2,3-dimethylquinoxaline and 30 g of p-nitrobenzaldehyde were heated under reflux for 30 minutes.