Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[C:4]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:3]=1.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].O>N1C=CC=CC=1>[CH2:15]([N:14]([CH2:17][CH3:18])[C:4]1[C:5]([N+:11]([O-:13])=[O:12])=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([NH:1][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=2[O:20][CH3:19])[CH:3]=1)[CH3:16]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CCN(CC)c1cc(N)c([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: O
Product: CCN(CC)c1cc(NC(=O)c2ccccc2OC)c([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 80.1 %

Procedure:
To a solution of 1-amino-3-diethylamino-4,6-dinitrobenzene (508 mg, 2.0 mmol) in 5 mL of pyridine, 2-methoxybenzoyl chloride (680 mg, 4.0 mmol) was added. After refluxing for 5 h, 50 mL of water was added to the reaction mixture, and the precipitate was collected by filtration and washed with 200 mL of water. Recrystallization from dichloromethane and methanol gave the desired product (622 mg, 80% yield) as a yellow solid: 1H-NMR (300 MHz, CDCl3) δ 1.29 (t, 6H, J=7.2 Hz), 3.39 (q, 4H, J=7.2 Hz), 4.13 (s, 3H), 7.07 (d, 1H, J=8.1), 7.11 (t, 1H, J=9.8 Hz), 7.55 (t, 1H, J=7.8 Hz), 8.23 (d, 1H, J=8.1 Hz), 8.83 (s, 1H), 8.98 (s, 1H); ESI MS m/z 389.1 [M+H]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]N1C(=O)CCC1=O.O[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:32][CH:31]=1>ClCCl>[C:36]1([C:33]2[CH:34]=[CH:35][C:30]([CH2:29][Br:20])=[CH:31][CH:32]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: OCc1ccc(-c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 93 %

Procedure:
Triphenylphosphine (1.58 g) and N-bromosuccinimide (1.07 g) were added to a stirred solution of 4-hydroxymethylbiphenyl (1.01 g) in dichloromethane (10 mL) under nitrogen. The mixture was stirred at room temperature for 15 hr and evaporated in vacuo. The residue was diluted with chloroform, and washed with saturated sodium hydrogencarobonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:100 to 1:50, v/v) to give the titled compound (1.26 g) as colorless crystals: 1H-NMR (400 MHz, CDCl3) δ 4.55 (s, 2H), 7.33-7.38 (m, 1H), 7.41-7.49 (m, 4H), and 7.54-7.60 (m, 4H).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][O:7][C:8]2([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=[O:15])[CH2:10][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.[CH3:34][O:35][C:36]1[CH:41]=[C:40]([CH3:42])[C:39]([S:43]([N:46]2[CH2:51][CH2:50][CH2:49][CH2:48][C@H:47]2[CH2:52][O:53][CH2:54]C(O)=O)(=[O:45])=[O:44])=[C:38]([CH3:58])[CH:37]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:1]1([CH2:5][CH2:6][O:7][C:8]2([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH2:13][CH2:12][N:11]([C:14](=[O:15])[CH2:54][O:53][CH2:52][C@@H:47]3[CH2:48][CH2:49][CH2:50][CH2:51][N:46]3[S:43]([C:39]3[C:40]([CH3:42])=[CH:41][C:36]([O:35][CH3:34])=[CH:37][C:38]=3[CH3:58])(=[O:45])=[O:44])[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH2:4]1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)O)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CCC(OCCN2CCC2)(c2cccnc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)N2CCC(OCCN3CCC3)(c3cccnc3)CC2)c(C)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 39 %

Procedure:
After the BOC deprotection of tert-butyl 4-(2-(azetidin-1-yl)ethoxy)-4-(pyridin-3-yl)piperidine-1-carboxylate [amine E] (0.15 g, 1.2 eq.) in the presence of TFA (10-13 eq.) in methylene chloride (see e.g. stage (iii)/amine H), the amine was added to a cooled (0° C.) solution comprising (S)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid [acid D] (1 eq.), EDCl (1.5 eq.), HOBT (1 eq.) and DIPEA (3 eq.) in methylene chloride (10 ml). When the addition was complete, the reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was diluted with methylene chloride and washed with aqueous ammonium chloride solution and aqueous sodium bicarbonate solution. After concentration, the crude product was purified by means of column chromatography (Alox). Yield: 39%. MS, Rt=2.7 min, m/z=615.4 [MH]+
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13](C)C)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1(C(N2C=CN=C2)=O)C=CN=[CH:17]1.Cl.[CH3:29][O:30][NH:31][CH3:32].C(N(CC)CC)C>C(Cl)Cl>[CH3:29][O:30][N:31]([CH3:32])[C:10](=[O:12])[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:13])[CH3:17]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CNOC
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C(C)(C)NC(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (5.86 g, 27.0 mmol) in DCM (100 mL) at 0° C. was added portion wise di(1H-imidazol-1-yl)methanone (4.81 g, 29.7 mmol). Cold bath was removed and the reaction was stirred at 20° C. for 30 minutes. O,N-dimethylhydroxylamine hydrochloride (3.16 g, 32.4 mmol) was then added and followed by slow addition of triethylamine (3.28 g, 32.4 mmol). The reaction mixture was stirred at 20° C. for overnight (18 hr), and diluted with DCM (200 mL) and washed with HCl (1 M, 2×50 mL) and saturated NaHCO3 solution (2×50 mL), H2O (50 mL) and brine (50 mL). The organic was then dried (Na2SO4) and concentrated under reduced pressure to give crude product (6.61 g). LCMS m/z 261.2 (M+H)+, Rt 0.77 min.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[C:14]([Cl:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]2[CH:31]=[CH:30][C:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][O:28][CH3:29])[CH2:24][CH2:25][C:19]=3[CH:18]=2)[N:10]=1.C(N(CC)CC)C.[F:39][C:40]([F:47])([F:46])[CH2:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[Cl:15][C:14]1[C:9]([NH:8][C@@H:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]2[NH:1][S:42]([CH2:41][C:40]([F:47])([F:46])[F:39])(=[O:44])=[O:43])=[N:10][C:11]([NH:16][C:17]2[CH:31]=[CH:30][C:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][O:28][CH3:29])[CH2:24][CH2:25][C:19]=3[CH:18]=2)=[N:12][CH:13]=1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4N)n3)cc2CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(=O)(=O)CC(F)(F)F)n3)cc2CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 53 %

Procedure:
N*4*-((1R,2R)-2-Amino-cyclohexyl)-5-chloro-N*2*-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl]-pyrimidine-2,4-diamine was dissolved in Methylene chloride (5 mL) and Triethylamine (0.15 mL, 1.1 mmol) was added, followed by 2,2,2-Trifluoroethanesulfonyl chloride (0.025 mL, 0.23 mmol). Stir under an atmosphere of Nitrogen at room temperature for 45 min, then partition between 10 mL satd. sodium bicarbonate and 10 mL DCM. Separate and extract the aqueous layer, 3×10 mL DCM. Dry the combined organics over sodium sulfate, filter and concentrate in vacuo. The resultant oil was purified on a sulfonic acid resin cartridge, washing with methanol, eluting with ammonia/methanol. Conc. in vacuo reconcentrating from DCM afforded an oil. Subsequent purification on silica gel (0-10% MeOH:DCM, 12 g SiO2) gave 2,2,2-Trifluoro-ethanesulfonic acid ((1R,2R)-2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-amide (55 mg, 53%) as a colorless film. LCMS (m/e) 591 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.88 (s, 1H), 7.21 (d, 1H, J=7.9 Hz), 7.18 (s, 1H), 7.01 (d, 1H, J=7.9 Hz), 6.97 (s, 1H), 5.36 (d, 1H, J=7.5 Hz), 5.31 (s, 1H), 3.84 (m, 1H), 3.61 (q, 2H, J=9.0 Hz), 3.55 (t, 2H, J=5.4 Hz), 3.36 (s, 3H), 3.29 (m, 1H), 2.9 (m, 4H), 2.72 (m, 6H), 2.17 (m, 2H), 1.82 (m, 2H), 1.34 (m, 4H).
Reaction SMILES: [Br:1][C@H:2]1[C:29](=[O:30])[N:4]2[C:5]([C:13]([O:15]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:14])=[C:6]([CH3:12])[C:7](=[CH2:11])[S:8](=[O:10])(=[O:9])[C@H:3]12.FC(F)(F)C(O)=O.CCCCCC>C1(OC)C=CC=CC=1>[Br:1][C@H:2]1[C:29](=[O:30])[N:4]2[C:5]([C:13]([OH:15])=[O:14])=[C:6]([CH3:12])[C:7](=[CH2:11])[S:8](=[O:10])(=[O:9])[C@H:3]12
Reactant: C=C1C(C)=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@H](Br)[C@H]2S1(=O)=O
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C=C1C(C)=C(C(=O)O)N2C(=O)[C@H](Br)[C@H]2S1(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled stirred solution of benzhydryl 7α-bromo-2-methylene-3-methyl-3-cephem-4-carboxylate-1, 1-dioxide (from step D, Example 2, 1.0 g, 2.047 mmol) in dry anisole (10 ml) was added trifluoroacetic acid (4.0 ml) and the mixture was stirred at ice-temperature for 1 hour; solvent was removed under reduced pressure to leave a yellow oil. Hexane was added directly to the yellow oil while a white solid was precipitated out which was collected by filtration (0.549 g, 83%).
Reaction SMILES: [CH:1]([C:3]1[C:4]([OH:27])=[C:5]([O:25][CH3:26])[CH:6]=[C:7]2[C:12]=1[O:11][C:10](=[O:13])[C:9]([CH2:14][C:15]([NH:17][CH2:18][CH2:19][O:20]COC)=[O:16])=[C:8]2[CH3:24])=[O:2].Cl>C(Cl)(Cl)Cl>[CH:1]([C:3]1[C:4]([OH:27])=[C:5]([O:25][CH3:26])[CH:6]=[C:7]2[C:12]=1[O:11][C:10](=[O:13])[C:9]([CH2:14][C:15]([NH:17][CH2:18][CH2:19][OH:20])=[O:16])=[C:8]2[CH3:24])=[O:2]
Reactant: COCOCCNC(=O)Cc1c(C)c2cc(OC)c(O)c(C=O)c2oc1=O
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COc1cc2c(C)c(CC(=O)NCCO)c(=O)oc2c(C=O)c1O
Yield: 11.3 %

Procedure:
A solution of 2-(8-Formyl-7-hydroxy-6-methoxy-4-methyl-2-oxo-2H-chromen-3-yl)-N-(2-(methoxymethoxy)ethyl)acetamide (400 mg, 1.06 mmol) in CHCl3 (40 mL) and conc.HCl (20 mL) was heated to reflux for 1 h, and then concentrated to give the residue and purified by prep.HPLC to give 2-(8-Formyl-7-hydroxy-6-methoxy-4-methyl-2-oxo-2H-chromen-3-yl)-N-(2-hydroxyethyl)acetamide (40 mg, 11.3%) as yellow solid. 1H NMR: (CDCl3, 400 MHz) δ 12.47 (d, J=0.4 Hz, 1H, OH), 10.02 (s, 1H, CHO), 7.22 (s, 1H, ArH), 6.60 (br, 1H, NH), 4.63 (s, 2H, CH2), 3.97 (s, 3H, OCH3), 3.60 (t, J=5.4 Hz, 4H, CH2), 3.45 (m, 2H, CH2), 3.36 (d, J=0.4 Hz, 2H, CH2), 2.57 (s, 3H, CH3); MS [ESI, MH+]: 380.2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[N+:19]([O-])=O)[O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[N:10][CH:11]=1.O1CCCC1>[C].[Pd].CO>[CH3:1][C:2]1[CH:3]=[C:4]([O:5][C:6]2[CH:11]=[N:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:7]=2)[CH:16]=[CH:17][C:18]=1[NH2:19]
Reactant: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)ccc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.4 %

Procedure:
A mixture of 5-(3-methyl-4-nitrophenoxy)-2-(methylsulfonyl)pyridine (12.58 g), 10% palladium carbon (2.5 g, containing water (50%)), tetrahydrofuran (200 mL), and methanol (50 mL) was stirred under a hydrogen atmosphere (balloon pressure) at room temperature for 18 hr. The catalyst was filtered off, and the obtained filtrate was concentrated under reduced pressure to give the title compound (11.4 g, yield 100%) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][NH:7][C:8](=[O:25])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19](F)[CH:18]=[CH:17][C:16]=2[N+:22]([O-:24])=[O:23])[CH:10]=1.[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][NH:7][C:8](=[O:25])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:33]([CH2:34][CH3:35])[CH2:31][CH3:32])[CH:18]=[CH:17][C:16]=2[N+:22]([O-:24])=[O:23])[CH:10]=1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(F)ccc2[N+](=O)[O-])c1
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)c1ccc([N+](=O)[O-])c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 16 h
Yield: 88.8 %

Procedure:
A 25° C. mixture of 500 mg of 2-(5-fluoro-2-nitrophenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide 14d, 131 mg of diethylamine, and 329 mg of K2CO3 in 4 mL of DMF was stirred for 16 h and then stirred for an additional 24 h at 60° C. The mixture was diluted with ethyl acetate, and the resulting solution was washed with water, and then with brine. The solution was dried (Na2SO4) and the solvent was removed at reduced pressure. The residue was purified by chromatography on silica gel to give 500 mg of a yellow solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]=[C:12]=[S:13].[NH2:14][CH:15]([C:21]#[N:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CCO>[NH2:22][C:21]1[S:13][C:12]([NH:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[N:14][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(N)C#N
Reactant: S=C=Nc1ccc2ccccc2c1
Solvent: CCO
Product: CCOC(=O)c1nc(Nc2ccc3ccccc3c2)sc1N
Temperature: 80 °C
Yield: 66.8 %

Procedure:
A mixture of 2-naphthalenyl isothiocyanate (0.5 g, 2.7 mmol) and ethyl 2-amino-2-cyanoacetate (0.38 g, 2.97 mmol) in EtOH (16 mL) was heated at 80° C. for 3 h. The reaction mixture was cooled to rt, and the solvent was concentrated in vacuo. The resulting solids were collected and washed with n-Hexane-EtOAc (1:1) to give 565 mg (67% yield) of the titled compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[CH3:24][O:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:30]5[CH:29]=[N:28][CH:27]=[C:26]([O:25][CH3:24])[CH:31]=5)=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: COc1cncc(-c2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)sc2CCO3)c1
Yield: 60 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine were reacted to give 343 (0.062 g, 60%). 1H NMR (500 MHz, DMSO) δ 8.72 (d, J=2.4, 1H), 8.50 (d, J=1.8, 1H), 8.29 (d, J=2.7, 1H), 8.11 (s, 1H), 7.71 (dd, J=8.4, 2.4, 1H), 7.64 (dd, J=2.6, 2.0, 1H), 7.21 (d, J=8.4, 1H), 5.82 (dd, J=13.2, 6.6, 1H), 4.43 (t, J=5.0, 2H), 3.92 (s, 3H), 3.49 (t, J=5.0, 2H), 1.56 (d, J=6.6, 6H). MS (ESI(+)): m/z 420.1 (M+H)
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:42][C:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCCC1
Product: CCN(Cc1ccc(OCCN2CCCC2)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 28 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-1-pyrrolidin-1-ylethanone (8.0 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (4.2 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[BH4-].[Na+].O>CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:10]
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1ccc(Br)cc1C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-Amino-5-bromo-phenyl)-phenyl-methanone (4.00 g, 14.49 mmol) is dissolved in methanol (50 mL). Sodium borohydride (0.55 g, 14.49 mmol) is added in small portions over 45 minutes. The reaction mixture is stirred at room temperature overnight. Water (10 mL) is added and the mixture stirred at room temperature for 15 minutes. The solvent is removed and the residue purified by column chromatography on silica gel using a petrol ether/ethylacetate gradient. This affords the desired compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2OC(=O)[C:11](=[C:15]=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].O.[NH2:18][NH2:19].CN(C)[CH:22]=[O:23].C(O)(=O)C>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]([CH2:22][OH:23])[CH2:11][C:15](=[O:16])[NH:18][N:19]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CN(C)C=O
Reactant: NN
Reactant: N#Cc1ccc(C2CC(=C=O)C(=O)O2)cc1
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(C2=NNC(=O)CC2CO)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
3.0 g (0.014 mol) of 4-(4-cyanophenyl)-carbonyl-γ-butyrolactone and 1 ml (0.021 mol) of hydrazine hydrate are stirred in 50 ml of ethanol and 50 ml of dimethylformamide at room temperature for 10 hours. After addition of 1 ml of acetic acid, the mixture is stirred at 80° C. for 18 hours and worked up as above.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[CH3:12][S:13]([C:15](SC)=[CH:16][N+:17]([O-:19])=[O:18])=O>CO>[N+:17]([CH:16]=[C:15]([S:13][CH3:12])[NH:11][CH2:10][CH2:9][S:8][CH2:7][C:3]1[N:4]=[CH:5][NH:6][C:2]=1[CH3:1])([O-:19])=[O:18]
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Reactant: Cc1[nH]cnc1CSCCN
Solvent: CO
Product: CSC(=C[N+](=O)[O-])NCCSCc1nc[nH]c1C
Yield: 49.6 %

Procedure:
A solution of 2-[(5-methyl-4-imidazolyl)methylthio]ethylamine (8.56 g) in methanol (115 ml) was added dropwise over 13 minutes to a stirred solution of 1-methylsulphinyl-1-methylthio-2-nitroethylene (9.06 g) in methanol (150 ml) at 40°. Evaporation of the reaction mixture and recrystallisation of the resultant solid from isopropanol yielded the title product (7.15 g), m.p. 147°-150°.
Reaction SMILES: CS(O[C@H:6]([CH3:16])[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[CH3:15])(=O)=O.[N-:17]=[N+:18]=[N-:19].[Na+].O>CN(C=O)C>[N:17]([C@@H:6]([CH3:16])[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[CH3:15])=[N+:18]=[N-:19]
Reactant: Cc1ccc(F)cc1C[C@@H](C)OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(F)cc1C[C@H](C)N=[N+]=[N-]
Temperature: 80 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
A solution of (R)-1-(5-fluoro-2-methylphenyl)propan-2-yl methanesulfonate (6.3 g, 2.56 mmol) in anhydrous DMF (30 mL) was added sodium azide (3.32 g, 5.11 mmol) and the solution was heated to 80° C. and stirred for 2 h. Then, the temperature was cooled to rt and 20 mL of water was added, extracted with EtOAc/hexane (1/1, v/v), dried over anhydrous MgSO4 and evaporated to give crude oil, which was passed through silicagel pad and evaporated under reduced pressure to give (S)-2-(2-azidopropyl)-4-fluoro-1-methylbenzene (F-3), which used as starting material for next reduction without more purification. To the solution of (S)-2-(2-azidopropyl)-4-fluoro-1-methylbenzene in 80 mL of EtOAc was added Pd/C (500 mg, 10% Pd) and the mixture was hydrogenated under Parr Apparatus (30˜40 psi) for 2 h. The catalyst was removed by filtration through Celite pad, then purified by column chromatography as an eluent (EtOAc/MeOH/NH4OH=93/5/2) to give (S)-1-(5-fluoro-2-methylphenyl)propan-2-amine (F) as pale yellow oil (total yield=30% through 4 steps). MS (ESI) m/z 168.0 [M+H]+; 1H NMR (CDCl3, 500 MHz) δ 7.10 (m, 1H), 6.84 (m, 2H), 3.19 (m, 1H), 2.69 (dd, J=13.5, 6.0 Hz, 1H), 2.56 (dd, J=13.5, 8.0 Hz, 1H), 2.28 (s, 3H), 1.68 (bs, 2H), 1.15 (d, J=6.0 Hz, 3H).
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([O:8]CC)(=[O:7])[CH3:6].C(C1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:15][CH:14]=1)#N.[OH-].[Na+]>C(O)(=O)C>[C:23]1([C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]([C:5]([OH:8])=[O:7])=[CH:14][N:15]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: N#Cc1cnc(-c2ccccc2)c2ccccc12
Reactant: CCOC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=C(O)c1cnc(-c2ccccc2)c2ccccc12

Procedure:
20.5 g of 1-phenylisoquinoline are dissolved in 100 ml of carbon tetrachloride, and 16 g of bromine are added at room temperature. The temperature is raised slowly and the mixture is kept under reflux for 1 hour. 7.9 g of pyridine in 10 ml of carbon tetrachloride are added dropwise to the boiling reaction mixture in the course of 2 hours, and the mixture is then heated at reflux temperature for a further 18 hours. The reaction solution is decanted off from the resinous precipitate and is concentrated, and the residue is crystallized from diisopropyl ether. 11.7 g of 4-bromo-1-phenylisoquinoline of melting point 123°-125° C. are obtained. 0.7 g of 4-bromo-1-phenylisoquinoline, 0.45 g of copper cyanide and 10 ml of dimethylformamide are heated at 160° C. for 6 hours. The reaction solution is decanted off, diluted with methylene chloride and washed with water. 0.75 g of crude product are isolated from the methylene chloride phase, and 0.2 g of 4-cyano-1-phenylisoquinoline of melting point 138°-140° is obtained from this crude product by column chromatography over silica gel using a 98:2 mixture of chloroform and ethyl acetate. 0.2 g of 4-cyano-1-phenylisoquinoline is heated with 10 ml of 20% strength sodium hydroxide solution at 100° C. for 4 hours. The solution is cooled and acidified with acetic acid. The precipitate is filtered off and dried. 0.18 g of 1-phenylisoquinoline-4-carboxylic acid of melting point 215°-217° is isolated.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][C:22]=2[C:31]([F:34])([F:33])[F:32])O1>>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=1[C:31]([F:32])([F:34])[F:33])[CH:11]=[CH:10]2
Reactant: Oc1ccc2nc(Cl)ccc2c1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C(F)(F)F)c1
Product: O=C(O)c1ccc(-c2ccc3cc(O)ccc3n2)c(C(F)(F)F)c1

Procedure:
Followed Scheme 3: starting with 2-chloroquinolin-6-ol and methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzoate (Intermediate 5).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:19]=[C:20](\[CH3:24])/[C:21]([OH:23])=[O:22])[CH:5]=[C:6]([F:18])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]([CH3:17])[CH3:16])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)[C:33]1C=C(O)C=C[CH:38]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4](/[CH:19]=[C:20](\[CH3:24])/[C:21]([O:23][CH2:33][CH3:38])=[O:22])[CH:5]=[C:6]([F:18])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]([CH3:16])[CH3:17])[CH:10]=1
Reactant: CN(C)c1cccc(O)c1
Reactant: C/C(=C\c1cc(F)c(Oc2cccc(N(C)C)c2)c(F)c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(C)=C/c1cc(F)c(Oc2cccc(N(C)C)c2)c(F)c1

Procedure:
E-3-[3,5-Difluoro-4-(3-dimethylaminophenoxy)phenyl]-2-methyl-propenoic acid guanidide hydrochloride ##STR15## 10 a) The ester from 8 a, 3 eq. of potassium carbonate and 1.1 eq. of 3-dimethylaminophenol were stirred in DMF at 150° C. for 5 hours. After working up and purification, ethyl E-3-[3,5-difluoro-4-(3-dimethylaminophenoxy)phenyl]-2-methyl-propenoate was isolated.