Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[C:8]1([Mg]Br)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>C1COCC1.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ni]Cl>[C:8]1([C:2]2[CH:7]=[N:6][CH:5]=[CH:4][N:3]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1cnccn1
Reactant: Br[Mg]c1ccccc1
Agent: Cl[Ni]Cl
Agent: Cl
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(-c2cnccn2)cc1
Reaction time: 1.33 h
Yield: 39 %

Procedure:
Chloropyrazine (20.68 gram, 177 mmol) and [1,2-bis(diphenylphosphino)ethane]nickel(II) chloride (41.08 gram, 77.8 mmol) in dry THF (1.5 liter) were mixed and stirred for 80 minutes in a flask (cooled with a water bath) under nitrogen. A solution of phenylmagnesium bromide (3M in Et2O) (103 ml, 309 mmol) was added slowly through a dropping funnel into the cooled brick-red slurry at room temperature under nitrogen over 3.5 hours. After stirring at room temperature overnight, TLC showed that the reaction was complete. 3N HCl (100 ml) was added slowly through a dropping funnel under nitrogen and the mixture was stirred for one hour. The THF layer was separated from the aqueous layer. The aqueous layer was adjusted to pH 12 with 6N NaOH and extracted with EtOAc (100 ml, 3×). The organic fractions (THF and EtOAc) were combined and dried over MgSO4, filtered and concentrated to give a solid. The product was purified by flash chromatography on 300 g of flash grade silica gel in 2.5% EtOAc/CH2Cl2 to give 10.79 gram (69 mmol, 39%) of 2-phenylpyrazine, m.p. 69-70 C.; FAB mass [M+1]+ 157;
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[CH2:2].[CH2:12](O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12])=[O:8])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(C(=O)O)cc1
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=Cc1ccc(C(=O)OCCCCCCCCCCCCCCCCCC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51 %

Procedure:
A stirred mixture of 2.91 g (20 mmol) of 4-vinylbenzoic acid, 5.84 g (22 mmol) of 1-octadecanol, 0.17 g (1 mmol) of 4-toluenesulfonic acid, and 75 ml of toluene was heated at reflux with water separated azeotropically using a Dean-Stark trap. After 16 hours, the mixture was cooled to ambient temperature and filtered through a short column of basic alumina, eluting with tetrahydrofuran. The filtrate was concentrated to deposit a solid product, which was purified by chromatography on silica gel (a heptane/dichloromethane eluate), followed by recrystallization from acetonitrile. A white solid was obtained, mass 3.98 g (51% yield).
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11]([O:13]CC)=[O:12].[OH-].[Na+]>C(O)C.C1COCC1>[Br:1][C:2]1[N:6]([C:7]([CH3:8])([CH3:9])[CH3:10])[N:5]=[CH:4][C:3]=1[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)n1ncc(C(=O)O)c1Br
Yield: 84.8 %

Procedure:
A mixed solution of the compound (13.5 g, 49.07 mmol) obtained in step 2 and 1N aqueous sodium hydroxide solution (65 mL, 65.00 mmol) in ethanol (70 mL) and THF (70 mL) was stirred at 60° C. for 2.5 hr. The organic solvent was evaporated under reduced pressure, and water and 1N hydrochloric acid (70 mL) were added thereto. The precipitate was collected by filtration, and washed with diethyl ether and hexane to give 5-bromo-1-tert-butyl-1H-pyrazole-4-carboxylic acid (10.29 g, 41.6 mmol, 85%) as a white powder.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.[Cl:24][C:25]1[C:31]([OH:32])=[CH:30][C:28]([NH2:29])=[C:27]([F:33])[CH:26]=1>CC(O)CCC.CN(C=O)C>[ClH:2].[Cl:24][C:25]1[C:31]([OH:32])=[CH:30][C:28]([NH:29][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][CH:4]=2)=[C:27]([F:33])[CH:26]=1
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: COc1cc2c(Cl)ccnc2cc1OCCCN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCCC(C)O
Product: COc1cc2c(Nc3cc(O)c(Cl)cc3F)ccnc2cc1OCCCN1CCCC1
Yield: 54.4 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinoline hydrochloride (325 mg, 0.82 mmol) and 4-chloro-2-fluoro-5-hydroxyaniline (133 mg, 0.82 mmol), (as described in EP 61741 A2), in 2-pentanol (10 ml) and DMF (1 ml) was heated at reflux for 5 hours. The volatiles were removed by evaporation and the residue was purified by column chromatography eluting with acetonitrile/water containing 1% TFA (30/70). Concentrated hydrochloric acid was added to the fractions and the solvents were removed by evaporation. The residue was azeotroped with toluene, and triturated with isopropanol. The solid was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinoline hydrochloride (215 mg, 50%).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:19])[C:14]=2[NH2:18])[C:9]1=[O:20])[CH3:7])(=[O:3])[CH3:2].[F:21][C:22]1[CH:23]=[C:24]([CH2:32][C:33](O)=[O:34])[CH:25]=[CH:26][C:27]=1[C:28]([F:31])([F:30])[F:29].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>>[C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:19])[C:14]=2[NH:18][C:33](=[O:34])[CH2:32][C:24]2[CH:25]=[CH:26][C:27]([C:28]([F:29])([F:30])[F:31])=[C:22]([F:21])[CH:23]=2)[C:9]1=[O:20])[CH3:7])(=[O:3])[CH3:2]
Reactant: O=C(O)Cc1ccc(C(F)(F)F)c(F)c1
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(N)c(C)ccc2c1=O
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: CN(C)C=O
Product: CC(=O)OC[C@@H](C)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)c(F)c3)c(C)ccc2c1=O
Temperature: 45 °C
Reaction time: 24 h

Procedure:
A round bottom flask was charged with (R)-2-(5-amino-6-methyl-1-oxoisoquinolin-2(1H)-yl)propyl acetate (175 mg, 0.000638 mol), 2-(3-fluoro-4-(trifluoromethyl)phenyl)acetic acid (210 mg, 0.00096 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (610 mg, 0.0016 mol), N,N-diisopropylethylamine (0.28 mL, 0.0016 mol) and N,N-dimethylformamide (8 mL, 0.1 mol). The reaction mixture was stirred at 45° C. for 24 hours. The reaction was quenched with water and extracted with ethyl acetate, washed with sodium bicarbonate, brine, and dried. The solvent was removed under reduced pressure and the residue was purified by flash chromatography to afford the product as a light yellow oil.
Reaction SMILES: C([O:5][C:6](=[O:52])[CH:7]([NH:12][C:13](=[O:51])[C:14]1[CH:19]=[C:18]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:16][C:15]=1[S:24][S:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:35])[CH3:34])=[CH:28][C:27]=1[C:36](=[O:50])[NH:37][CH:38]([C:43]([O:45]C(C)(C)C)=[O:44])[CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:8][CH:9]([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:21]([NH:20][C:18]1[CH:17]=[CH:16][C:15]([S:24][S:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:35])[CH3:34])=[CH:28][C:27]=2[C:36](=[O:50])[NH:37][CH:38]([C:43]([OH:45])=[O:44])[CH2:39][CH:40]([CH3:41])[CH3:42])=[C:14]([CH:19]=1)[C:13]([NH:12][CH:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6]([OH:52])=[O:5])=[O:51])(=[O:23])[CH3:22]
Reactant: CC(=O)Nc1ccc(SSc2ccc(NC(C)=O)cc2C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)c(C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1ccc(SSc2ccc(NC(C)=O)cc2C(=O)NC(CC(C)C)C(=O)O)c(C(=O)NC(CC(C)C)C(=O)O)c1
Yield: 77.3 %

Procedure:
This compound was prepared according to the procedure described in Example 50 using [S-(R*,R*)] 2-{5-acetylamino-2-[4-acetylamino-2-(1-tert-butoxycarbonyl-3-methyl-butylcarbamoyl)-phenyldisulfanyl]-benzoylamino}-4-methyl-pentanoic acid tert-butyl ester (0.2 g, 0.2 mmol) from Example 44, 10 mL dichloromethane, and 10 mL trifluoroacetic acid. The crude product was recrystallized from dimethylformamide/water to afford 0.1 g of the title compound, mp 241-242° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.N1CCCCC1.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1>CO>[Cl:17][C:18]1[CH:26]=[C:25]2[C:21](/[C:22](=[CH:5]\[C:4]3[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[C:3]=3[F:10])/[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1cccc(Cl)c1F
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(Cl)ccc2/C1=C\c1cccc(Cl)c1F
Reaction time: 8 h
Yield: 96.1 %

Procedure:
3-Chloro-2-fluorobenzaldehyde (6.24 g, 39.4 mmol) was added to a solution of piperidine (3.88 mL, 39.4 mmol) and 6-chlorooxindole (6.0 g, 35.8 mmol) dissolved in methanol (100 mL). After stirring overnight, the resulting solid was filtered and washed with methanol and hexanes to give 10.6 g of (E)-6-chloro-3-(3-chloro-2-fluorobenzylidene)indolin-2-one (3) as a green solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C@@H:9]2[C:18]3[C:13](=[C:14]([F:20])[CH:15]=[CH:16][C:17]=3[F:19])[O:12][CH2:11][C@H:10]2[CH2:21][OH:22])=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[H-].[Na+].O>C1COCC1.C(OCC)(=O)C>[CH2:27]([O:26][CH2:25][CH2:24][O:22][CH2:21][CH:10]1[CH:9]([S:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:18]2[C:13](=[C:14]([F:20])[CH:15]=[CH:16][C:17]=2[F:19])[O:12][CH2:11]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCCOCc1ccccc1
Reactant: OC[C@@H]1COc2c(F)ccc(F)c2[C@H]1Sc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccc(F)c2c1OCC(COCCOCc1ccccc1)C2Sc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trans-[4-(4-chloro-phenylsulfanyl)-5,8-difluoro-chroman-3-yl]-methanol (0.6 g, 1.65 mmole) and (2-bromo-ethoxymethyl)-benzene (0.71 g, 3.3 mmole) were dissolved in 30 ml THF and NaH (0.5 g) was added. The reaction was stirred at room temperature overnight. (2-Bromo-ethoxymethyl)-benzene (0.71 g, 3.3 mmole) and NaH (0.5 g) were added and the reaction was refluxed overnight. 50 ml water and 50 ml EtOAc were added. The organic layer washed with Sat. NaCl solution (50 ml), dried over Na2SO4 and concentrated. The product was purified by column chromatography (EtOAc/Hex. from 0/100 to 25/75 in 40 minute). Yield: 0.42 g, 53%. 1H NMR (CDCl3 400 MHz δ 7.42 (d, J=8.8 Hz, 2H), 7.25-7.37 (m, 7H), 6.96 (m, 1H), 6.57 (m, 1H), 4.60 (dd, J=11.7 and 2.2 Hz, 1H), 4.52 (bs, 3H), 4.40 (t, J=11.0, 1H), 3.3-3.56 (m, 6H), 2.38 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].F[C:8]1[CH:13]=[C:12]([F:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20]>C(O)C>[F:14][C:12]1[C:11]([C:15]([F:16])([F:17])[F:18])=[CH:10][C:9]([N+:19]([O-:21])=[O:20])=[C:8]([CH:13]=1)[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6]
Reactant: NCCCCO
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(F)cc1F
Solvent: CCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(F)cc1NCCCCO
Reaction time: 8 h
Yield: 79.8 %

Procedure:
With ice-cooling, 4-aminobutanol (0.72 g) dissolved in ethanol (5 ml) was added dropwise to ethanol (10 ml) solution of 1,5-difluoro-2-nitro-4-trifluoromethylbenzene (0.73 g), and the reaction was carried out overnight at room temperature. The reaction solution was concentrated and the resulting residue was purified by a silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give 4-(5-fluoro-2-nitro-4-trifluoromethylanilino)butanol (0.76 g). The resulting anilinobutanol (0.66 g) and imidazole (1.5 g) were allowed to react with each other in DMF (10 ml) at 140° C. for 1 hour, the reaction solution was concentrated and then the resulting residue was purified by a silica gel column chromatography (chloroform:methanol =15:1) to give 4-[5-(1H-imidazol-1-yl)-2-nitro-4-trifluoromethylanilino)butanol (0.68 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:31]C(OC)=O)[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](C4C=CC(=O)N(C)C=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([Mg][Br:39])C.[CH2:40]1[CH2:44][O:43]C[CH2:41]1>C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[Br:39][C:20]1[CH:21]=[CH:22][C:17]([C@@H:15]([N:11]2[CH2:10][CH2:9][C@@:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)([CH2:31][C:44]3([OH:43])[CH2:41][CH2:40]3)[O:13][C:12]2=[O:14])[CH3:16])=[CH:18][CH:19]=1
Reactant: C1CCOC1
Reactant: COC(=O)C[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(=O)n(C)c3)cc2)C(=O)O1
Reactant: CC[Mg]Br
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC2(O)CC2)(c2ccc(F)cc2)OC1=O
Reaction time: 2 h
Yield: 2 %

Procedure:
To a solution of methyl 2-((S)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-ethyl)-2-oxo-1,3-oxazinan-6-yl)acetate (150 mg, 0.33 mmol), and tetraisopropoxytitanium (189 mg, 0.66 mmol) in THF (20 mL) was added 3.0 M ethylmagnesium bromide (4 mL, 12 mmol) at rt under nitrogen. Then the mixture was stirred for 2 h. The reaction was quenched with aqueous NH4Cl solution, and the mixture was filtered. The filtrate was extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by preparative HPLC to give (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-((1-hydroxycyclopropyl)methyl)-1,3-oxazinan-2-one (2.51 mg, 2%). 1H NMR (CDCl3): 0.03 (m, 1H), 0.18 (m, 1H), 0.49 (m, 1H), 0.60 (m, 1H), 1.43 (m, 3H), 2.08 (s, 2H), 2.26 (m, 1H), 2.37 (m, 2H), 2.88 (m, 1H), 5.53 (m, 1H), 6.66 (d, 2H), 6.97 (t, 2H), 7.16 (m, 2H), 7.26 (m, 2H).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:5]=[N:4][C:3]=1[O:14][CH3:15].[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][Si](C(C)(C)C)(C)C)[CH:30]=2)[CH:25]=[C:24]1B(O)O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>O1CCOCC1.O>[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([OH:32])[CH:30]=2)[CH:25]=[C:24]1[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:5]=[N:4][C:3]=1[O:14][CH3:15])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccc(O[Si](C)(C)C(C)(C)C)cc21
Reactant: COc1nnc(-c2ccncc2)cc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(O)cc2n1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
600 mg 4-Iodo-3-methoxy-6-pyridin-4-yl-pyridazine, 974 mg 1-(tert-butoxycarbonyl)-6-(tert-butyldimethylsiloxy)indole-2-boronic acid, 2.5 g cesium carbonate, and 78 mg [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) are dissolved in a mixture of 18 mL dioxane and 5.4 mL water. Argon is bubbled through the solution for 5 minutes. The mixtures is heated to reflux for 2 hours. After diluting with EtOAc, the organic phase is ished with water and brine, dried with MgSO4 and concentrated in vacuo. The crude product is dissolved in 30 mL THF. After addition of 1.51 g tetrabutylammonium fluoride trihydrate, the red solution is stirred for 2 hours. The reaction mixture is diluted with EtOAc, ished with saturated aqueous ammonium chloride, water, and brine, dried with MgSO4 and concentrated in vacuo. Purification by HPLC afforded 760 mg (95%) 6-hydroxy-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C@@H:16]1([NH2:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:26][C@@H:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2)cc1
Product: Clc1ccc(-c2ccc(CN[C@H]3CCCc4ccccc43)cc2)cc1

Procedure:
4′-Chloro[1,1′-biphenyl]-4-carbaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:8][C:9]([O:11]C)=O)[C:4]([Cl:7])=[CH:5][CH:6]=1.[CH3:13][NH2:14]>>[Cl:1][C:2]1[N:3]([CH2:8][C:9]([NH:14][CH3:13])=[O:11])[C:4]([Cl:7])=[CH:5][CH:6]=1
Reactant: COC(=O)Cn1c(Cl)ccc1Cl
Reactant: CN
Product: CNC(=O)Cn1c(Cl)ccc1Cl
Reaction time: 8 h

Procedure:
A mixture of methyl (2,5-dichloro-1H-pyrrol-1-yl)acetate (1.04 g) and methylamine (5 cm3, 33% solution in ethanol) was allowed to stand at room temperature overnight. The solvent was then evaporated and the residue crystallised from isopropanol to give the title compound (0.65 g) m.p. 193°-4° C.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]([C:7]([CH2:9][NH2:10])=[O:8])=[CH:3]1.C(=O)(O)[O-].[Na+].[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:10][CH2:9][C:7]([C:4]2[CH:5]=[CH:6][S:2][CH:3]=2)=[O:8])=[O:22])=[CH:19][CH:18]=1
Reactant: NCC(=O)c1ccsc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(CNC(=O)c1ccc(Cl)cc1)c1ccsc1
Yield: 94.9 %

Procedure:
19.4 g of N-[(3-thienylcarbonyl)methyl]amine hydrochloride, 36 g of sodium bicarbonate and 21 g of 4-chlorobenzoyl chloride are treated in the same manner as described in Preparation 1-(3). 29 g of N-(4-chlorobenzoyl)-N-[(3-thienylcarbonyl)methyl]amine are thereby obtained.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]2)=[C:4]([F:18])[CH:3]=1.CC(C)=O.N([O-])=O.[Na+].[C:27]([O:31][CH3:32])(=[O:30])[CH:28]=[CH2:29].[BrH:33]>O>[F:18][C:4]1[CH:3]=[C:2]([CH2:29][CH:28]([Br:33])[C:27]([O:31][CH3:32])=[O:30])[CH:7]=[CH:6][C:5]=1[N:8]1[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]1
Reactant: Cc1nn(-c2ccc(N)cc2F)c(=O)n1C(F)F
Reactant: C=CC(=O)OC
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)C(Br)Cc1ccc(-n2nc(C)n(C(F)F)c2=O)c(F)c1
Temperature: 8 °C

Procedure:
A mixture of 9.0 g (0.035 mole) of 1-(4-amino-2-fluorophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one in 25 mL of 48% hydrobromide acid was stirred and 70 mL of acetone was added. The reaction mixture was cooled to 8° C. and a solution of 2.5 g (0.036 mole) of sodium nitrite in 7 mL of water was added below the surface of the reaction mixture. The reaction mixture temperature was kept below 15° C. during the addition. Upon completion of addition 25.0 g (0.30 mole) of methyl acrylate was added. The reaction mixture was then cooled to 0°-5° C. and 0.15 g of cuprous bromide was added slowly. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it was stirred for 1 hour. After this time the reaction mixture was diluted with water and was extracted with diethyl ether. The ether extract was dried with magnesium sulfate and filtered. The filtrate was passed through a pad of silica gel and concentrated under reduced pressure to yield 11.3 g of methyl 3-[3-fluoro-4(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl]-2-bromopropionate as an oil. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH2:10])=O)=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.N1C(Cl)=NC(Cl)=NC=1Cl>CN(C)C=O>[Cl:1][C:2]1[C:7]([C:8]#[N:10])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12
Reactant: NC(=O)c1cnc2ccsc2c1Cl
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Product: N#Cc1cnc2ccsc2c1Cl
Temperature: 0 °C
Yield: 90.7 %

Procedure:
To a solution of 7-chlorothieno[3,2-b]pyridine-6-carboxamide (10.8 g, 51 mmol) in 80.0 mL of N,N-dimethylformamide is added cyanuric chloride (5.72 g, 31 mmol). After 30 minutes the suspension is poured into ice water. The solid is filtered, washed with ice water and dried in vacuo to give 9.0 g of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile as an off white solid, mp 105-107° C.; 1H NMR (DMSO-d6) δ 7.83 (s, 1H), 8.61 (s, 1H), 9.12 (s, 1H); MS 195.0, 197.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][NH2:27])=[O:25])=[CH:22][CH:21]=1)#[N:19].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([NH:27][NH:26][C:24](=[O:25])[C:23]2[CH:22]=[CH:21][C:20]([C:18]#[N:19])=[CH:29][CH:28]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[C@@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1)C(=O)O
Reactant: N#Cc1ccc(C(=O)NN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1)C(=O)NNC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a pre-cooled (−30° C.) solution of (2R,3R)-2-(3-chloro-4-cyanophenylamino)-3-hydroxybutanoic acid (1.06 g, 4.16 mmol) and 4-cyanobenzohydrazide (671 mg, 4.16 mmol) in anhydrous THF (60 mL) was added 1-Hydroxybenzotriazole monohydrate (637 mg, 4.16 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide-HCl (1.60 g, 8.32 mmol) at −30° C. followed by triethylamine (1.16 mL, 8.32 mmol). The reaction mixture warmed to room temperature and stirred for 16 h, then quenched with 5% aq. citric acid (150 mL). The solution was extracted with EtOAc (150 mL). The organic extract was washed with 5% aq. citric acid (2×75 mL), sat. aq. NaHCO3 (3×80 mL), H2O (2×100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound as an off white solid (1.65 g, 100%): 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.11 (dm, J=8.8 Hz, 2H), 7.94 (dm, J=8.6 Hz, 2H), 7.54 (d, J=8.6 Hz, 1H), 6.96 (d, J=2.3 Hz, 1H), 6.85 (dd, J=2.3, 8.8 Hz, 1H), 6.44 (d, J=7.4 Hz, 1H), 4.21-4.11 (m, 2H), 1.35 (d, J=6.3 Hz, 3H).
Reaction SMILES: [Se](=O)=[O:2].[Br:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=1>O1CCOCC1.O>[Br:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH:15]=[O:2])=[O:16])=[CH:10][CH:9]=1
Reactant: CC(=O)c1ccc(OCCBr)cc1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: O=CC(=O)c1ccc(OCCBr)cc1
Yield: 97.4 %

Procedure:
A suspension of selenium dioxide (0.821 g, 7.4 mmol) in 1,4-dioxane (40 mL) and water (3 mL) was heated at 55° C. until selenium dioxide was dissolved. To the solution was added 1-[4-(2-bromoethoxy)phenyl]ethanone (1.80 g, 7.4 mmol), and the reaction was heated to reflux for 4 hours. The reaction was filtered, concentrated, and purified by column chromatography (SiO2, 50% ethyl acetate/hexane) to provide the title compound (1.853 g, 97% yield): ES−MS (m/z) 257 [M+H]+.