Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[N:4]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:3]=1.[F:21][C:22]1[C:30]([NH:31][S:32]([CH2:35][CH2:36][CH3:37])(=[O:34])=[O:33])=[CH:29][CH:28]=[C:27]([F:38])[C:23]=1[C:24](O)=[O:25].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:21][C:22]1[C:30]([NH:31][S:32]([CH2:35][CH2:36][CH3:37])(=[O:33])=[O:34])=[CH:29][CH:28]=[C:27]([F:38])[C:23]=1[C:24]([NH:11][C:8]1[CH:9]=[C:10]2[C:2]([I:1])=[CH:3][N:4]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1)=[O:25]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Reactant: Nc1cnc2c(c1)c(I)cn2S(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
3-Iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-amine (0.506 g, 1.27 mmol), 2,6-difluoro-3-(propylsulfonamido)benzoic acid (0.389 g, 1.39 mmol), EDCI (0.267 g, 1.39 mmol) and HOBt (0.188 g, 1.39 mmol) were dissolved in DMF (10 mL) and stirred at room temperature overnight. The organic portion was washed with water (3×), brine, dried over Na2SO4 and concentrated. The resulting residue was purified by column chromatography (1:1:1 hexane/Et2O/DCM) giving 2,6-difluoro-N-(3-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (0.738 g, 88.2%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[OH:22][C@@H:23]1[CH2:27][NH:26][C@H:25]([C:28]([NH2:30])=[O:29])[CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH2:27][C@@H:23]([OH:22])[CH2:24][C@H:25]3[C:28]([NH2:30])=[O:29])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: NC(=O)[C@@H]1C[C@H](O)CN1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)[C@@H]1C[C@H](O)CN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with (2S,4S)-4-hydroxypyrrolidine-2-carboxamide hydrochloride (851233-67-5) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=397.5 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[N-:10]=[N+:11]=[N-:12].[Na+].C(N(CC)CC)C>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[N:10]=[N:11][NH:12][N:9]=2)[CH:7]=1
Reactant: N#Cc1cncc(Br)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Brc1cncc(-c2nn[nH]n2)c1
Temperature: 25 °C

Procedure:
A solution of 3-bromo-5-cyanopyridine (1 eq), sodium azide (1.2 eq), triethylamine (1.2 eq) and AcOH (1.2 eq) was stirred at 100C for 14 h. The reaction mixture was cooled to rt, diluted with aqueous acetic acid solution and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to afford the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1O>C(O)(=O)C>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)=[CH:3][CH:2]=1
Reactant: O=Cc1ccncc1
Reactant: Nc1ccccc1O
Solvent: CC(=O)O
Product: c1ccc2oc(-c3ccncc3)nc2c1
Temperature: 100 °C

Procedure:
A 500 mg portion of pyridine-4-aldehyde was dissolved in 15 ml of acetic acid, and the solution was mixed with 509 mg of o-aminophenol and stirred with heating at 100° C. for 6 hours. The solvent was concentrated under a reduced pressure, and the residual oily matter was mixed with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate, and then the solvent was evaporated under a reduced pressure. Thereafter, the thus obtained mixture was purified by a silica gel column chromatography (ethyl acetate:hexane 1:1) to obtain the title compound (90 mg) in light yellow color.
Reaction SMILES: [C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5].[NH4+:9].[NH4+].P(O)([O-])([O-])=O.[K+].[K+].S([O-])([O-])(=O)=O.[Mg+2].C(=O)([O-])[O-].[Ca+2]>>[NH2:9][C@H:2]([C:1]([OH:8])=[O:7])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: [NH4+]
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])[O-]
Product: N[C@@H](CC(=O)O)C(=O)O
Temperature: 35 °C
Reaction time: 24 h

Procedure:
Next, 100 ml of a nutrient medium (pH 7) containing 3% of ammonium fumarate, 0.2% of dipotassium phosphate, 0.025% of magnesium sulfate, 4% of corn steep liquor, and 0.05% of calcium carbonate was inoculated with Escherichia coli and then shaken at 35° C. for 24 hours. Thereafter, 50 ml of the resulting culture of Eschericia coli and 50 ml of a fresh nutrient medium were added to the aforesaid gel-containing flask, which was shaken at 35° C. for 24 hours. After removal of the supernatant, the gel was washed three times with 50-ml portions of sterilized water. Then, 100 ml of a fresh nutrient medium was added to the gel-containing flask, which was shaken at 35° C. As a result, aspartic acid was produced at a rate of 872 μmol/hr/g of gel.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)O1.I[C:20]1[CH:21]=[C:22]([CH:36]=[CH:37][C:38]=1[CH3:39])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1)=[O:24].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:39][C:38]1[C:20]([C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)=[CH:21][C:22]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=2)=[O:24])=[CH:36][CH:37]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1I
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1-c1ccc([N+](=O)[O-])cc1
Yield: 57.1 %

Procedure:
4,4,5,5-Tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane (0.35 g, 0.0014 mol) was mixed with 3-iodo-4-methyl-N-[3-(trifluoromethyl)phenyl]benzamide (0.73 g, 0.0018 mol) and potassium carbonate (0.50 g, 0.0036 mol) in toluene (15.00 mL), ethanol (2.10 mL) and water (2.00 mL) and the mixture was degassed. To the reaction was added tetrakis(triphenylphosphine)palladium(0) (0.10 g, 0.000086 mol) and the mixture was heated to reflux for 8 hours. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The concentrate was chromatographed on silica gel using 30% EtOAc/hexanes to give the product (0.32 g, 57% yield). 1H NMR (CDCl3): 8.33 (dd, 2H), 7.76-7.93 (m, 5H), 7.43-7.54 (m, 5H), 2.35 (s, 3H). MS (EI) m/z=401 (M+H).
Reaction SMILES: [CH3:1][C:2]([OH:29])([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C:13]3[C@@H:23]([CH2:24][CH2:25]2)[C@@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([OH:28])[CH2:19][CH2:20]2)=[CH:15][CH:14]=3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].O=O>>[CH3:1][C:2]([OH:29])([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([OH:28])[CH2:19][CH2:20]2)=[CH:15][CH:14]=3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3]
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@@]4(C)[C@@H]3CC[C@]12C
Agent: O=O
Product: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
9β,10α-cholesta-5,7-diene-3β,25-diol (5.0 g.) in 1 l. dry oxygen-free tetrahydrofuran, is irradiated in a like fashion to that described in Example 1. Working up in an analogous fashion to Example 1, some cholesta-5,7-diene-3β,25-diol is initially isolated. After a thermal treatment of the materials contained in the filtrate, similar to that of Example 1, 25-hydroxycholecalciferol is isolated.
Reaction SMILES: C[O-].[Na+].[Na].[CH3:5][SH:6].Cl[C:8]1[N:13]=[C:12]([CH:14]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][CH:9]=1>CS(C)=O.CO>[CH3:5][S:6][C:8]1[N:13]=[C:12]([CH:14]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: CS
Reactant: Clc1cccc(C(Oc2ccccc2)Oc2ccccc2)n1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CS(C)=O
Solvent: CO
Product: CSc1cccc(C(Oc2ccccc2)Oc2ccccc2)n1
Temperature: 13 °C

Procedure:
To a mixture of sodium methoxide (made from 100 ml (2.47 m) of methanol and 1.50 g (0.652 m) of sodium metal) which had been cooled to 13° C. was added 7.0 ml (0.126 m) of methylmercaptan. The mixture was allowed to warm to room temperature and then 20.0 g of 6-chloro-2-(diphenoxymethyl)pyridine and 150 ml of dimethylsulfoxide was added thereto. The mixture was heated to 90° C. and after 4 days at this temperature, the reaction mixture was cooled to room temperature and poured into 300 ml of ice. The solution was extracted with methylene chloride and the extract was dried over magnesium sulfate and the solvent stripped off under reduced pressure. The residue was further purified using preparative high pressure liquid chromatography with a 2:98 mixture of ethylacetate and hexane. The oil thus obtained crystallized in n-hexane and was purified by recrystallization from n-hexane leaving the above named compound as a white solid in a yield of 49 g (98 percent pure). The product melted at 58°-59° C. and its structure was confirmed by its NMR spectrum. Upon analysis, the product was found to have carbon, hydrogen and nitrogen contents of 70.42, 5.19 and 4.20 percent, respectively, as compared with the theoretical contents of 70.59, 5.26 and 4.33 percent, respectively, as calculated for the above named compound (Compound 3).
Reaction SMILES: [N:1]1([C:7](=[S:9])[NH2:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:11][C:12](=O)[C:13]([F:16])([F:15])[F:14].CO.ClCCl>C(O)C>[F:14][C:13]([F:16])([F:15])[C:12]1[N:8]=[C:7]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[S:9][CH:11]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: NC(=S)N1CCNCC1
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: FC(F)(F)c1csc(N2CCNCC2)n1
Temperature: 70 °C
Yield: 41 %

Procedure:
To a solution of 6.89 mmol 1-piperazinecarbothioamide in 10 ml ethanol was added 8.26 mmol 3-bromo-1,1,1-trifluoroacetone and the mixture was heated at 70° C. for 2 h. The mixture was then concentrated in vacuo and the residue resuspended in dichloromethane. Insoluble material was removed by filtration and the filtrate was concentrated in vacuo. Chromatography (SiO2, methanol/dichloromethane) afforded the title compound as a yellow crystalline solid (yield 41%). MS (m/e): 238.1 (M+H+, 100%).
Reaction SMILES: [N:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[O:6][CH2:5][CH2:4][N:3]3[C:2]=1[NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[N:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[O:6][CH2:5][CH2:4][N:3]3[C:2]=1[N:13]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=1)[S:14]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15]
Reactant: O=S(=O)(Nc1nc2cccc3c2n1CCO3)c1ccccc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)N(Cc1ccc(C(F)(F)F)cc1)c1nc2cccc3c2n1CCO3
Temperature: 120 °C

Procedure:
To a solution of N-(3,4-Dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-yl)-benzenesulfonamide (125 mg, 0.40 mmol) in DMF (2.5 mL) was added 1-bromomethyl-4-trifluoromethyl-benzene (190 mg, 0.80 mmol) and potassium carbonate (55 mg). The resulting mixture was heated to 120° C. in a microwave reactor for 1 h. The resulting mixture was then diluted with EtOAc, washed with H2O and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2), eluting with a hexanes-EtOAc gradient to yield N-(3,4-dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-yl)-N-(4-trifluoromethyl-benzyl)-benzenesulfonamide as a crude residue (1st compound to elute off the column) The residue was purified by HPLC (reverse phase C-18 column, 45-100% acetonitrile/water containing 0.05% trifluoroacetic acid) to yield N-(3,4-dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-yl)-N-(4-trifluoromethyl-benzyl)-benzenesulfonamide as its corresponding TFA salt. MS 474 (M+1)+
Reaction SMILES: C(C1OC[C@H](C(C)(C)C)N=1)(C1OC[C@H](C(C)(C)C)N=1)(C)C.C(OC(=O)C=[N+]=[N-])C.[Br:30][C:31]1[CH:36]=[CH:35][C:34]([C@@H:37]2[CH2:39][C@H:38]2[C:40]([O:42]CC)=[O:41])=[CH:33][CH:32]=1.BrC1C=CC(C=C)=CC=1.[Li+].[OH-]>[O-]S(C(F)(F)F)(=O)=O.[Cu+]>[Br:30][C:31]1[CH:32]=[CH:33][C:34]([C@@H:37]2[CH2:39][C@H:38]2[C:40]([OH:42])=[O:41])=[CH:35][CH:36]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(Br)cc1
Agent: [Cu+]
Agent: C=Cc1ccc(Br)cc1
Agent: CC(C)(C1=N[C@@H](C(C)(C)C)CO1)C1=N[C@@H](C(C)(C)C)CO1
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(Br)cc1

Procedure:
An enantioselective cyclopropanation analogous to a literature procedure (Evans et al. J. Am. Chem. Soc. 1991, 113, 726) using commercial 2,2′-isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline] in conjunction with copper(I) triflate and ethyldiazoacetate was used to prepare optically active ethyl (1R,2R)-2-(4-bromophenyl)cyclopropanecarboxylate from 4-bromostyrene. The absolute configuration was assigned by analogy based on the sense of the optical rotation. Selective hydrolysis of the trans isomer with LiOH (1 equivalent based on the trans ester) from the mixture of cis and trans esters (that was obtained by the cyclopropanation procedure) gave the title compound.
Reaction SMILES: Br.[Br:2][C:3]1[C:8](=[O:9])[N:7]2[C:10]3([NH:37][C:38](=[O:39])[C:6]2=[C:5]([Cl:40])[CH:4]=1)[CH2:16][N:15](S(C1C=CC(C)=CC=1)(=O)=O)[CH2:14][CH2:13][N:12](S(C1C=CC(C)=CC=1)(=O)=O)[CH2:11]3>C(O)(=O)C.O1CCOCC1>[Br:2][C:3]1[C:8](=[O:9])[N:7]2[C:10]3([NH:37][C:38](=[O:39])[C:6]2=[C:5]([Cl:40])[CH:4]=1)[CH2:11][NH:12][CH2:13][CH2:14][NH:15][CH2:16]3
Reactant: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)CC3(C2)NC(=O)c2c(Cl)cc(Br)c(=O)n23)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=C1NC2(CNCCNC2)n2c1c(Cl)cc(Br)c2=O
Temperature: 100 °C

Procedure:
To a stirred solution of hydrogenbromide (1.43 g, 15.24 mmol) in acetic acid in 1,4-dioxane (30 mL), 6-bromo-8-chloro-1′,4′-ditosyl-2H-spiro[imidazo[1,5-a]pyridine-3,6′-[1,4]diazepane]-1,5-dione (1 g, 1.52 mmol) was added at room temperature. The vial was sealed and heated the reaction mass to 100° C. for 16 h. After completion, solvent was removed under reduced pressure and crude was triturated with dichloromethane to afford 6-bromo-8-chloro-2H-spiro[imidazo[1,5-a]pyridine-3,6′-[1,4]diazepane]-1,5-dione (4) as brown solid. Yield: 0.5 g, 94%; MS (ESI) m/z 362.28 [M+1]+.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.Br[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1>C1COCC1.[Zn+2].[Br-].[Br-].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:1]1([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: Br[Mg]C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C2CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into a 1-L three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution mixture of ZnBr2 (41.5 g, 184 mmol) and tetrahydrofuran (500 mL). The mixture was cooled to 0° C., then cyclopropylmagnesium bromide (2 M in THF) (92 mL, 184 mmol) was added drop-wise with stirring over 30 min. The mixture was then cooled to −40° C. and Pd(dppf)Cl2 (3.00 g, 4.1 mmol) was added portion-wise over 1 min. Methyl 4-bromobenzoate (10.0 g, 46.50 mmol) in THF (50 mL) was added drop-wise over 30 min at -40° C. The resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction was then carefully quenched by the addition of aqueous NH4Cl (sat., 500 mL). The mixture was extracted with ethyl acetate (3×300 mL) and the combined organic layers were washed with brine (3×300 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether as the eluent to yield 8.87 g (crude) of the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[OH:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17].[H-].[Na+]>CN(C=O)C>[NH2:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([O:12][C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])[CH:7]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: Nc1cc(Br)ncc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Oc2cc(N)c([N+](=O)[O-])cn2)c1
Temperature: 65 °C

Procedure:
Under nitrogen, to a solution of 2-bromo-5-nitro-4-pyridineamine (3.67 g, 16.8 mmol) and methyl 3-hydroxybenzoate (2.82 g, 18.5 mmol) in DMF (100 mL), was added NaH (810 mg, 60% suspension, 20.2 mmol). 5 min later, the reaction mixture was heated to 65° C. The reaction mixture was concentrated, taken up in EtOAC, washed with NaOH solution (1.0N), saturated NH4Cl solution and brine, dried over Na2SO4, filtered and concentrated to afford the title compound, which was used directly to next step without further purification. MS (ES+) m/e 290 [+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[NH:16][CH:15]=2)[CH:5]=[C:4]([Cl:27])[C:3]=1[NH:28][C:29](=[O:31])[CH3:30].[CH3:32]OC1C=C2C(=CC=1)NC=C2CC(O)=O.NC1C(C)=CC(CN)=CC=1Cl>>[Cl:27][C:4]1[CH:5]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[NH:16][CH:15]=2)[CH:7]=[C:2]([CH3:32])[C:3]=1[NH:28][C:29](=[O:31])[CH3:30]
Reactant: COc1ccc2[nH]cc(CC(=O)O)c2c1
Reactant: COc1ccc2[nH]cc(CC(=O)N=C(N)NCc3cc(Cl)c(NC(C)=O)c(Cl)c3)c2c1
Agent: Cc1cc(CN)cc(Cl)c1N
Product: COc1ccc2[nH]cc(CC(=O)N=C(N)NCc3cc(C)c(NC(C)=O)c(Cl)c3)c2c1

Procedure:
In a manner similar to that used in the preparation of the compound of example 2, but using 2-(5-methoxy-1H-indol-3-yl)acetic acid in step 9 (A) and 4-amino-3-chloro-5-methylbenzylamine (preparation G) in step 9 (B), the title compound was prepared. MS (ESI) (M+H)+=442.04 1H-NMR (500 MHz, CD3OD) δ 7.20-7.39 (m, 3 H), 7.16 (s, 1 H), 7.05 (d, J=2.14 Hz, 1 H), 6.82 (dd, J=8.55, 2.44 Hz, 1 H), 4.46 (s, 2 H), 3.93 (s, 2 H), 3.82 (s, 3 H), 2.24 (s, 3 H), 2.18 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[N:32]1([CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:29])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:35]4[CH2:36][CH2:37][N:32]([CH2:38][CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=5)[CH2:33][CH2:34]4)=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: c1ccc(CCN2CCNCC2)nc1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(CCc2ccccn2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-piperazinyl-2-(2-pyridinyl)ethane as in General Procedure 10 to give the title compound. LCMS: m/z=620.98 (M+H+); retention time=0.53 minutes.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:19]#[N:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[C:30]1[C:31]([C:46](OCC)=O)=[CH:32][C:33]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)=[CH:34][CH:35]=1.[Cl-].[NH4+]>C1COCC1.CCCCCC>[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)=[CH:32][C:31]=1[CH2:46][C:13]1([C:19]#[N:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)c1cc(OCc2ccc(OC)cc2)ccc1-c1cc(OC)ccc1F
Reactant: N#CC1CCCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(CC3(C#N)CCCCC3)c2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Under a nitrogen atmosphere, to a solution of diisopropylamine (0.13 mL) in THF (7 mL) was added a solution (1.6 M, 0.58 mL) of butyllithium in hexane at 0° C., and the mixture was stirred at 0° C. for 10 min. The reaction mixture was cooled to −78° C., and cyclohexanecarbonitrile (0.12 mL) was added. The mixture was stirred at −78° C. for 1 hr, and a solution of ethyl 2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)biphenyl-2-carboxylate (201 mg) in THF (3 mL) was added. The mixture was stirred at −78° C. for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (168 mg) as a colorless oil.