Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)[CH:4]([CH3:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11].[C:14](Cl)(=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O>[C:14]([C:9]1[CH:8]=[CH:7][C:6]2[O:11][CH:12]=[CH:4][C:5]=2[CH:10]=1)(=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: COC(=O)C(C)c1ccccc1O
Reactant: CCCCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCCCC(=O)c1ccc2occc2c1
Yield: 9.3 %

Procedure:
To a solution of methyl 2-hydroxyphenylacetic acid methyl ester (1000 mg, 6.02 mmol) in nitrobenzene (10 ml) was added heptanoyl chloride (900 mg, 6.02 mmol), followed by aluminium chloride (1.6 g, 12.0 mmol, 2 equiv). The solution was heated to 60 C for 18 h, then cooled on ice before quenching with aqueous hydrochloric acid (1 M, 50 ml). The mixture was extracted with dichloromethane. (3×50 ml) and concentrated. Chromatography on silica gel using ethyl acetate/petroleum spirits (20:80) as eluant gave a semi-solid yellow residue. Recrystallization from dichloromethane/petroleum spirits at −15 C gave the title compound as a pale yellow solid (129 mg). Mp 64-67° C.;
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][C:13](Cl)=[N:14][CH:15]=3)[N:10]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:37][C:38]([O:41][C:42]([NH:44][CH:45]1[CH2:50][CH2:49][CH:48]([NH2:51])[CH2:47][CH2:46]1)=[O:43])([CH3:40])[CH3:39].CCN(CC)CC>CC(O)C>[C:38]([O:41][C:42](=[O:43])[NH:44][CH:45]1[CH2:46][CH2:47][CH:48]([NH:51][C:13]2[N:12]=[C:11]3[N:10]([C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:9]=[C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=4)[C:16]3=[CH:15][N:14]=2)[CH2:49][CH2:50]1)([CH3:40])([CH3:37])[CH3:39]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: Clc1ncc2c(-c3cccc(Br)n3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2n1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4cccc(Br)n4)nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3n2)CC1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
The mixture of 3-(6-bromo-pyridin-2-yl)-6-chloro-1-trityl-1H-pyrazolo[3,4-d]pyrimidine (from Example 34 supra) (3.8 g, 6.89 mmol), tert-butyl (1r,4r)-4-aminocyclohexylcarbamate (1.8 g, 8.40 mmol) and Et3N (1.2 mL, 8.3 mmo,) in IPA (80 mL) was stirred at 90° C. for 15 hours. The reaction was cooled to room temperature and the precipitate was collected by filtration to give {-4-[3-(6-bromo-pyridin-2-yl)-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester as white powder. (Yield 1.5 g, 30%).
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1.[CH3:11][OH:12].C(Cl)(Cl)Cl>[N+]([O-])([O-])=O.[Ag+].C(Cl)(Cl)Cl>[C:6]([C@H:9]1[C@:6]([CH3:9])([CH:7]=[CH2:8])[CH2:5][CH2:4][C@@H:3]([C:3]([CH3:4])=[CH2:8])[C@@H:11]1[OH:12])([CH3:7])=[CH2:5]
Reactant: COc1ccc(C=O)cc1
Reactant: CO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: ClC(Cl)Cl
Product: C=C[C@]1(C)CC[C@@H](C(=C)C)[C@H](O)[C@H]1C(=C)C

Procedure:
Diethylaluminum chloride (210 ul, 1.8 M in toluene, 0.379 mmol, 1.1 equivalent) was added dropwise to a solution of ##STR4c## (76 mg, 0.344 mmol, 1.0 equivalent) in dry dichloromethane (10 ml) at −78 C. Agter 1.5 h, triethylamine (500 ul) was added, the cooling bath was removed, and the solution was added to a mixture of saturated NaHCO3 (20 ml) and dichloromethane (2×20 ml), and the organic fractions were combined, dried (MgSO4), and concentrated in vacuo. Flash chromatography (15 g of SiO2; eluent, 4% EtOAc-hexanes; product, fractions 11-23; 10 ml/fraction) afforded a 96:4 mixture of ##STR5a## and a minor diastereomer (70.1 mg, 0.318 mmol, 92% yield): Rf starting material, 0.58; product, 0.41 (5:1 hexanes-EtOAc, anisaldehyde). The diastereomeric mixture was separated by AgNO3-impregnated radial chromatography (2 mm plate; eluent, 5:1 EtOAc-hexanes; product, fractions 10-33; 3 ml/fraction) followed by passage through silica gel (10 g; 150 ml of 4% EtOAc-hexanes) to afford pure ##STR5a## (88% yield) as a clear oil: AgNO3-impregnated TLC: Rf ##STR5a##, 0.08; minor, 0.17 (12% MeOH—CHCl3; anisaldehyde); [α]23D+17.8° (c=0.91, CHCl3); FTIR (film) 3566, 3486, 2969, 2931, 1639, 1454, 1375, 1004, 910, 889 cm-1; sup.1 H NMR (500 MHz, CDCl3) δ 5.78 (dd, 1H, J=10.9, 17.4), 5.06 (s, 1H), 4.88-4.92 (m, 4H), 4.76 (s, 1H), 3.77 (t, 1H, J=10.4), 2.08 (dt, 1H, J=4.8, 10.8), 1.98 (d, 1H, J=10.4), 1.90 (bs, 1H), 1.80 (s, 3H), 1.79 (s, 3H), 1.51-1.66 (m, 3H), 1.42 (dt, 1H, J=3.1, 13.0), 1.06 (s, 3H); sup.13 C NMR (101 MHz, CDCl3) d 148.9, 147.1, 144.2, 114.1, 112.2, 110.3, 69.3, 59.7, 53.7, 41.3, 39.0, 26.2, 25.0, 19.5, 18.1; HRMS (EI, Pos) m/z calculated for [C15H24O]+220.1827, found 220.1826.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7](=[O:12])[C:6]=2[C:13]=1[O:14]C.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7](=[O:12])[C:6]=2[C:13]=1[OH:14]
Reactant: COc1c(Br)ccc2[nH]c(=O)oc(=O)c12
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=c1[nH]c2ccc(Br)c(O)c2c(=O)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
A mixture of Example 385B (20 g) in dichloromethane (600 mL) at 0° C. was treated with AlCl3 (39 g, 293 mmol) in several portions and stirred vigorously overnight at room temperature. The mixture was treated with brine (300 mL), stirred for 10 minutes, and extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated to provide the desired product (18 g) which was used directly in the next step.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][C:3]=1[CH3:10].[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)[CH3:12]>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])=[CH:4][C:3]=1[CH3:10]
Reactant: CC(=O)c1ccccc1
Reactant: Cc1cc(NN)ccc1I
Product: CC(=NNc1ccc(I)c(C)c1)c1ccccc1

Procedure:
Analogously to the process described under Example 1A, 992 mg (4.0 mmol) of the compound from Example 6A and 721 mg (6.0 mmol) of acetophenone give 1.405 g (100% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[C:14]([OH:21])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.[CH3:24][N+:25]([CH3:27])=[CH2:26].[I-]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([CH2:24][N:25]([CH3:27])[CH3:26])=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[C:14]([OH:21])[C:11]=3[C:12]=2[CH3:13])=[CH:22][CH:23]=1
Reactant: C=[N+](C)C
Reactant: CCCc1ccc2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Agent: [I-]
Solvent: ClCCl
Product: CCCc1cc(CN(C)C)c2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Reaction time: 0.25 h
Yield: 124.1 %

Procedure:
A solution of 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-benzofuran (155 mg gm; 0.5mmole) in methylene chloride (2 mL) was reacted with Eschenmoser's salt (dimethyl methylene-ammonium iodide) (105 mg; 0.5mmole) overnight at room temperature. The reaction mixture was concentrated in vacuo. The residue was taken up in ethylacetate, potassium carbonate was added and the mixture was stirred for a period of 15 minutes. The solids were separated and the ethylacetate solution was evaporated to yield 228 mg of 2-(p-methoxybenzyl)--3-methyl-4-hydroxy-5-propyl-7-dimethylaminomethylbenzofuran.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])#[N:2].[Cl-].C([NH+](CC)CC)C.[N-:19]=[N+:20]=[N-:21].[Na+].O>C1(C)C=CC=CC=1>[NH:2]1[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])=[N:21][N:20]=[N:19]1
Reactant: COC(=O)CCCCC#N
Reactant: [N-]=[N+]=[N-]
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)CCCCc1nnn[nH]1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
Methyl 5-cyanopentanoate (4.8 g, 34 mmol) is dissolved in toluene, triethylammonium chloride (14 g, 102 mmol) and sodium azide (6.63, 102 mmol) is added. The mixture is heated to reflux for overnight. The reaction mixture is cooled to room temperature, water is added to extract (3×100 mL) methyl 5-tetrazol-5-ylpentanoate from the organic. To the aqueous phase, concentrate HCl is added to adjust pH to 2. The product is extracted from the aqueous solution with EtOAc (3×50 mL). The organic is combined, dried and concentrated to yield 4.25 g (68%) of methyl 5-tetrazol-5-ylpentanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:3]=1.[Br:17]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=2[C:6]#[N:7])=[CH:11][CH:12]=1
Reactant: Cc1ccc(-c2cc(Cl)ccc2C#N)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(Cl)cc1-c1ccc(CBr)cc1

Procedure:
6.83 g of 4-chloro-2-(4-methylphenyl)benzonitrile, 5.34 g of N-bromosuccinimide and 0.1 g of α,α'-azobis(isobutyronitrile) were heated in 220 ml of carbon tetrachloride under reflux for 2 hr. The succinimide was removed by filtration, and the filtrate was concentrated. The residue was crystallized from a mixed solvent of tetrahydrofuran-isopropyl ether. The yield was 5.6 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:13]3[S:14][C:15]([Cl:18])=[CH:16][CH:17]=3)=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClC1[CH:31]=[C:30]([C:32]2C(C3SC(Cl)=CC=3)=NN(CC(C)C)C=2)[CH:29]=CN=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:12]=[N:11][N:10]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:9]=2[C:13]2[S:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cc(-c2c[nH]nc2-c2ccc(Cl)s2)ccn1
Reactant: CC(C)Cn1cc(-c2ccnc(Cl)c2)c(-c2ccc(Cl)s2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)Cn1ncc(-c2ccnc(Cl)c2)c1-c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 2-chloro-4-[3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (6.7 mmol) in 53 mL N,N-dimethylformamide were added bromoisobutyle (10.1 mmol) and cesium carbonate (7.4 mmol). The reaction mixture was stirred overnight at room temperature and the solvent was then evaporated. The residue was diluted with water and extracted three times with ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (heptane:ethyl acetate 1:0 to 1:1) to afford 2.21 g of a mixture of 2-chloro-4-[1-isobutyl-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine and 2-chloro-4-[1-isobutyl-5-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (8:2; 88% yield). The mixture was used as such in the next step.
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[CH2:5][C:6]1[CH:7]=[C:8]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[I-].[Na+]>CS(C)=O>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])=[CH:7][C:6]=1[CH2:5][C:1]#[N:2]
Reactant: COc1ccc(Oc2ccccc2Cl)cc1CCl
Reactant: [C-]#N
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(Oc2ccccc2Cl)cc1CC#N
Reaction time: 0.67 h
Yield: 57.2 %

Procedure:
Powdered potassium cyanide (2.05 g) was added to a solution of 2-chlorophenyl 3-chloromethyl-4-methoxyphenyl ether (8.5 g) and sodium iodide (4.7 g) in dimethyl sulfoxide (50 ml) at room temperature and stirred at the same temperature for an hour and then at 70° C. for 40 minutes. The reaction mixture was treated in a similar manner to that of Example 3-(7) to give oily 2-[2-methoxy-5-(2-chlorophenoxy)phenyl]acetonitrile (4.7 g).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:16]1([CH2:22][CH2:23]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCO>[CH2:23]([S:15][C:13]1[O:14][C:10]([C:7]2[CH:8]=[CH:9][C:4]3[NH:3][CH:2]=[N:1][C:5]=3[CH:6]=2)=[N:11][N:12]=1)[CH2:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Sc1nnc(-c2ccc3nc[nH]c3c2)o1
Reactant: BrCCc1ccccc1
Solvent: CCO
Product: c1ccc(CCSc2nnc(-c3ccc4[nH]cnc4c3)o2)cc1

Procedure:
1 (0.33 g, 1.5 mmol), TEA (0.209 mL, 1.5 mmol), phenylethylbromide (0.206 mL, 1.5 mmol) were dissolved in 10 mL of EtOH and kept under reflux overnight. The solvent was removed and the remaining oil was purified by flash-chromatography on silica gel, applying a CHCl3/MeOH gradient.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH:11](O)[CH2:10][CH2:9]2.C(=O)([O-])O.[Na+]>ClCCl>[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH:11]([Cl:3])[CH2:10][CH2:9]2
Reactant: O=S(Cl)Cl
Reactant: OC1CCc2cc(Br)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClC1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3.09 mL (37.45 mmol) of thionyl chloride, dissolved in cooled dichloromethane, are added dropwise at −10° C. to a solution of 3.8 g (17.83 mmol) of 5-bromoindan-1-ol in 200 mL dichloromethane. The reaction mixture is allowed to come up slowly to ambient temperature and stirred for 14 hours at ambient temperature. Then ice and 100 mL of dilute sodium hydrogen carbonate solution are added successively. The organic phase is extracted twice with 50 mL of water. The combined organic phases are dried over magnesium sulfate, filtered and the solvent is distilled off. Yield: 3.7 g (90% of theory); C9H8BrCl (M=231.52); Rf value: 0.91 (silica gel, petroleum ether/ethyl acetate (6:4)).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([OH:7])[CH:4]=[C:3]([CH2:8][C@H:9]([NH2:13])[C:10]([OH:12])=[O:11])[CH:2]=1.[CH2:14]=O>S(=O)(=O)(O)O>[OH:7][C:5]1[CH:4]=[C:3]2[C:2](=[CH:1][CH:6]=1)[CH2:14][NH:13][CH:9]([C:10]([OH:12])=[O:11])[CH2:8]2
Reactant: N[C@@H](Cc1cccc(O)c1)C(=O)O
Reactant: C=O
Agent: O=S(=O)(O)O
Product: O=C(O)C1Cc2cc(O)ccc2CN1
Temperature: 70 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To 61.5 g of D, L-m-tyrosine suspended in 250 ml of 0.05N sulfuric acid aqueous solution, 48 ml of 37% formalin aqueous solution was added dropwise. The reaction mixture was stirred at 70° C. for 12 hours, and subjected to crystallization under ice cooling for 2 hours. The obtained crystal were filtered off, and dried at 60° C. under reduced pressure to obtain 65.6 g of Compound 1 (yield 100%). Compound 1 thus obtained was dissolved in an aqueous solution of 2N sodium hydroxide, and was then adjusted to pH 5 with concentrated hydrochloric acid. The precipitate was filtered off, washed with water and dried at 60° C. under reduced pressure to obtain 52.5 g of purified product of Compound 1.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C@@H:2]([CH3:4])[OH:3].C(N(CC)CC)C.Cl.CN(C)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(#N)C>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:3][C@H:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H](C)O
Agent: CN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)[C@@H](C)OS(=O)(=O)c1ccc(C)cc1
Yield: 87.2 %

Procedure:
A solution of methyl(R)-(+)-lactate (6.66 g) in acetonitrile (33 ml) was cooled to 5° C. and triethylamine (9.8 ml) added followed by trimethylamine hydrochloride (0.62 g). A separate solution of p-toluenesulfonyl chloride (11.6 g) in acetonitrile (33 ml) was added dropwise over 20 min maintaining the temperature below 5° C. The reaction mixture was filtered and concentrated, Diethylether and water were added and the organic fraction dried (MgSO4) and concentrated in vacuo to give the sub-title compound as a yellow oil (13.71 g).
Reaction SMILES: C([N:8]([CH2:39][CH3:40])[CH2:9][C:10]([NH:12][C@H:13]([C:25]([NH:27][C@H:28]([C:36]([NH2:38])=[O:37])[CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:26])[CH2:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:11])(OC(C)(C)C)=O.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>ClCCl>[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42].[NH:8]([CH2:39][CH3:40])[CH2:9][C:10]([NH:12][C@H:13]([C:25]([NH:27][C@H:28]([C:36]([NH2:38])=[O:37])[CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:26])[CH2:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:11]
Reactant: CCN(CC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](CC1CCCCC1)C(N)=O)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNCC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](CC1CCCCC1)C(N)=O
Temperature: 5 °C

Procedure:
BOC-N(Et)Gly-(L)-Asp(OBzl)-(L)-Cha-NH2 is dissolved in dichloromethane (~1:12 wt/wt), and to that solution is added TFA at ambient temperature. This is then stirred until HPLC indicates complete reaction (3-5 hours). The solution is concentrated to about 1/2 volume at 40°-45° C. To this warm solution is added MTBE (~1:10 wt/wt vs. BOC-N(Et)Gly-(L)-Asp(OBzl)-(L)-Cha-NH2) while maintaining the temperature >40° C. The mixture is slowly cooled to about 5° C. and stirred for 1 hour to ensure complete crystallization. The resulting solids are filtered, and washed with chilled MTBE. The solids are dried under reduced pressure and analyzed for content of TFA·N(Et)Gly-(L)-Asp(OBzl)-(L)-Cha-NH2 (HPLC wt/wt assay). Yield is generally nearly quantitative, purity >95 A %.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:36])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][C:16]=2[O:31][CH2:32][C:33]([OH:35])=[O:34])(=[O:11])=[O:10])[CH:8]=1)#[N:2].[OH-].[Na+:38]>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:36])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][C:16]=2[O:31][CH2:32][C:33]([O-:35])=[O:34])(=[O:10])=[O:11])[CH:8]=1)#[N:2].[Na+:38]
Reactant: CS(=O)(=O)c1ccccc1-c1ccc(CCNS(=O)(=O)c2cc(C#N)ccc2O)c(OCC(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1ccccc1-c1ccc(CCNS(=O)(=O)c2cc(C#N)ccc2O)c(OCC(=O)[O-])c1

Procedure:
To a stirred solution of 146 g of [4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]-acetic acid in 580 mL of ethanol was added 137 mL of 2 mol/L sodium hydroxide solution under ice-cooling, and the solvent was removed under reduced pressure. The residue was suspended with 1.16 L of ethanol, and the mixture was stirred under reflux for an hour, then at room temperature overnight. The obtained white solid was collected by filtration to give 129 g of sodium [4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: OB(O)c1ccccc1
Product: Cc1c2n(c3c(-c4ccccc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (66 mg, 90%), MS (ISP) m/z=295.5 [(M+H)+], mp 244° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available phenylboronic acid (39.6 mg, 0.325 mmol).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[NH2:14][C:15]1[N:20]=[C:19]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])[CH:18]=[CH:17][CH:16]=1>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([C:21]([C:22]#[N:23])([CH3:25])[CH3:24])[N:20]=2)[CH:7]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Reactant: CC(C)(C#N)c1cccc(N)n1
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(C(C)(C)C#N)n1
Temperature: 130 °C

Procedure:
A mixture of ethyl 4,6-dichloropyridazine-3-carboxylate (1.4 g, 6.33 mmol) and 2-(6-aminopyridin-2-yl)-2-methylpropanenitrile (2.04 g, 12.7 mmol) was dissolved in acetonitrile (3.00 mL) and heated to 130° C. for 18 h. The mixture was cooled, concentrated, the residue was adsorbed on silica gel and purified by flash chromatography (silica gel 45 μM, 160 g, Thomson) eluting with 0 to 20% acetone in dichloromethane over 20 min, impure desired product was isolated, all fractions containing desired product were concentrated and the residue dissolved in a dichloromethane and evaporated to a small volume where a solid precipitated, filtered and dried and corresponded to the desired ethyl 6-chloro-4-(6-(2-cyanopropan-2-yl)pyridin-2-ylamino)pyridazine-3-carboxylate (792 mg, 36.2% yield). 1H NMR (CHLOROFORM-d) δ: 10.86 (s, 1H), 9.27 (s, 1H), 7.75 (t, J=7.9 Hz, 1H), 7.26 (d, J=7.9 Hz, 1H), 6.90 (d, J=7.9 Hz, 1H), 4.58 (q, J=7.2 Hz, 2H), 1.81 (s, 6H), 1.52 (t, J=7.2 Hz, 3H); LC-MS 346.1 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CS(C)=O
Product: COc1c(N2CCNCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 2.5 h
Yield: 16.3 %

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), anhydrous piperazine (180 mg) and anhydrous dimethyl sulfoxide (DMSO; 3 ml) was stirred for 2.5 hours at 70° to 80° C. on an oil bath. The reacting mixture was concentrated under reduced pressure and cold water was added to the residue. The precipitate was collected by filtration and recrystallized from a mixed solution of dichloromethane-methanol (1:1) to give the title compound (40 mg) as pale yellow prisms, mp 187° C. (decompd.).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:2].[H-].[Na+].Br[CH2:17][CH2:18][CH2:19]Br>CS(C)=O>[C:1]([C:3]1([C:4]2[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:19][CH2:18][CH2:17]1)#[N:2]
Reactant: COC(=O)c1cccc(CC#N)c1
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1cccc(C2(C#N)CCC2)c1
Yield: 42.3 %

Procedure:
Using methyl 3-(cyanomethyl)benzoate (1.8 g, 10 mmol), sodium hydride (60% in oil, 1.2 g, 30 mmol), 1,3-dibromopropane (3.0 g, 15 mmol) and dimethyl sulfoxide (30 mL) as starting materials and in the same manner as in Reference Example 31, the title compound (0.91 g, 42%) was obtained as a colorless oil.