Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[NH:20][N:19]=[N:18][CH:17]=2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH:36]([C:42](=O)[CH2:43][CH2:44][CH3:45])[C:37](OCC)=[O:38])=[CH:31][CH:30]=1)#[N:22].N12CCCN=C1CCCCC2>C(N(CC)C1C=CC=CC=1)C.C(OCC)(=O)C>[Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]2[C:37](=[O:38])[C:36]([CH2:35][C:32]3[CH:33]=[CH:34][C:29]([C:24]4[C:23]([C:21]#[N:22])=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:30][CH:31]=3)=[C:42]([CH2:43][CH2:44][CH3:45])[N:20]3[N:19]=[N:18][CH:17]=[C:16]23)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(Nc2cnn[nH]2)CC1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)c1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(O[Si](C)(C)C(C)(C)C)CC2)c2cnnn12

Procedure:
N-(4-{[tert-Butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-1,2,3-triazol-5-amine (5.55 g) and a solution of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (13.07 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.85 g) in N,N-diethylaniline (30 mL) were stirred at 185° C. for 15 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=90/10→80/20 (volume ratio)] to give the title compound as a brown amorphous compound (1.58 g, 15%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[C:11](=[N:24][NH2:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(C)([O-])C.[Na+].C1(B(O)O)C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:12]1([C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:24][NH:25][C:2]2[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CN(C)c1ccnc(Br)c1
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(C)c1ccnc(NN=C(c2ccccc2)c2ccccc2)c1
Temperature: 80 °C

Procedure:
To a mixture of 3.3 g (16.41 mmol) of 2-bromo-N,N-dimethylpyridin-4-amine in 40 mL of anhydrous toluene, 3.5 g (18.05 mmol) of benzophenone hydrazone, 2.2 g (23 mmol) of anhydrous sodium tert-butoxide and 100 mg (0.82 mmol) of benzeneboronic acid in 40 mL of toluene are added, under argon, at room temperature, after having degassed the reaction medium under argon, 74 mg (0.33 mmol) of palladium acetate and 205 mg (0.33 mmol) of racBINAP. The reaction medium is then heated for 4 hours at 80° C. The reaction medium is taken up in 200 mL of EtOAc, washed successively with water (3×30 mL), with saturated NaHCO3 solution (30 mL) and with brine (30 mL) and then dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with a DCM/MeOH gradient of from 0 to 10% MeOH. After concentrating under reduced pressure, 4.5 g of 2-[2-(diphenylmethylidene)hydrazino]-N,N-dimethylpyridin-4-amine are obtained in the form of a red solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[N:18]=[N:17][C:16]=1[O:27]C)=[C:9]2[C:29]1[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[CH3:34][N:32]1[CH:33]=[C:29]([C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:11][C:10]=2[C:15]2[C:16](=[O:27])[NH:17][N:18]=[C:19]([C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)[CH:20]=2)[CH:30]=[N:31]1
Reactant: CCOC(=O)c1ccc2[nH]c(-c3cc(-c4ccncc4)nnc3OC)c(-c3cnn(C)c3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1cc(-c2c(-c3cc(-c4ccncc4)n[nH]c3=O)[nH]c3ccc(C(=O)O)cc23)cn1

Procedure:
350 mg of 2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-indole-5-carboxylic acid ethyl ester is dissolved in 4 ml ethanol and 4 ml aqueous 2N NaOH and heated by microwave irradiation for 10 min at 150° C. The solution is neutralized with aqueous HCl and the product is purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). Yield 39 mg. LC-MS (ES+) 413 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25]([OH:27])=O.Cl.[N:33]1[CH:38]=[CH:37][C:36]([C:39]2([NH2:42])[CH2:41][CH2:40]2)=[CH:35][N:34]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([C:25](=[O:27])[NH:42][C:39]2([C:36]3[CH:37]=[CH:38][N:33]=[N:34][CH:35]=3)[CH2:41][CH2:40]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: NC1(c2ccnnc2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccnnc5)CC4)ccc3C)c(F)c12
Temperature: 25 °C

Procedure:
To a mixture of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.050 g, 0.114 mmol, 1.0 eq), 1-(pyridazin-4-yl)cyclopropanamine HCl (0.015 g, 0.113 mmol, 1.0 eq) in DMF at 0° C. was added TEA (0.060 g, 0.594 mmol, 5.0 eq) and BOP reagent (0.076 g, 0.172 mmol, 1.5 eq). The reaction mixture was stirred at RT. overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC. Yield: 0.030 g (50.0%). 1H NMR (400 MHz, CDCl3): δ 9.03 (d, J=5.6 Hz, 1H), 8.98 (m, 1H), 8.01-7.98 (m., 2H), 7.81-7.78 (dd, J=2.0, 8.0 Hz, 1H), 7.73 (d, J=2 Hz, 1H), 7.44 (d, J=8.4, 2 H), 7.28-7.26 (dd, 1H), 7.23-7.18 (m, 3H), 7.08 (s, 1H), 6.20 (bs, 1H), 3.04 (d, J=5.2 Hz, 3H), 2.29 (s, 3H), 1.61-1.54 (m, 4H). 19F NMR (376.57 MHz, CDCl3): δ −109.53, −119.52. LCMS: (ES+) m/z=539.2 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2Br)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:38])[C:19](=[O:37])[N:20]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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].C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[F:39])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:38])[C:19](=[O:37])[N:20]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1F
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(Br)c(N4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(-c4ccccc4F)c(N4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Temperature: 90 °C
Yield: 69.2 %

Procedure:
To a mixture of 4-[7-bromo-4-methyl-3-oxo-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.31 g, 0.508 mmol), (2-fluorophenyl)boronic acid (0.107 g, 0.762 mmol), potassium carbonate (0.140 g, 1.015 mmol) in dioxane (12 mL) and water (2 mL) was added PdCl2(dppf)-CH2Cl2 adduct (0.041 g, 0.051 mmol) and the reaction mixture was heated at 90° C. overnight. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 3-15% EtOAc in petroleum ether) to give 4-[7-(2-fluoro-phenyl)-4-methyl-3-oxo-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.22 g, 69%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.40 (m, 1H), 7.32 (m, 1H), 7.21-7.09 (m, 2H), 6.95 (s, 1H), 6.61 (s, 1H), 5.19-5.07 (m, 1H), 4.76 (q, J=6.8 Hz, 1H), 4.72-4.57 (d, J=13.2 Hz, 2H), 3.71-3.64 (m, 2H), 3.25 (m, 4H), 2.71 (t, J=4.8 Hz, 4H), 1.52 (d, J=6.8 Hz, 3H), 1.44 (s, 9H), 1.04-0.93 (m, 2H), 0.05-0.02 (m, 9H)
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[H-].[Na+].C1(C)C=CC=CC=1.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CN(C)C=O.O>[N:22]1([CH2:21][CH2:20][O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[CH:1]=[O:9])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: O=Cc1ccccc1O
Reactant: ClCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=Cc1ccccc1OCCN1CCOCC1

Procedure:
Salicylaldehyde (34 g) is treated first with 13.4 g of 50% sodium hydride in 220 ml of dimethylformamide and then with 185 ml of a 2 N toluene solution of N-(2-chloroethyl)morpholine. The mixture is heated at 105°-110° C. for 4 hours, cooled and poured into 300 ml of water. The product is extracted three times with ether. The extracts are combined, dried, concentrated on a rotary evaporator and the residue distilled to give 56.6 g of product as an oil, boiling point 145°-150° C. at 0.05-0.1 mm of Hg.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:21](O)=[O:22])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].[Cl-].O>COCCOCCOC>[CH:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([CH2:21][OH:22])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCC1CCCCC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: O=C(N[C@H](CO)Cc1ccc(O)cc1)OCC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 15 ml of diglyme (bis(2-methoxymethyl)ether) was dissolved 1.0 g of N-(cyclohexylmethoxycarbonyl)-tyrosine. To the solution were added 570 mg of sodium borohydride and 50 ml of diglyme solution containing 7 g of anhydrous alminium chloride. The mixture was stirred at room temperature for two hours. After addition of 150 ml of water, the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate. The extract was washed with water, dried and concentrated to dryness. The residue was crystallized from ethyl acetatepetroleum ether to give N-(cyclohexylmethoxycarbonyl)-tyrosinol.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].Br[C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH2:18][CH2:19][C:20]2=[O:25]>>[O:25]=[C:20]1[C:21]2[C:17](=[C:16]([C:2]#[C:1][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=3)[CH:24]=[CH:23][CH:22]=2)[CH2:18][CH2:19]1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Reactant: O=C1CCc2c(Br)cccc21
Product: COC(=O)CCc1ccc(C#Cc2cccc3c2CCC3=O)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (94 mg, 0.50 mmol) and 4-bromo-2,3-dihydro-1H-inden-1-one (116 mg, 0.55 mmol) according to the general procedure IF to give 110 mg (69%) of an yellow solid after purification by flash chromatography (SiO2, EtOAc:PE, 1:5): Rf=0.34 (EtOAc:PE, 1:2); 1H NMR (CDCl3) δ 7.76-7.68 (m, 2H), 7.55-7.43 (m, 2H), 7.38 (t, J=7.6 Hz, 1H), 7.22 (d, J=8.3 Hz, 2H), 3.68 (s, 1H), 3.29-3.21 (m, 2H), 2.98 (t, J=7.7 Hz, 3H), 2.77-2.71 (m, 2H), 2.65 (t, J=7.7 Hz, 2H); 13C NMR (CDCl3) δ 206.6, 173.0, 157.1, 141.5, 137.3, 136.8, 131.8 128.5, 127.5, 123.3, 122.3, 120.7, 94.8, 85.3, 51.7, 36.1, 35.3, 30.8, 25.5; ESI-MS m/z 341.1 (M+Na+).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([NH:15][C:16]2[C:17](=[O:35])[N:18]([C:22]3[CH:23]=[C:24]([CH:31]=[CH:32][C:33]=3[CH3:34])[C:25]([NH:27][CH:28]3[CH2:30][CH2:29]3)=[O:26])[CH:19]=[CH:20][N:21]=2)[CH2:14][CH2:13][CH2:12]1.[CH:36]([NH2:39])([CH3:38])[CH3:37]>>[CH:28]1([NH:27][C:25](=[O:26])[C:24]2[CH:31]=[CH:32][C:33]([CH3:34])=[C:22]([N:18]3[CH:19]=[CH:20][N:21]=[C:16]([NH:15][C:11]4([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[O:4][CH2:3][CH2:2][NH:39][CH:36]([CH3:38])[CH3:37])[CH2:14][CH2:13][CH2:12]4)[C:17]3=[O:35])[CH:23]=2)[CH2:30][CH2:29]1
Reactant: CC(C)N
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CCC2)c1=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCNC(C)C)CCC2)c1=O

Procedure:
The title product was prepared from 3-(3-(1-(2-(2-chloroethoxy)phenyl)cyclobutylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide (Example 268g) and isopropylamine using a similar method to that described for example 167f. MS: APCI(+ve) 516 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:16]([OH:17])=[CH:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][CH:20]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][CH:20]=[C:19]2[O:17][C:16]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][N:10]=2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1cc2cccnc2nc1-c1ccccn1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4cccnc4nc3-c3ccccn3)c2cc1OC
Temperature: 140 °C
Reaction time: 48 h
Yield: 12.1 %

Procedure:
2-Pyridin-2-yl-[1,8]naphthyridin-3-ol (9 mg), 4-chloro-6,7-dimethoxyquinoline (27 mg), and 4-dimethylaminopyridine (16 mg) were suspended in o-dichlorobenzene (1.5 ml), and the mixture was stirred at 140° C. for 48 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (2 mg, yield 12%).
Reaction SMILES: [K+].[Br-].[CH3:3][C:4]1[S:8][CH:7]=[C:6](/[CH:9]=[C:10](/[C@H:12]2[O:29][C:27](=[O:28])[CH2:26][C@H:25]([OH:30])[C:24]([CH3:32])([CH3:31])[C:22](=[O:23])[C@H:21]([CH3:33])[C@@H:20]([OH:34])[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=[CH:14][CH2:13]2)\C)[N:5]=1.[CH3:35]C1OC=C(/C=C(/[C@H]2OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC[C@H]3O[C@H]3C2)\C)N=1.CC1SC=C(/C=C(/[C@H]2OC(=O)C[C@H](O)[C@H](C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCCC=CC2)\C)N=1>CO>[CH3:3][C:4]1[S:8][CH:7]=[C:6](/[CH:9]=[CH:10]/[C@H:12]2[O:29][C:27](=[O:28])[CH2:26][C@H:25]([OH:30])[C:24]([CH3:32])([CH3:31])[C:22](=[O:23])[C@H:21]([CH3:33])[C@@H:20]([OH:34])[C@@H:19]([CH3:35])[CH2:18][CH2:17][CH2:16][CH:15]=[CH:14][CH2:13]2)[N:5]=1
Reactant: C/C(=C\c1coc(C)n1)[C@@H]1C[C@@H]2O[C@@H]2CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Reactant: C/C(=C\c1csc(C)n1)[C@@H]1CC=CCCCC[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Agent: C/C(=C\c1csc(C)n1)[C@@H]1C/C=C\CCCC[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Agent: C/C(=C\c1csc(C)n1)[C@@H]1C/C=C\CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)[C@@H](C)[C@@H](O)CC(=O)O1
Agent: C/C(=C\c1csc(C)n1)[C@@H]1CC=CCCC[C@H](C)[C@H](O)[C@@H](C)C(=O)[C@@H](C)[C@@H](O)CC(=O)O1
Solvent: CO
Product: Cc1nc(/C=C/[C@@H]2CC=CCCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O2)cs1

Procedure:
colorless amorphous solid; [α]D22−75.2 (c 2.5, MeOH); UV (MeOH) λmax nm (ε) 210 (16800), 248 (17800); IR (KBr) νmax 3443, 2932, 2881, 1734, 1689, 1465, 1255, 1183, 976 cm−1; 1H NMR (CDCl3, 300 MHz) δ 6.93 (1H, s, H-19), 6.62 (1H, dd, J=15.6, 0.6 Hz, H-17), 6.49 (1H, dd, J=15.6, 6.6 Hz, H-16), 5.52 (1H, dddd, J=9.5, 6.6, 2.8, 0.6 Hz, H-15), 5.42 (1H, m, H-12), 5.41 (1H, m, H-13), 4.13 (1H, ddd, J=11.0, 5.3, 2.8 Hz, H-3), 3.69 (1H, ddd, J=3.7, 2.8, 2.5 Hz, H-7), 3.11 (1H, dq, J=2.5, 6.8 Hz, H-6), 2.95 (1H, d, J=5.3 Hz, 3-OH), 2.90 (1H, d, J=2.8 Hz, 7-OH), 2.69 (3H, s, H-21), 2.67 (1H, ddd, J=14.9, 9.5, 8.4 Hz, H-14a), 2.48 (1H, dd, J=15.6, 11.0 Hz, H-2a), 2.33 (1H, dd, J=15.6, 2.8 Hz, H-2b), 2.30 (1H, bd, J=14.9 Hz, H-14b), 2.14 (1H, m, H-11a), 2.03 (1H, m, H-11b), 1.71 (1H, m, H-8), 1.63 (1H, m, H-10a), 1.31 (1H, m, H-9a), 1.29 (3H, s, H-23), 1.17 (3H, d, J=6.8 Hz, H-24), 1.16 (1H, m, H-10b), 1.14 (1H, m, H-9b), 1.05 (3H, s, H-22), 0.97 (3H, d, J=7.1 Hz, H-25); 13C NMR, see Table 1; EIMS m/z 463 [M]+ (21), 310 (10), 276 (21), 171 (83), 154 (100), 150 (27), 111 (18); HREIMS m/z 463.2382 (calcd. for C25H37NO5S, 463.2392).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([C:31]2[S:35][C:34]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[N:33][CH:32]=2)(=[O:30])=[O:29])[CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([C:10]([N:39]2[CH2:38][CH2:37][N:36]([C:34]3[S:35][C:31]([S:28]([C:24]4[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=4)(=[O:30])=[O:29])=[CH:32][N:33]=3)[CH2:41][CH2:40]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: O=S(=O)(c1cccnc1)c1cnc(N2CCNCC2)s1
Reactant: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Agent: Cl
Product: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(S(=O)(=O)c3cccnc3)s2)CC1)C(F)(F)F
Yield: 49 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A2) and 1-[5-(pyridine-3-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride (Example 46(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a light brown crystalline solid (yield 49%). MS (m/e): 605.2 (M+H+, 100%).
Reaction SMILES: [N:1]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([O:5]N1C(=O)CCC1=O)=O.[NH2:23][C@@H:24]([C:32]([OH:34])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[N:1]1([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([NH:23][C@@H:24]([C:32]([OH:34])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)ON1C(=O)CCC1=O
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](Cc1ccccc1)C(=O)O
Yield: 67 %

Procedure:
Condesation of BocProOH (6.46 g.) and N-hydroxysuccinimide (3.5 g.) using dicyclohexylcarbodiimide gave BocProOSu in 75% yield. Condensation of BocProOSu (5.0 g.) and HDPheOH (2.75 g.) by the salt coupling method gave BocPro-DPheOH in 67% yield. Condensation of BocPro-DPheOH (3.98 g.) and HPheOMe hydrochloride salt (2.4 g.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocPro-DPhe-PheOMe in 74% yield. Hydrazinolysis of Boc-Pro-DPhe-PheOMe (3.14 g.) gave BocPro-DPhe-PheNHNH2 in 79% yield.
Reaction SMILES: [CH3:1][N:2](C(OC(C)(C)C)=O)[C@H:3]([C:14]([NH:16][C@@H:17]([C:19]([N-:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:20])[CH3:18])=[O:15])[CH2:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([OH:12])=[CH:7][C:6]=1[CH3:13].[ClH:38].CO.O1CCOCC1>CO>[ClH:38].[CH3:1][NH:2][C@H:3]([C:14]([NH:16][C@@H:17]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:20])[CH3:18])=[O:15])[CH2:4][C:5]1[C:6]([CH3:13])=[CH:7][C:8]([OH:12])=[CH:9][C:10]=1[CH3:11]
Reactant: Cc1cc(O)cc(C)c1C[C@@H](C(=O)N[C@H](C)C(=O)[N-]CCCc1ccccc1)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN[C@@H](Cc1c(C)cc(O)cc1C)C(=O)N[C@H](C)C(=O)NCCCc1ccccc1

Procedure:
N-methyl-BOC-2,6-dimethyltyrosyl-(D)-alanylphenylpropylamide (iso F) from Example 12 was treated with methanol-HCl/dioxane as described in Example 12, except that no methanol was used after the removal of methanol-HCl/dioxane, so no reduction of volume was necessary before lyophilization. The product is
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Br[C:20]1[N:21]=[C:22]([CH3:26])[N:23]([CH3:25])[CH:24]=1>>[Cl:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[N:21]=[C:22]([CH3:26])[N:23]([CH3:25])[CH:24]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1nc(Br)cn1C
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Cl
Product: Cc1cc(-c2cn(C)c(C)n2)cc(C)c1Cl

Procedure:
The title compound is prepared from 2-chloro-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 4-bromo-1,2-dimethyl-imidazole following a procedure analogous to that described in Step 1 of Intermediate 56.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2[CH:26]=[CH:27][CH:28]=[N:29][C:24]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCC1.CCN(CC)CC>C(Cl)Cl>[O:12]=[C:10]([N:29]1[CH2:28][CH2:27][CH2:26][CH2:24]1)[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH3:14]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.1 %

Procedure:
To a mixture of (S)-2-(tert-butoxycarbonylamino)butanoic acid (1.4 g, 6.89 mmol), HATU (3.14 g, 8.27 mmol), and pyrrolidine (1.216 mL, 13.78 mmol) in DCM (50 mL) was added Et3N (1.920 mL, 13.78 mmol). The reaction mixture was stirred at room temperature for 5 h and then washed with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4 and concentrated. Purification by silica column chromatography (MeOH/DCM, 0-10%) afforded the title compound as a light yellow oil (1.75 g, 99%). 1H NMR (500 MHz, CDCl3) δ 0.94 (t, J=7.57 Hz, 3 H) 1.34-1.48 (m, 9 H),1.49-1.68 (m, 1 H) 1.68-1.81 (m, 1 H) 1.81-1.92 (m, 2 H) 1.92-2.03 (m, 2 H) 3.34-3.47 (m,2 H) 3.52 (dt, J=12.08, 7.14 Hz, 1 H) 3.65 (dt, J=10.13, 6.65 Hz, 1 H) 4.30-4.42 (m, 1 H) 5.35 (d, J=8.30 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[N:7]=1.Cl.[NH2:12][C@@H:13]([C:18]([NH2:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16].CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][C@H:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:18]([NH2:20])=[O:19])[CH:5]=[N:4][C:3]=1[C:9]#[N:10]
Reactant: N#Cc1ncc(Cl)nc1Cl
Reactant: CC(C)C[C@@H](N)C(N)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)C[C@@H](Nc1cnc(C#N)c(Cl)n1)C(N)=O
Yield: 99.9 %

Procedure:
A solution of 3,5-dichloropyrazine-2-carbonitrile (348 mg, 2.00 mmol), D-leucinamide hydrochloride (333 mg, 2.00 mmol) and DIEA (1.00 mL, 5.75 mmol) in NMP (8 mL) was stirred at room temperature for 20 h. Water and EtOAc were added. Organic phase was separated, dried over Na2SO4, concentrated in vacuo to give (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-4-methylpentanamide as an oil (535 mg).