Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[F-].[K+].Cl[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C1COCC1>[C:1]([C:4]1[CH:5]=[C:6]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: Clc1cccnc1
Reactant: CC(=O)c1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1CCOC1
Product: CC(=O)c1cccc(-c2cccnc2)c1
Temperature: 50 °C
Yield: 91.8 %

Procedure:
An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %), 2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol %), 3-acetylphenylboronic acid (246 mg, 1.5 mmol), and potassium fluoride (173 mg, 3.0 mmol). The tube was evacuated and backfilled with argon, and THF (1 mL) and 3-chloropyridine (0.095 mL, 1.0 mmol) were added through a rubber septum. The tube was sealed with a teflon screwcap, and the reaction mixture was heated to 50° C. with stirring until the starting aryl chloride had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL) and poured into a separatory funnel. The mixture was washed with water (20 mL), and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 181 mg (92%) of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH2:9][CH2:8][CH2:7][NH:6][CH:5]=1)(=[O:3])[CH3:2].Br[CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14]>>[CH3:14][CH:13]([CH3:15])[CH2:12][CH2:11][N:6]1[CH2:7][CH2:8][CH2:9][C:4]([C:1]([CH3:2])=[O:3])=[CH:5]1
Reactant: CC(=O)C1=CNCCC1
Reactant: CC(C)CCBr
Product: CC(=O)C1=CN(CCC(C)C)CCC1

Procedure:
Methyl 1-(3-methylbutyl)-1,4,5,6-tetrahydro-3-pyridyl ketone was prepared from 3-acetyl-1,4,5,6-tetrahydropyridine and 1-bromo-3-methylbutane according to the procedure of Part b) of Example 1. The product distilled as a pale yellow oil (b.pt. 103°-106° C./0.1 mm Hg).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[S:6]([C:9]1[S:10][C:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21](Br)[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7].[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[C:38](B(O)O)=[CH:37][N:36]([C:42]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:35]=2)=[CH:30][CH:29]=1>>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[S:6]([C:9]1[S:10][C:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:38]4[C:34]([C:31]5[CH:30]=[CH:29][C:28]([F:27])=[CH:33][CH:32]=5)=[N:35][N:36]([C:42]([C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)([C:55]5[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=5)[C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)[CH:37]=4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7]
Reactant: OB(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1-c1ccc(F)cc1
Reactant: CN(C)CCN(C)S(=O)(=O)c1ccc(-c2ncnc3ccc(Br)cc23)s1
Product: CN(C)CCN(C)S(=O)(=O)c1ccc(-c2ncnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)s1
Yield: 29.5 %

Procedure:
131 mg 5-(6-bromoquinazolin-4-yl)-thiophen-2-sulfonic acid (2-dimethylaminoethyl)-methyl-amide (compound in Production Example 376) and 168 mg 3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolylboronic acid (compound in Production Example 25) were subjected to the same reaction as in Example 9, and the isomer was separated and purified by a column to give 66 mg of the title compound as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4][C:3]=1[F:18].S(=O)(=O)(O)O.[CH3:24]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15]([O:17][CH3:24])=[O:16])=[CH:4][C:3]=1[F:18]
Reactant: CO
Reactant: O=C(O)CCc1cnoc1-c1ccc(Cl)c(F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc(Cl)c(F)c1
Yield: 98 %

Procedure:
A mixture of 3-[5-(4-chloro-3-fluorophenyl)-4-isoxazolyl]propionic acid (5.08 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[5-(4-chloro-3-fluorophenyl)-4-isoxazolyl]propionate (5.25 g, yield 98%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 53–54° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]1[C:22]3[C:17](=[CH:18][C:19]([CH:23]=[CH2:24])=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:14]=1[O:25][Si](C(C)(C)C)(C)C)=[C:8]([O:33][Si](C(C)(C)C)(C)C)[CH:7]=[CH:6]2)=[CH2:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH:23]([C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[C:13]([C:9]1[C:10]3[C:5](=[CH:4][C:3]([CH:1]=[CH2:2])=[CH:12][CH:11]=3)[CH:6]=[CH:7][C:8]=1[OH:33])=[C:14]([OH:25])[CH:15]=[CH:16]2)=[CH2:24]
Reactant: C=Cc1ccc2c(-c3c(O[Si](C)(C)C(C)(C)C)ccc4cc(C=C)ccc34)c(O[Si](C)(C)C(C)(C)C)ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: C=Cc1ccc2c(-c3c(O)ccc4cc(C=C)ccc34)c(O)ccc2c1

Procedure:
An optically active binaphthol (VII) is reacted with bromine in acetic anhydride to obtain 6,6'-dibromo-2,2'-dihydroxy-1,1'-binaphthyl (XII). The hydroxyl groups of compound (XII) are protected using tert-butyldimethylsilyl oxytriflate (TBDMSOTf) and 2,6-lutidine to obtain 6,6'-dibromo-2,2'-bis(tert-butyldimethylsilyloxy)-1,1'-binaphthyl (XIII). Compound (XIII) is converted to an anion form using sec-butyllithium (sec-BuLi), and dimethylformamide (DMF) is caused to act thereon to obtain 6,6'-diformyl-2,2'-bis(tert-butyldimethylsilyloxy)-1,1'-binaphthyl (XIV). Compound (XIV) is reacted with triphenylmethylphosphonium bromide (Ph3P+CH3Br-) and potassium t-butoxide (t-BuOK) to obtain 6,6'-divinyl-2,2'-bis(tert-butyldimethylsilyloxy)-1,1'-binaphthyl (XV). Compound (XV) is reacted with tetrabutylammonium fluoride (TBAF) for silyl removal to obtain 6,6'-divinyl-2,2'-dihydroxy-1,1'-binaphthyl, which is heated together with phosphorus trichloride to obtain 6,6'-divinyl-1,1'-binaphthalene-2,2'-dioxychlorophosphine (XVI). The 6,6'-divinyl-1,1'-binaphthalene-2,2'-dioxychlorophosphine (XVI) is reacted with 2'-diphenylphosphino-2-hydroxy-1,1'-binaphthyl (XI) in the presence of triethylamine (NEt3) to obtain 2'-diphenylphosphino-1,1'-binaphthalen-2-yloxy(6,6'-divinyl-1,1'-binaphthalene-2,2'-diyloxy)phosphine (XVII).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:13]1=[O:19])[C:5]([O:7]C)=[O:6].[OH-].[Li+]>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:13]1=[O:19])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(N2CCCCOC2=O)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(=O)O)ccc1N1CCCCOC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
150 mg (0.57 mmol) methyl 3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzoate are suspended in 1 ml of ethanol and combined with 0.26 ml (0.87 mmol) 8% aqueous lithium hydroxide solution. The mixture is stirred for 3 hours at ambient temperature and then evaporated down i. vac. The aqueous residue is extracted twice with ethyl acetate, then acidified and extracted twice more with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down i. vac.
Reaction SMILES: C(O[C:4](=[O:12])[CH:5]([Na])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[H-].[Na+].C(OCC)(=O)CC(OCC)=O.[CH2:26]([O:33][C:34]([N:36]1[CH2:38][CH2:37]1)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.P(=O)(O)(O)O>O1CCCC1>[CH2:9]([O:8][C:6]([CH:5]1[CH2:38][CH2:37][N:36]([C:34]([O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:35])[C:4]1=[O:12])=[O:7])[CH3:10]
Reactant: O=C(OCc1ccccc1)N1CC1
Reactant: CCOC(=O)C([Na])C(=O)OCC
Agent: O=P(O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)C1=O
Reaction time: 22 h

Procedure:
To a solution of sodiomalonic acid diethyl ester prepared from sodium hydride (704 mg), diethyl malonate (3 ml), and tetrahydrofuran (10 ml) is added aziridine-1-carboxylic acid benzyl ester (1.8 g). After 22 hours at room temperature, the mixture is neutralized with 10% phosphoric acid, washed with water, dried and concentrated to give 1-carbobenzoxy-2-oxopyrroidine-3-carboxylic acid ethyl ester (1.85 g). Oil. IR (CHCl3) ν: 1785, 1730 cm-1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:25])=[CH:4][C:5]([N+:22]([O-])=O)=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.O.NN>C(O)C.[Ni]>[NH2:22][C:5]1[CH:4]=[C:3]([CH3:25])[C:2]([Cl:1])=[CH:7][C:6]=1[NH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1
Reactant: Cc1cc([N+](=O)[O-])c(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1Cl
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(N)c(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1Cl
Temperature: 45 °C

Procedure:
1,1-Dimethylethyl 4-[(5-chloro-4-methyl-2-nitrophenyl)amino]-1-piperidinecarboxylate (D6) (0.270 mmol, 100 mg) was dissolved in ethanol (10 ml) and an aqueous suspension of Raney-Nickel (0.3 ml) was added at room temperature; the mixture was heated to 40-50° C. and hydrazine monohydrate (15 eq., 4 mmol, 0.14 ml) was added over 20-30 min; the reaction mixture was then heated at 40° C. for 10 extra minutes and then it was then cooled to room temperature, filtered through celite and the solvent was evaporated to yield the crude product. Crude product was subsequently purified by chromatography (ethyl acetate/hexane) to yield the title compound, 80 mg, 88%, M+−Boc=240.
Reaction SMILES: [CH3:1]O.[OH-].[Na+].Cl.[F:6][CH2:7][CH2:8][N:9](NC)[C:10](=[O:14])[C:11]([OH:13])=[O:12]>O>[F:6][CH2:7][CH2:8][N:9]([CH3:1])[C:10](=[O:14])[C:11]([OH:13])=[O:12]
Reactant: CO
Reactant: CNN(CCF)C(=O)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(CCF)C(=O)C(=O)O
Reaction time: 1 h
Yield: 66 %

Procedure:
To a mixed solvent comprising 6 ml of methanol and 5 ml of water, there was suspended 1.56 g of N-(2-fluoroethyl)-N-methylmethoxyoxalylamide, then 3.2 g of a 15% aqueous solution of sodium hydroxide was dropwise added, with ice-cooling, to the suspension and then the mixture was stirred for one hour. Concentrated hydrochloric acid was added to the reaction system, the mixture was then extracted with ethyl acetate, the organic phase thus separated was washed with water, dried over magnesium sulfate and then the ethyl acetate was distilled off from the organic phase to thus give, as the target product, 0.94 g (yield: 66%, a solid product) of N-(2-fluoroethyl)-N-methylaminooxamic acid.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH:15][C:16](=[O:30])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:19][CH:18]=2)[C:12](O)=[O:13])=[CH:6][CH:5]=1.Cl.[F:34][CH2:35][CH2:36][NH2:37]>>[F:34][CH2:35][CH2:36][NH:37][C:12](=[O:13])[CH:11]([NH:15][C:16](=[O:30])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:19][CH:18]=1)[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:32])([F:31])[F:1])=[CH:9][CH:8]=1
Reactant: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)O)c1ccc(OCCC(F)(F)F)cc1
Reactant: NCCF
Agent: Cl
Product: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)NCCF)c1ccc(OCCC(F)(F)F)cc1
Yield: 116.5 %

Procedure:
A reaction similar to that described in Example 32 (32c) was conducted using 3-[4-(trifluoromethoxy)phenyl]-2-{[4-(3,3,3-trifluoropropoxy)benzoyl]amino}propanoic acid (6.00 g) prepared in Example 70 (70a) and 2-fluoroethylamine hydrochloride (1.71 g) to give 7.67 g of the title compound (white powder).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([O:12]C)[CH:9]=[CH:10][CH:11]=1.B(Br)(Br)Br>>[CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1
Reactant: COc1cccc(OCCN(C)C)c1
Agent: BrB(Br)Br
Product: CN(C)CCOc1cccc(O)c1

Procedure:
3-(2-(Dimethylamino)ethoxy)anisole is reacted with boron tribromide to give 3-(2-(dimethylamino)ethoxy)phenol which is reacted with sodium hydride and N-(3-bromopropyl)phthalimide and the product deprotected with methylamine to give 3-(3-(2-(dimethylamino)ethoxy)phenoxy)propylamine.
Reaction SMILES: [OH:1][CH:2]([CH2:9][CH:10]([OH:31])/[CH:11]=[CH:12]/[C:13]1[N:14]([CH3:30])[C:15](=[O:29])[C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[Na+]>CO.O>[OH:1][CH:2]([CH2:9][CH:10]([OH:31])/[CH:11]=[CH:12]/[C:13]1[N:14]([CH3:30])[C:15](=[O:29])[C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)CC(O)CC(O)/C=C/c1c(-c2ccccc2)c2ccccc2c(=O)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1c(/C=C/C(O)CC(O)CC(=O)O)c(-c2ccccc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.6 %

Procedure:
A solution of ethyl (E)-3,5-dihydroxy-7-(2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)-hept-6-enoate (0.35 g; prepared as described in Example 1) in methanol (15 ml) was cooled to 10° C. and treated with a solution of sodium hydroxide (0.17 g) in water (10 ml) dropwise during 10 minutes. The reaction mixture was warmed to room temperature, stirred for one hour and evaporated to dryness, and the residual solid, which was crude sodium (E)-3,5-dihydroxy-7-(2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)hept-6-enoate, was dissolved in water (50 ml). The aqueous solution was washed with diethyl ether (20 ml) and acidified to pH 5 by treatment with glacial acetic acid. The resulting yellow solid was filtered off and washed well with water, to give (E)-3,5-dihydroxy-7-(2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)hept-6-enoic acid (0.10 g), m.p. 170° C. [Elemental analysis: C, 70.0; H, 5.92; N, 3.37%; calculated: C, 70.2; H, 5.89; N, 3.56%].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:15]#[N:16])[C:11]=1[N:12]([CH3:14])[CH3:13])[N:8]=[C:7]([CH:17]=[O:18])[CH:6]=[CH:5]2.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:15]#[N:16])[C:11]=1[N:12]([CH3:14])[CH3:13])[N:8]=[C:7]([CH2:17][OH:18])[CH:6]=[CH:5]2
Reactant: CN(C)c1c(Br)cc2ccc(C=O)nc2c1C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C)c1c(Br)cc2ccc(CO)nc2c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The 6-bromo-7-dimethylamino-2-formylquinolin-8-carbonitrile (2.4 g, 7.9 mmol, 1.0 eq) was added to MeOH (20 mL) at 0° C. Sodium borohydride (328 mg, 8.7 mmol, 1.1 eq) was then introduced and the mixture was stirred at room temperature for 1 hour. The solution was quenched with HCl 1 M, ethanol was evaporated and water was added. The solution was extracted with dichloromethane and the organic layer was washed twice with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The 6-bromo-7-dimethylamino-2-(hydroxymethyl)quinoline-8-carbonitrile was obtained as an orange solid (2.4 g, 98%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([NH:5][C@@H:6]([C:8]([OH:10])=O)[CH3:7])=[O:4].S(Cl)(Cl)=O.[C:17]1([O:23][CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl.CO.N1C=CC=CC=1>[F:11][C:2]([F:1])([F:12])[C:3]([NH:5][C@H:6]([CH3:7])[C:8]([C:20]1[CH:21]=[CH:22][C:17]([O:23][CH3:24])=[CH:18][CH:19]=1)=[O:10])=[O:4]
Reactant: COc1ccccc1
Reactant: C[C@@H](NC(=O)C(F)(F)F)C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COc1ccc(C(=O)[C@@H](C)NC(=O)C(F)(F)F)cc1
Temperature: 45 °C
Reaction time: 7 h
Yield: 32 %

Procedure:
To the mixture of N-(trifluoroacetyl)-D-alanine (10.00 g; 0.054 mol) and pyridine (100 μl) in CH2Cl2 (100 ml), thionyl chloride (4.1 ml; 0.057 mol) is added dropwise at room temperature and then stirred for 7 hours at 45° C. Anisole (7.0 ml; 0.065 mol) is added and the solution is cooled on an ice-bath. AlCl3 (7.92 g; 0.059 mol) is added in portions and stirred at room temperature for 36 hours. The reaction is terminated with the addition of cold 1M HCl (150 ml) and ice (100 ml). The organic phase is washed with 1M HCl (2×100 ml), water (2×100 ml), saturated NaHCO3 solution (2×100 ml), dried over anhydrous sodium sulphate and concentrated. Heptane (35 ml) is added to the residue while stirring. The formed para-product is filtered off and washed with heptane (2×25 ml). White needle-like crystals are obtained: 4.80 g (32,3% yield); >99% e.e.; [α]57923−40.4; [α]54623−47.0 (c 1.0; MeOH), ortho-product assay 1-2%, melting point 110-114° C., 1H-NMR (CDCl3): 1.52 (d, 3H, CH3; J=7.2 Hz); 3.91 (s, 3H, MeO); 5.47 (m, 1H, CH); 7.00 (m, 2H, H-2.6); 7.64 (broad s, 1H, NHCOCF3); 7.97 (m, 2H, H-3.5).
Reaction SMILES: [CH3:1][C@H:2]([NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C:3]([O:5]C1C=CC([N+]([O-])=O)=CC=1)=O.[NH:26]1[CH2:37][CH2:36][CH2:35][C@H:27]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>C(OCC)(=O)C>[NH:15]([C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[C@H:2]([C:3]([N:26]1[CH2:37][CH2:36][CH2:35][C@H:27]1[C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])=[O:5])[CH3:1]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 15 h

Procedure:
10.32 g of Z-Ala-ONP and 5.0 g of H-Pro-OtBu in 10 ml of ethyl acetate are allowed to stand for one hour at 0°C and 15 hours at room temperature. The mixture is then diluted with 100 ml of ethyl acetate, washed with 50 % saturated potassium carbonate solution and water, dried over sodium sulphate and evaporated. The resulting oil is homogeneous according to a thin layer chromatogram on silica gel (Rf = 0.65 in the system chloroform-methanol (9:1)) and is directly used further.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.[Li]CCCC.[CH3:16][N:17]1[C:21]([CH:22]=[O:23])=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[N:19]=[N:18]1>C1COCC1>[OH:23][CH:22]([C:21]1[N:17]([CH3:16])[N:18]=[N:19][C:20]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[CH2:1][C:2]1[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(C(=O)O)s1
Reactant: Cn1nnc(-c2ccccn2)c1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(CC(O)c2c(-c3ccccn3)nnn2C)sc1C(=O)O
Temperature: -75 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
To a suspension of 2,4-dimethylthiazole-5-carboxylic acid (157 mg, 1.0 mmol) in THF (8 mL) was added dropwise n-BuLi (1.6 M in hexanes, 1.25 mL, 2.0 mmol) under Ar at −75° C. The brown suspension was stirred at −75° C. for 2 h and then a solution of 3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazole-4-carbaldehyde (188 mg, 1.0 mmol) in THF (3 mL) was added at −75° C. and the brown suspension was stirred at −75° C. for 2 h. The mixture was then quenched with an aqueous solution of citric acid (5%, 10 mL), allowed to warm to room temperature. The mixture was then poured into saturated ammonium chloride solution and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by recrystallisation from ethylacetate-heptane afforded the title compound (288 mg, 83%) as a light red solid. MS: m/e=344.0 [M−H]−.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[O:17][CH2:16][CH2:15][N:14]([C:18]4[S:19][C:20]5[C:21](=[O:29])[NH:22][C:23]([CH3:28])([CH3:27])[CH2:24][C:25]=5[N:26]=4)[C:13]=3[CH:30]=2)[CH:5]=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:39][N:40]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[N:41]1>C1COCC1.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.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>[CH3:27][C:23]1([CH3:28])[NH:22][C:21](=[O:29])[C:20]2[S:19][C:18]([N:14]3[C:13]4[CH:30]=[C:9]([O:8][C:6]5[CH:5]=[CH:4][CH:3]=[C:2]([C:43]6[CH:42]=[N:41][N:40]([CH3:39])[CH:44]=6)[N:7]=5)[CH:10]=[CH:11][C:12]=4[O:17][CH2:16][CH2:15]3)=[N:26][C:25]=2[CH2:24]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1(C)Cc2nc(N3CCOc4ccc(Oc5cccc(Br)n5)cc43)sc2C(=O)N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2cccc(Oc3ccc4c(c3)N(c3nc5c(s3)C(=O)NC(C)(C)C5)CCO4)n2)cn1
Temperature: 130 °C
Yield: 39.9 %

Procedure:
To a suspension of Example 382 (40 mg, 0.082 mmol) in THF (3 mL) and water (1 mL) was added tetra-n-butylammonium bromide (53 mg, 0.164 mmol), potassium phosphate (35 mg, 0.164 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (34 mg, 0.164 mmol) and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.008 mmol). The reaction was heated at 130° C. under microwave irradiation for 20 minutes then cooled to r.t. The resulting mixture was partitioned between DCM (50 mL) and water (50 mL); the organic phase was washed with brine (50 mL), dried (MgSO4), and concentrated in vacuo. The residue was purified by preparative HPLC (Method 6) to yield the title compound (16 mg, 40%) as a white solid. δH (CDCl3) 8.00 (1H, d, J 2.6 Hz), 7.88 (1H, s), 7.83 (1H, s), 7.63 (1H, t, J 8.1 Hz), 7.16 (1H, d, J 7.5 Hz), 6.98 (1H, d, J 8.9 Hz), 6.90 (1H, dd, J 8.7 and 2.4 Hz), 6.61 (1H, d, J 8.3 Hz), 5.28 (1H, s), 4.40-4.34 (2H, m), 4.15-4.08 (2H, m), 3.91 (3H, s), 2.82 (2H, s), 1.36 (6H, s). LCMS (ES+) 487.0 (M+H)+, RT 3.25 minutes (Method 1).
Reaction SMILES: [CH2:1]([N:8]1[C:17]([C:18]([OH:20])=[O:19])=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:27][CH3:28])[CH:14]=2)[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:32](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:32][O:19][C:18]([C:17]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9](=[O:29])[C:10]2[C:15]([C:16]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[CH:14][C:13]([O:27][CH3:28])=[CH:12][CH:11]=2)=[O:20]
Reactant: COc1ccc2c(=O)n(Cc3ccccc3)c(C(=O)O)c(-c3ccccc3)c2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1c(-c2ccccc2)c2cc(OC)ccc2c(=O)n1Cc1ccccc1
Reaction time: 12 h
Yield: 72.4 %

Procedure:
2-Benzyl-6-methoxy-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (160 mg) was dissolved in DMF (3 ml), and methyl iodide (0.06 ml) and potassium carbonate (120 mg) were added at room temperature. The mixture was stirred for 12 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The solvent was dried over anhydrous sodium sulfate and evaporated under reduced pressure, and the obtained residue was crystallized from ethyl acetate-hexane to give the title compound (120 mg).