Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C(=O)N([O:8][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][C@@H:15]2[S:19][CH2:18][C@@H:17]3[NH:20][C:21]([NH:23][C@H:16]23)=[O:22])=[O:10])C(=O)C1>CS(C)=O.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[OH:10][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]1[C@@H:16]2[C@@H:17]([NH:20][C:21]([NH:23]2)=[O:22])[CH2:18][S:19]1)=[O:8]
Reactant: O=C1N[C@H]2[C@H](CS[C@H]2CCCCC(=O)ON2C(=O)CCC2=O)N1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.9 mg of biotin-NHS was dissolved in 0.25 mL DMSO, and added dropwise into 5 mL of 2.5% bovine serum albumin (BSA) in 100 mM sodium phosphate, pH 7.5. The solution was stirred for 2 h at room temperature. Unreacted biotin-NHS was removed by centrifugation using a 10K cutoff tube. BSA concentration was determined from its absorbance at 280 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3=[C:16]([CH2:19][N:20]4[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]4)[CH:17]=[CH:18][N:14]3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:54][C:55]1[CH:60]=[CH:59][N:58]=[CH:57][CH:56]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3=[C:16]([CH2:19][N:20]4[CH2:21][CH2:22][CH:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:24][CH2:25]4)[CH:17]=[CH:18][N:14]3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:54][C:55]1[CH:60]=[CH:59][N:58]=[CH:57][CH:56]=1
Reactant: OCc1ccncc1
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccn3ncnc(Nc4ccc(O)c(Cl)c4)c23)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccn3ncnc(Nc4ccc(OCc5ccncc5)c(Cl)c4)c23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 21A (0.047 g, 0.1 mmol), triphenylphosphine (79 mg, 0.3 mmol), and 4-hydroxymethylpyridine (22 mg, 0.2 mmol) in dry THF was added diethyl azodicarboxylate (0.047 ml, 0.3 mmol). The mixture was stirred at room temperature overnight and purified by preparative HPLC to give Compound 21B as a colorless semi-solid (TFA salt). Analytical HPLC retention time=2.303 min. (Chromolith Speed ROD column 4.6×50 mm, 10–90% aqueous methanol over 4 minutes containing 0.2% trifluoroacetic acid, 4 mL/min, monitoring at 254 nm) and a LC/MS M++1=564+.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([NH:10][C:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[F:25])[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:14]2)=[O:12])=[CH:8][CH:9]=1)=[O:4].[Li+].[OH-].Cl>O1CCCC1>[Cl:24][C:20]1[C:19]([F:25])=[C:18]([C@@H:17]2[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:14][C@H:13]2[C:11]([NH:10][C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=2)=[O:12])[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)s2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 66 h
Yield: 67.5 %

Procedure:
To a solution of rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-thiophene-2-carboxylic acid methyl ester prepared in Example 150 (90 mg, 0.15 mmol) in tetrahydrofuran (3 mL) was added an aqueous solution (3 mL) of LiOH (36 mg, 1.5 mmol). The reaction mixture was stirred at room temperature for 66 h, and the “pH” of the solution was adjusted to 5 by aqueous HCl solution. The mixture was extracted ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated to give rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-thiophene-2-carboxylic acid as a yellow solid (60 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]([SH:12])=[N:9]2)=[CH:4][CH:3]=1.Cl[Sn:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]([S:12][Sn:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1c2ccc(Cl)cc2nc(S)n1-c1ccccc1
Reactant: Cl[Sn](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1c2ccc(Cl)cc2nc(S[Sn](c2ccccc2)(c2ccccc2)c2ccccc2)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 4 g (0.014 mole) 7-chloro-2-mercapto-3-phenyl-4(3H)-quinazolinone (the product of Example 3) and 5.4 g (0.014 mole) chlorotriphenyl tin in methylene chloride (about 75 ml), 1.4 g (0.014 mole) triethylamine in methylene chloride (about 25 ml) was added dropwise. The resulting mixture was stirred for about one hour at ambient temperature, refluxed about 5 hours, stirred overnight, refluxed about 4 hours and cooled. The mixture was washed with water. The organic fraction was dried and stripped to give the above-identified product as a solid, melting point 110° to 112° C.
Reaction SMILES: C[O:2][C:3](=[O:45])[C@@H:4]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([C:15]2[C:24]([CH3:25])=[CH:23][C:22]3[C:21]([CH3:27])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:29])([CH3:28])[C:17]=3[CH:16]=2)[CH3:14])=[CH:8][CH:7]=1.[OH-].[Li+].Cl>C1COCC1.O>[C:37]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[NH:30][C@@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH:13]([C:15]2[C:24]([CH3:25])=[CH:23][C:22]3[C:21]([CH3:27])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:29])[C:17]=3[CH:16]=2)[CH3:14])=[CH:10][CH:11]=1)[C:3]([OH:45])=[O:2])(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COC(=O)[C@H](Cc1ccc(OC(C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1)Nc1ccccc1C(=O)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2c(cc1C(C)Oc1ccc(C[C@H](Nc3ccccc3C(=O)c3ccccc3)C(=O)O)cc1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2S)-2-(2-Benzoylphenylamino)-3-(4(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphtalen-2-yl)-ethoxy)-phenyl)-propionic acid methyl ester (100 mg; 0.17 mmol) in THF (12 ml) was added a solution of lithium hydroxide (16 mg; 0.37 mmol) in water (8 ml). The reaction mixture was stirred at room temperature for 4 hours and 1 N HCl was added to pH 6. The mixture was extracted with methylene chloride (2×50 ml). The combined organic phases were dried and evaporated. The product was crystallized as the L-lysine salt from methanol-hexanes. Yield 95 mg. Compound 4.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.[CH2:15]([O:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([C:27](=O)[C:28](OC)=[O:29])=[CH:23][NH:24]2)=[CH:20][CH:19]=1)[CH3:16].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[CH2:15]([O:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([C:27]3[C:28](=[O:29])[NH:14][C:12](=[O:13])[C:11]=3[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[N:2]([CH3:1])[CH:3]=[CH:4]4)=[CH:23][NH:24]2)=[CH:20][CH:19]=1)[CH3:16]
Reactant: CCOc1ccc2c(C(=O)C(=O)OC)c[nH]c2c1
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOc1ccc2c(C3=C(c4cccc5ccn(C)c45)C(=O)NC3=O)c[nH]c2c1
Temperature: 70 °C
Yield: 25.7 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)acetamide (381 mg, 2.02 mmol) and methyl 2-(6-ethoxy-1H-indol-3-yl)oxoacetate (500 mg, 2.02 mmol) in DMF (17 mL) was added a 1.0 M solution of potassium tert-butoxide in THF (2.0 mL, 2.0 mmol) at 4° C. under N2. The reaction was stirred for 20 min at this temperature, and additional potassium tert-butoxide (1.0 M, 4.1 mL, 4.1 mmol) was added. The resulting dark purple solution was heated up to 70° C. over night. The mixture was cooled to 4° C. and quenched with 1.0 N hydrochloric acid (12 mL) and poured into EtOAc (500 mL). The organic layer was separated, dried (MgSO4), and concentrated to a red solid. Flash chromatography (SiO2, 30% EtOAc/hexanes) gave the title compound (200 mg, 26%) as a red solid, mp 212–215° C. 1H NMR (CDCl3) δ 8.44 (s, 1H), 7.88 (s, 1H), 7.68 (m, 1H), 7.60 (s, 1H), 7.00 (m, 2H), 6.92 (s, 1H), 6.72 (s, 1H), 6.52 (s, 1H), 6.32 (s, 2H), 3.92 (q, J=6.5 Hz, 2H), 3.72 (s, 3H), 1.38 (t, J=6.5 Hz, 3H). MS (ESI, Negative Mode): m/z=384 [C23H19N3O3−H]−
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](=[O:11])[CH2:8][C:7]=2[CH:12]=1.C(O)C>C(O)C.C(OCC)(=O)C.[Pd]>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](=[O:11])[CH2:8][C:7]=2[CH:12]=1
Reactant: O=C1Cc2cc(CCl)ccc2O1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)CC(=O)O2
Reaction time: 2 h

Procedure:
A solution of the product of Step 1, above (55) (10.89 mmol), in ethanol/ethyl acetate (23 ml/5 ml) was added to 10 ml ethanol over 10% palladium catalyst on carbon (100 mg). The mixture was hydrogenated on a Parr shaker at 45 psi for 2 hours. The reaction mixture was filtered through celite and the organics were concentrated to dryness to obtain the title compound (56).
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:11][O:12][C:13](=[O:43])[C@H:14]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Sn](CCCC)(CCCC)CCCC)=[CH:26][CH:25]=1)[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CN(C=O)C.ClCCl.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>[CH3:11][O:12][C:13](=[O:43])[C@H:14]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:2]2[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Cl:8])[CH:7]=2)=[CH:28][CH:29]=1)[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17]
Reactant: Cn1cc(Cl)cc(Br)c1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2cc(Cl)cn(C)c2=O)cc1)NC(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 4 h
Yield: 53.6 %

Procedure:
A solution of 3-bromo-5-chloro-1-methyl-2-pyridone (660 mg, 2.97 mmol) and N-[(1,1-dimethylethoxy)carbonyl]-4-[(tributyl)stannyl]-L-phenylalanine methyl ester (1.7 g, 2.99 mmol) in DMF (30 mL) was deoxygenated by alternately freezing the mixture in a liquid nitrogen bath under vacuum and thawing under argon (3×). Tetrakis(triphenylphosphine)palladium (140 mg, 0.20 mmol) was added and the mixture was heated to 90° C. for 3 hr as the mixture turned dark. TLC indicated that the reaction was not complete and an additional 140 mg portion of the catalyst was added and heating continued for 4 hr. The mixture was allowed to cool and was diluted with dichloromethane and was filtered through a pad of celite. The filtrate was evaporated to dryness and the residue was dissolved in 1:1 ether:ethyl acetate (60 mL). The solution was washed with water (3×10 mL) and brine (1×10 mL) and was dried (MgSO4). The residue obtained upon concentration was chromatographed over 150 g of silica gel eluting with 7:3 ethyl acetate:hexane to give 4-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine methyl ester (670 mg, 54%). LRMS-Electrospray: m/z 863 (2M+Na), 858 (2M+NH4), 443 (M+Na), 438 (M+NH4), 421(M+H).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:29])[C@@H:14]([OH:28])[CH2:15][C@@H:16]3[C@@:21]4([CH3:27])[CH2:22][CH2:23][C@@H:24]([OH:26])[CH2:25][C@H:20]4[CH2:19][CH2:18][C@H:17]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][C:5](OC)=[O:6].O>C1COCC1>[OH:26][C@@H:24]1[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:20]([CH2:19][CH2:18][C@@H:17]3[C@@H:16]2[CH2:15][C@H:14]([OH:28])[C@@:13]2([CH3:29])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:2]([CH3:1])[CH2:3][CH2:4][CH2:5][OH:6])[CH2:25]1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](CCCO)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Yield: 103.5 %

Procedure:
A suspension of LiA1H4 (0.15 g, 3 mols. equiv.) in dry THF (25 ml) was stirred under nitrogen whilst standing in an ice/methanol bath. Methyl deoxycholate (5b) (0.5 g, 1.2 mmol) in dry THF (30 ml) was then added dropwise and the resultant mixture stirred at ambient temperature for 2.5 hours. Water was then introduced carefully to the mixture until all the excess LiA1H4 had been destroyed. The resultant mixture was acidified with 2M HCl and extracted into EtOAc (3×). The combined organic extracts were washed with water (2×), dried and evaporated to give a white foam (0.47 g, 100%). Recrystallisation of 0.41 g from ethyl acetate afforded pure 3α,12α,24-trihydroxy-5β-cholane (7b)8 (0.30 g, 73%): m.p. 110°-116° C. [Lit8 107°-114° C.); 1H nmr (90 MHz; CDCl3 /DMSO d6) δ 0.67 (3H, s, 18-CH3), 0.90 (3H, s, 19-CH3), 3.2-3.7 (1H, m, 3β-H), 3.4-3.6 (2H, t(broadened), 24-CH2), 3.8-4.0 (1H, m, 12β-H); IR (KBr) 3366 (OH's) cm-1.
Reaction SMILES: FC1C=C(C=CC=1)COC1C=CC(N)=CC=1.[F:17][C:18]([F:37])([F:36])[C:19]1[CH:35]=[CH:34][C:22]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1>>[F:17][C:18]([F:36])([F:37])[C:19]1[CH:35]=[CH:34][C:22]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Agent: Nc1ccc(OCc2cccc(F)c2)cc1
Product: Nc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Yield: 98 %

Procedure:
Prepared in analogy to 4-(3-fluoro-benzyloxy)-phenylamine, by hydrogenation of 4-(4-trifluoromethyl-benzyloxy)-nitrobenzene. Yield: 98% of a slightly yellow solid. MS: m/e=268.3 (M++H).
Reaction SMILES: [C:1]1(=[O:11])[O:6]C(=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C1(=O)NC(=O)C2=CC=CC=C12.C(O)(=O)C1C(=CC=CC=1)N.[S-2].[Na+].[Na+].[S].C(S)(=S)C1C(=CC=CC=1)O.N.[NH4+].S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O.[Cl:61]C1C=CC=CC=1C.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O.[Na+].[Na+]>CO>[Cl:61][C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1ccccc1Cl
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: N
Agent: Nc1ccccc1C(=O)O
Solvent: CO
Product: O=C(O)c1ccccc1Cl

Procedure:
A further production process comprises converting phthalic acid anhydride into phthalimide and phthalimide into anthranilic acid, diazotising the anthranilic acid and reacting the diazotised product with sodium sulphide/sulphur to dithiosalicylic acid, esterifying the dithiosalicylic acid with methanol, and reacting the esterified product by means of oxidating chlorination to methyl benzoate-o-sulphonic acid chloride and subsequently converting this with ammonia into the saccharin ammonium salt. Another method consists of oxidising o-chlorotoluene with sodium bichromate to give o-chlorobenzoic acid, subsequently reacting this with sodium sulphite to o-sulphobenzoic acid, esterifying this with methanol and reacting the esterified product with thionyl chloride or sulphuryl chloride to methyl benzoate-o-sulphonic acid chloride, and converting this with ammonia into the saccharin ammonium salt.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([OH:12])=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].C[C:20]([C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1F)=[O:21]>C(#N)C>[F:28][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([O:12][C:8]2[CH:9]=[N:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])[C:22]=1[CH:20]=[O:21]
Reactant: CC(=O)c1c(F)cccc1F
Reactant: Oc1cnc2c(F)cccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1c(F)cccc1Oc1cnc2c(F)cccc2c1
Yield: 57.2 %

Procedure:
After 30 ml of acetonitrile was added to 3.0 g of 8-fluoro-3-hydroxyquinoline, 3.1 g of potassium carbonate and 3.5 g of 2,6-difluoroacetophenone were added. After the reaction solution was heated under reflux for 3 hours, the reaction solution was filtered with CELITE. After the filtrate was extracted with ethyl acetate, the organic layer was concentrated and purified by silica gel column chromatography to obtain 3.0 g of 2-fluoro-6-(8-fluoroquinolin-3-yloxy)-benzaldehyde (Compound Number 341).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH2:9]1)=O)(C)(C)C.[NH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1>>[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=4)[N:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2cccc(-c3ccnc(Cl)n3)c2)C1
Reactant: NCCc1ccc(O)cc1
Product: Oc1ccc(CCNc2nccc(-c3cccc(NC4CCCNC4)c3)n2)cc1

Procedure:
Intermediate 8 was coupled with tyramine following procedure F and the resulting product deprotected by procedure G. LC-MS showed the product had the expected M+H+ of 390. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.2 (d, 1H) 6.95-7.6 (m, 8H) 6.7 (m, 2H) 4.95 (m, 1H) 3.7-3.9 (m, 2H) 3.5 (m, 1H) 2.8-3.2 (m, 5H) 1.6-2.4 (m, 5H).
Reaction SMILES: Cl[C:2]1[C:3]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)(=[O:15])=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:23][O:24][C:25]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:26]=1[NH2:27]>CCO>[CH3:23][O:24][C:25]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:26]=1[NH:27][C:2]1[C:3]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)(=[O:15])=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COc1ccc(OC)c(N)c1
Reactant: O=S(=O)(Nc1nc2ccccc2nc1Cl)c1cccc(F)c1
Solvent: CCO
Product: COc1ccc(OC)c(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(F)c2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
N-(3-chloroquinoxalin-2-yl)-3-fluorobenzenesulfonamide (125 mg, 0.4 mmole) and 2,5-dimethoxyaniline (170.4 mg, 1.1 mmole) are taken in 0.5 ml of EtOH and the resulting suspension is stirred at 100° C. in an orbital shaker, overnight. The precipitate obtained is filtered and washed with EtOH then ether to afford the title compound as a dark green solid (163 mg, 97%). HPLC (max plot) 96%, rt. 4.88 min. LC/MS: (ES+): 455.2.
Reaction SMILES: Br[CH2:2][C:3]([N:5]([CH2:7][CH2:8][CH2:9][CH3:10])[CH3:6])=[O:4].[C:11]([O-:14])(=[S:13])[CH3:12].[K+]>CO>[C:11]([S:13][CH2:2][C:3]([N:5]([CH2:7][CH2:8][CH2:9][CH3:10])[CH3:6])=[O:4])(=[O:14])[CH3:12]
Reactant: CC([O-])=S
Reactant: CCCCN(C)C(=O)CBr
Agent: [K+]
Solvent: CO
Product: CCCCN(C)C(=O)CSC(C)=O
Temperature: 40 °C
Yield: 100 %

Procedure:
4.16 g of bromo-N-butyl-N-methylacetamide of Preparation B of Example 78, Step A in 1.5 ml of methanol were added to a suspension of 2.28 g of potassium thioacetate in 10 ml of methanol and the mixture was heated for one hour at 40° C. under an argon atmosphere. After evaporation to dryness under reduced pressure, the residue was dissolved with ethyl ether, the insoluble part filtered off and the solution was evaporated to dryness to obtain 4.06 g of oily product.
Reaction SMILES: C([N:11]1[CH2:15][CH2:14][CH:13]2[CH2:16][C:12]12[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(OCC1C=CC=CC=1)=O>C(OCC)(=O)C>[NH:11]1[CH2:15][CH2:14][CH:13]2[CH2:16][C:12]12[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CC(C)(C)OC(=O)C12CC1CCN2C(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C12CC1CCN2
Yield: 85 %

Procedure:
Compound (5) was dissolved in ethyl acetate (300 ml) and the solution was flushed with argon. Palladium-on-carbon (5%, 3 g) was added and hydrogen was bubbled into the stirred suspension until no starting material remained (2 hours as indicated by TLC). The flask was then flushed with nitrogen and the catalyst was removed by filtration. The catalyst was washed with methanol (3×100 ml) and the combined filtrates were concentrated. The residue was then distilled with a Kuglerohr apparatus at reduced pressure to give 6.6 g (85%) of compound (6) as a light yellow oil: bp=90°-120° C./0.8 mm; 1H NMR (C6D6): δ2.83 (m, 1H), 2.32 (m, 1H), 2.10 (br s, 1H), 1.76 (m, 1H), 1.3-1.65 (m, 3H), 1.36 (s, 9H), 0.85 (t, J=6 Hz) ppm. 13NMR (C6D6) δ172.2 (C=O), 80.1 (quat), 50.1 (quat), 44.3 (CH2), 28.1 (CH2), 27.7 (CH), 16.7 (CH2) ppm.
Reaction SMILES: [CH:1]([Si:4]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[C:7]=1[NH2:13])([CH3:3])[CH3:2].[C:20](OCC)(=O)[CH:21]=[O:22].C1(C)C=CC=CC=1>C(O)C>[CH:17]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:14]([CH3:16])[CH3:15])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:7]=1[N:13]=[CH:20][C:21](=[O:22])[NH:12]2)([CH3:19])[CH3:18]
Reactant: CC(C)[Si](Oc1cccc(N)c1N)(C(C)C)C(C)C
Reactant: CCOC(=O)C=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)[Si](Oc1cccc2[nH]c(=O)cnc12)(C(C)C)C(C)C
Reaction time: 8 h

Procedure:
A solution of (b) (80.7 g) in ethanol (1 liter) was treated with a 50% solution of ethyl glyoxalate in toluene (60 ml, 294 mmol) and heated to reflux for 2 hours. The mixture was left at room temperature overnight and filtered affording 5-triisopropylsilanyloxy-1H-quinoxalin-2-one. The filtrate was evaporated and the residue chromatographed eluting with a 0-3% gradient of methanol in dichloromethane affording 8-triisopropylsilanyloxy-1H-quinoxalin-2-one as a white solid (14.9 g).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][C:9]1[CH:10]=[C:11]([NH:16][CH2:17][CH2:18][C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[CH:12]=[CH:13][C:14]=1[CH3:15].[C:29]1([CH2:35][C:36](O)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:8][C:9]1[CH:10]=[C:11]([N:16]([CH2:17][CH2:18][C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[C:36](=[O:37])[CH2:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:12]=[CH:13][C:14]=1[CH3:15]
Reactant: O=C(O)Cc1ccccc1
Reactant: Cc1ccc(NCCc2ccc(C(F)(F)F)nc2)cc1C
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)Cc2ccccc2)cc1C

Procedure:
In analogy to example 1, step 4 (without TFA addition), (3,4-dimethyl-phenyl)-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-amine (prepared in example 1, step 3) was coupled to phenylacetic acid to provide the title compound as a pale yellow oil. MS m/e: 413.2 [M+H]+.
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[C:11]([I:12])=[CH:10][N:9]([CH2:13][CH:14]3[CH2:16][CH2:15]3)[C:5]=2[N:6]=[CH:7][N:8]=1.C(=O)=O.CC(C)=O>O1CCOCC1.CC(O)C>[CH:14]1([CH2:13][N:9]2[C:5]3[N:6]=[CH:7][N:8]=[C:3]([NH2:1])[C:4]=3[C:11]([I:12])=[CH:10]2)[CH2:16][CH2:15]1
Reactant: N
Reactant: Clc1ncnc2c1c(I)cn2CC1CC1
Agent: O=C=O
Solvent: CC(C)O
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: Nc1ncnc2c1c(I)cn2CC1CC1
Temperature: 100 °C

Procedure:
Gaseous ammonia (from a lecture bottle) was condensed into a suspension of 4-chloro-7-cyclopropylmethyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (394.8 mg, 1.184 mmol) in dioxane (3 mL) and iPrOH (2 mL) in a sealable glass tube, cooled by dry ice/acetone, until the volume increased by ≈1 mL, then the tube was sealed and heated to 100° C. overnight. The solvents were evaporated, water was added, the mixture was extracted with CH2Cl2 (3×20 mL), and the combined CH2Cl2 extracts were washed with brine, dried over MgSO4, filtered and concentrated to give the title compound as a white solid. 1H NMR (CDCl3, 400 MHz): δ=0.36-0.43 (m, 2H), 0.58-0.66 (m, 2H), 1.19-1.29 (m, 1H), 4.03 (d, J=6.8 Hz, 2H), 5.63 (brs, 2H), 7.19 (s, 1H), 8.27 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): δ=4.02 (2C, −), 11.28 (+), 48.46 (Cquart), 49.19 (−), 103.96 (Cquart), 128.70 (+), 150.03 (Cquart), 152.05 (+), 156.88 (Cquart). MS (ES+): m/z 315.1 (100) [MH+]. HPLC: tR=2.3 min (OpenLynx, polar—5 min).