Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)=[C:5]([N+:20]([O-])=O)[CH:4]=1)#[N:2].O.NN.[CH:26](O)=O>C(O)C.[Pd].C(OC)(OC)OC>[C:1]([C:3]1[CH:8]=[CH:7][C:6]2[N:9]([C:10]3[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=3)[CH:26]=[N:20][C:5]=2[CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc(Nc2ccc(C#N)cc2[N+](=O)[O-])cc1
Reactant: O=CO
Agent: [Pd]
Agent: NN
Solvent: COC(OC)OC
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(-n2cnc3cc(C#N)ccc32)cc1
Temperature: 25 °C
Yield: 64.6 %

Procedure:
A mixture of 4-fluoro-3-nitrobenzonitrile (2.00 g, 12.04 mmol) and methyl 4-aminobenzoate (1.94 g, 12.83 mmol) in DMSO (40 mL) was cooled in an ice-bath and potassium tert-butoxide (2.96 g, 26.38 mmol) was added over 15 min. The reaction mixture was allowed to stir at room temperature for 3 h. The reaction mixture was quenched with ice; the solid product was recovered by filtration, washed with water and dried under vacuum to afford 2.4 g (68%) of methyl 4-[(4-cyano-2-nitrophenyl)amino]benzoate. To a solution of methyl 4-[(4-cyano-2-nitrophenyl)amino]benzoate (0.2 g, 0.67 mmol) in ethanol (4 mL) was added palladium on carbon (10 wt. %, 0.06 g) and hydrazine hydrate (0.13 g, 2.60 mmol) and the reaction mixture was heated at reflux for 2 h. The reaction mixture was cooled to room temperature, filtered through celite, and the solvent evaporated. The residue was dissolved in ethyl acetate, washed with water, dried (Na2SO4) and evaporated under reduced pressure to afford a crude oil. To a solution of the oil in trimethyl orthoformate (10 mL) was added formic acid (0.31 g, 7.7 mmol, 3 eq) and the reaction mixture was heated at reflux for 2 h. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was partitioned between water and ethyl acetate and the organic layer was dried (Na2SO4) and evaporated to afford a crude solid. Purification by flash column chromatography (silica, CHCl3/MeOH 98:2) afforded 0.12 g (63%) of methyl 4-(5-cyano-1H-benzimidazol-1-yl)benzoate. MS [M+H] 277.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:25]=[CH:24][C:16]([O:17][CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:32].[Na+].OP([O-])(O)=O.[Na+]>C(#N)C.O.C(O)(C)(C)C>[C:21]([NH:20][CH2:19][CH2:18][O:17][C:16]1[CH:24]=[CH:25][C:13]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][C:2]=2[Cl:1])[NH:8][CH:7]=[C:6]3[C:11]([OH:32])=[O:12])=[CH:14][CH:15]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)NCCOc1ccc(-c2cc3c(C=O)c[nH]c3cc2Cl)cc1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CC#N
Solvent: O
Product: CC(=O)NCCOc1ccc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)cc1
Temperature: 0 °C
Reaction time: 40 h
Yield: 25.7 %

Procedure:
To a solution of N-{2-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenoxy]ethyl}acetamide (80 mg, 0.23 mmol) in acetonitrile (3 mL) was added tert-butanol (3 mL) and 2-methyl-2-butene (1.89 mL). The reaction mixture was cooled to 0° C., and treated with a solution of sodium chlorite (452 mg, 6.74 mmol) and sodium phosphate monobasic (930 g, 6.74 mmol) in water (3 mL) dropwise. The reaction mixture was stirred at room temperature for 40 h. The reaction mixture was quenched with sodium sulfite and concentrated in vacuo to give a solid. The crude product was washed with DMF and the filtrate was concentrated in vacuo to give a brown residue, which was purified by prep-HPLC to give 5-{4-[2-(acetylamino)ethoxy]phenyl}-6-chloro-1H-indole-3-carboxylic acid (22 mg, 26%) as an off-white solid. MS (ES+) 373.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1 H), 8.14 (br. s., 1 H), 8.06 (s, 1 H), 7.93 (s, 1 H), 7.62 (s, 1 H), 7.34 (d, 2 H), 7.02 (d, 2 H), 4.03 (t, 2 H), 3.45-3.43 (m, 2 H), 1.84 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[CH2:17]([N:21]=[C:22]=[S:23])[CH2:18][CH2:19][CH3:20].C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.C=CC1C=CC=C(C=C)C=1.C=CC1C(C=C)=CC=CC=1>O1CCCC1>[CH2:17]([NH:21][C:22](=[S:23])[NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN=C=S
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Agent: C=Cc1ccc(C=C)cc1
Agent: C=Cc1cccc(C=C)c1
Agent: C=Cc1ccccc1C=C
Solvent: C1CCOC1
Solvent: C=Cc1ccccc1
Product: CCCCNC(=S)Nc1cccc(C(=O)C2CCN(C)CC2)c1
Reaction time: 0.17 h

Procedure:
4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and poly(4-vinyl pyridine) (50 mg, 0.400 mmol, 2% cross-linked) in tetrahydrofuran (2 mL) were allowed to stand 10 min. Butyl isothiocyanate (41 μL, 0.344 mmol) was added and the reaction mixture was mixed for 96 h at ambient temperature. An addition amount of butyl isothiocyanate (100 μL, 0.829 mmol) was added to the reaction mixture and mixing was continued for another 6 days. Polystyrene methylisocyanate (230 mg, 0.230 mmol, 1% crosslinked poly(styrene-co-divinylbenzene) was added, and the reaction mixture was mixed 7 days at ambient temperature. The reaction mixture was filtered and the filter cake was rinsed with methanol. Glacial acetic acid (0.5 mL) was added to the filtrate solution and the solution was mixed. This mixture was poured over a Varian Mega Bond Elut™ strong cation exchange column. The column was rinsed extensively with methanol to remove impurities, then treated with a 2M ammonia in methanol to elute the product from the column. The solvent was evaporated and the residue was purified by radial chromatography (silica gel, 1000 micron rotor, methylene chloride:2M ammonia in methanol, 100:2 then 100:4). The solvent was concentrated in vacuo to give 20.3 (53%) of the title compound.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([CH2:7][S:8]([CH2:11][C:12]#[N:13])(=[O:10])=[O:9])=[CH:3][CH:2]=1.[CH2:15]([O:17][CH:18](OCC)OCC)[CH3:16].C(OC(=O)C)(=O)C>>[CH2:15]([O:17][CH:18]=[C:11]([S:8]([CH2:7][C:4]1[CH:3]=[CH:2][C:1]([CH3:14])=[CH:6][CH:5]=1)(=[O:9])=[O:10])[C:12]#[N:13])[CH3:16]
Reactant: CCOC(OCC)OCC
Reactant: Cc1ccc(CS(=O)(=O)CC#N)cc1
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C#N)S(=O)(=O)Cc1ccc(C)cc1
Yield: 89.7 %

Procedure:
To a solution of 4.4 g (21 mmol) of 2 in 17.5 mL (105 mmol) of triethylorthoformate was added 9.9 mL (105 mmol) of acetic anhydride. The resulting solution was heated to reflux for 18 h before being concentrated to a solid. Recrystallization from AcOEt-hexanes gave 5.0 g (90%) of the title compound as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>>[ClH:17].[Cl:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:9][NH:8][CH2:16]2
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(N3CCCCC3)cc2C1
Agent: Cl
Product: Clc1cc2c(cc1N1CCCCC1)CNC2

Procedure:
Prepared in analogy to Example A3(e) from 5-chloro-6-piperidin-1-yl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Brown solid. MS (m/e): 239.2 ({37Cl}M+H+, 35%), 237.1 ({35Cl}M+H+, 100%).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:25][O:26]C(=O)C1C=CC(OC)=CC=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].[ClH:39]>CO.O>[ClH:39].[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:25][OH:26])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(COC(=O)c3ccc(OC)cc3)cccc2c1Nc1ccc(O)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCC(=O)c1cnc2c(CO)cccc2c1Nc1ccc(O)cc1C
Yield: 62 %

Procedure:
A solution of 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-(4-methoxybenzoyloxymethyl)quinoline (2.34 g, 4.8 mmol) and sodium hydroxide (0.38 g, 9.6 mmol) in methanol (50 ml) was heated at reflux for 30 minutes, then diluted with water and neutralised with dilute hydrochloric acid. The solid was filtered off and washed with water, then converted to the hydrochloride. Recrystallisation from aqueous ethanol gave 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-(hydroxymethyl)quinoline hydrochloride (1.16 g, 62%), m.p. 167°-171°.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[C:6]([NH:8][C:9]1[C:10]([NH:19][CH2:20][CH2:21][CH3:22])=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)=O)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1>[CH2:1]([S:3][C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[C:6]1[N:19]([CH2:20][CH2:21][CH3:22])[C:10]2=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=[C:9]2[N:8]=1)[CH3:2]
Reactant: CCCNc1ncc(C(F)(F)F)cc1NC(=O)c1ccccc1SCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: CCCn1c(-c2ccccc2SCC)nc2cc(C(F)(F)F)cnc21
Temperature: 160 °C
Yield: 77.1 %

Procedure:
A mixture of 2-ethylsulfanyl-N-(2-propylamino-5-trifluoromethyl-pyridin-3-yl)-benzamide (710 mg), p-toluenesulfonic acid monohydrate (1.1 g), and xylene (10 ml) was stirred with heating at 160° C. for 10 hours. Into the reaction mixture cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 522 mg of 2-(2-ethylsulfanylphenyl)-3-propyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 24).
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1.C(N(CC)C(C)C)(C)C.Br[CH2:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25].O>CN1C(=O)CCC1>[Cl:1][C:2]1[N:7]([CH2:21][C:22]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=2[C:24]#[N:25])[C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1
Reactant: N#Cc1ccc(F)cc1CBr
Reactant: Cn1c(=O)cc(Cl)[nH]c1=O
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(=O)cc(Cl)n(Cc2cc(F)ccc2C#N)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Alternatively, 33 was made as follows. To a solution of 6-chloro-3-methyluracil (750 g) and N,N-diisopropylethylamine (998 mL) in NMP (3 L) was added (at <30° C. over 25 min) a solution of 32 (2963 g crude material containing 1300 g of 32 in 3 L of toluene). The mixture was then heated at 60° C. for 2 hours or until completion (as determined, for example, by HPLC). Heating was then stopped and the mixture was allowed to cool overnight. Purified water (3.8 L) was added, and the resultant slurry was stirred at ambient temperature for 1 hour and at <5° C. for one hour. The mixture was then filtered under vacuum and the wet cake was washed with IPA (2×2.25 L). The material was then dried in a vacuum oven at 40±5° C. for 16 or more hours to afford 33 as a tan solid (>85% yield; purity was >99% (AUC)).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H](C3C=CC=CC=3)C)[CH2:11][C@H:10]2[F:22])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>ClCCl>[CH2:27]([O:26][C:24]([N:12]1[CH2:13][C@H:9]([C:6]2([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:8][CH2:7]2)[C@H:10]([F:22])[CH2:11]1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C[C@H]2F)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C1([C@H]2CN(C(=O)OCc3ccccc3)C[C@H]2F)CC1
Yield: 83.7 %

Procedure:
4-(S)-(1-Ethoxycarbonylcyclopropyl)-3-(S)-fluoro-1-(1-(S)-phenylethyl]pyrrolidine (5.08 g, 16.63 mmol) was dissolved in dry dichloromethane (50 ml). Under ice cooling, benzyl chloroformate (3.56 ml, 25.0 mmol) was added dropwise into this solution. Then the liquid reaction mixture was heated under reflux for 1 hour and dichioromethane was evaporated under reduced pressure. The residue was subjected. to flash silica gel column chromatography (eluent: n-hexane:ethyl acetate=3:1) to obtain 4.67 g (83.7%) of the title compound as a colorless oily substance.
Reaction SMILES: C(N(CC)CC)C.[N-:8]=[N+:9]=[N-:10].[Na+].[N+]([C:15]1[CH:34]=[CH:33][CH:32]=[C:17]2[C:18]([N:20]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)[C:21](=[O:22])[C:16]=12)=[O:19])([O-])=O>CS(C)=O>[N:8]([C:32]1[CH:33]=[CH:34][CH:15]=[C:16]2[C:21]([N:20]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)[C:18](=[O:19])[C:17]=12)=[O:22])=[N+:9]=[N-:10]
Reactant: O=C(O)c1ccc(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: [N-]=[N+]=Nc1cccc2c1C(=O)N(c1ccc(C(=O)O)cc1)C2=O
Temperature: 50 °C
Yield: 80.1 %

Procedure:
1.4 ml (0.01 mol) of triethylamine, followed by 0.72 g (0.011 mol) of sodium azide, are added to a mixture of 3.12 g (0.01 mol) of 4-(3-nitrophthalimidyl)-benzoic acid and 20 ml of dimethylsulphoxide. The reaction mixture is heated for 6 hours at 50° C. and is then evaporated in vacuo at 80° C.; the residue is stirred with 70 ml of water and the resulting solution is then brought to pH 1 with hydrochloric acid. The product which has precipitated is filtered off with suction, washed with 5 ml of methanol and dried for 24 hours in a drying cabinet at 80° C./100 mm Hg. 2.47 g (80% of theory) of 4-(3-azidophthalimidyl)-benzoic acid are obtained; melting point 300° C. (with decomposition). IR spectrum (KBr): 1790 and 1740 cm-1 (CO--N--CO); 2150 cm-1 (N3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)=[CH:12][C:11]([C:22]([O:24]CC)=[O:23])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C(O)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)=[CH:12][C:11]([C:22]([OH:24])=[O:23])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)c1cc(-c2cccc(OC)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Product: COc1cccc(-c2cc(C(=O)O)nn2-c2ccc(F)c(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 53A in analogy to the synthesis of the compound of Example 71A. 515 mg (93% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[S:8][C:9]=1[CH2:10][CH2:11][OH:12])[CH2:2][CH2:3][CH3:4].[Cl:23][C:24]1[CH:31]=[C:30](O)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:17][CH:18]=2)[S:8][C:9]=1[CH2:10][CH2:11][O:12][C:30]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([Cl:23])[CH:31]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCO
Reactant: N#Cc1ccc(O)cc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCOc1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To an iced cooled solution of 1.1 g 2-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol dissolved in 50 ml dichloromethane were added 0.56 g commercially available 2-Chloro-4-hydroxybenzonitrile and 0.95 g triphenylphosphine. To this solution was added dropwise 0.57 ml Diethylazodicarboxylate. The cooling bath was removed and reaction mixture stirred at room temperature for six hours. The solvent was removed in vacuo and the residue purified by RP-HPLC to provide 400 mg 4-{2-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-chloro-benzonitrile as lyophilisate.
Reaction SMILES: [C:1]([N:5]1[C:14](=[O:15])[C:13]2[CH:12]=[C:11]([CH3:16])[N+:10]([O-])=[CH:9][C:8]=2[C:6]1=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:20])=O>>[C:1]([N:5]1[C:14](=[O:15])[C:13]2[CH:12]=[C:11]([CH2:16][Cl:20])[N:10]=[CH:9][C:8]=2[C:6]1=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc2c(c[n+]1[O-])C(=O)N(C(C)(C)C)C2=O
Product: CC(C)(C)N1C(=O)c2cnc(CCl)cc2C1=O
Reaction time: 3 h

Procedure:
31.5 g of N-tert-butyl-6-methylpyridine-3,4-dicarboximide-1-oxide from 6.004 are added a little at a time to 300 ml of phosphorus oxychloride, and the mixture is heated stepwise until it refluxes and is stirred for 3 hours. The reaction mixture is evaporated down under reduced pressure, the residue is taken up in methylene chloride and the solution is stirred into ice water. The organic phase is washed several times with water, dried, filtered over alumina and evaporated down under reduced pressure. 28.9 g of the title compound of melting point 62°-64° C. are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:24](O)=[O:25])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:40][C:41]1[CH:46]=[CH:45][N:44]=[CH:43][N:42]=1>O1CCCC1>[N:44]1[CH:45]=[CH:46][C:41]([NH:40][C:24](=[O:25])[CH:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:12]=2)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(Oc2ccccc2)c1)C(=O)O
Reactant: Nc1ccncn1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(Cc1cccc(Oc2ccccc2)c1)C(=O)Nc1ccncn1
Reaction time: 0.5 h
Yield: 136.8 %

Procedure:
N-(t-butoxycarbonyl)-3-phenoxyphenylalanine (1 g) was dissolved in dry tetrahydrofuran (30 ml) and triethylamine (2 ml) was added thereto. Thereafter, ethyl chlorocarbonate (0.3 g) was added under ice-cooling, followed by stirring for 30 minutes. To this solution, 4-aminopyrimidine (0.24 g) was added, followed by stirring at room temperature for 10 hours. After distilling off the solvent, the residue was extracted with ethyl acetate, followed by washing with water. After drying, the solvent was distilled off to obtain N-(t-butoxycarbonyl)-3-phenoxy-DL-phenylalanine 4-pyrimidylamide (I) (1.5 g), which was confirmed as a substantially pure product by an NMR analysis, in the form of a white powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][C:22]([CH2:26][CH3:27])([CH3:25])[CH2:23][CH3:24])[N:7]=1)=[O:5])C.[Li+].[OH-]>CO.C1COCC1.O>[Br:19][C:17]1[CH:16]=[CH:15][C:14]([O:20][CH2:21][C:22]([CH2:26][CH3:27])([CH3:25])[CH2:23][CH3:24])=[C:13]([CH:18]=1)[CH2:12][N:8]1[C:9]([CH3:11])=[CH:10][C:6]([C:4]([OH:5])=[O:3])=[N:7]1
Reactant: CCOC(=O)c1cc(C)n(Cc2cc(Br)ccc2OCC(C)(CC)CC)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCC(C)(CC)COc1ccc(Br)cc1Cn1nc(C(=O)O)cc1C
Temperature: 100 °C

Procedure:
To a solution of 1-[5-bromo-2-(2-ethyl-2-methyl-butoxy)-benzyl]-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester, 22, (0.17 g, 0.38 mmol) in a mixture of MeOH (3 mL) and THF (6 ml) was added a solution of LiOH in 3 ml of H2O. The resulting mixture was heated at 100° C. in an Emrys microwave reactor for 20 minutes. The mixture was poured into water (20 mL) and extracted with EtOAc (3×15 mL). The organic layers were combined, washed with brine (30 mL), dried (MgSO4) and the volatiles were removed in vacuo to yield 1-[5-bromo-2-(2-ethyl-2-methyl-butoxy)-benzyl]-5-methyl-1H-pyrazole-3-carboxylic acid, 23.
Reaction SMILES: C(OC(=O)[NH:7][C:8]12[CH2:15][CH:14]3[CH2:16][C:10]([C:17](=[O:19])[NH2:18])([CH2:11][CH:12]1[CH2:13]3)[CH2:9]2)(C)(C)C.Cl>ClCCl>[NH2:7][C:8]12[CH2:15][CH:14]3[CH2:16][C:10]([C:17]([NH2:18])=[O:19])([CH2:11][CH:12]1[CH2:13]3)[CH2:9]2
Reactant: CC(C)(C)OC(=O)NC12CC3CC1CC(C(N)=O)(C3)C2
Agent: Cl
Solvent: ClCCl
Product: NC(=O)C12CC3CC(C1)C(N)(C3)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-Carbamoylhexahydro-2,5-methanopentalen-3a-yl)carbamic acid tert-butyl ester (1.8 g) dissolved in dichloromethane (50 ml), 11 equivalents of HCl (4M in dioxane) added and the mixture stirred at room temperature overnight. LCMS: amine is fully deprotected. The reaction solution was concentrated by rotary evaporation, the HCl salt of the amine was released with 50 ml of saturated Na2CO3 solution+3 ml of 2M NaOH, and the mixture was extracted a total of 8 times with 20 ml of dichloromethane and once with EtOAc. The organic solutions were combined, dried over MgSO4, filtered, concentrated by rotary evaporation and dried under high vacuum. The residue (0.91 g) was used further without further workup.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2:17][C@@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[C:21]([N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[CH:22]=[CH:23][CH:24]=2)[CH2:19]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:34][N:31]1[CH2:32][CH2:33][N:28]([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:20]=2[CH2:19][C@H:18]([NH:17][C:14](=[O:16])[C:11]2[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=4)=[CH:13][CH:12]=2)[CH2:27][CH2:26]3)[CH2:29][CH2:30]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(-c4ccc(O)cc4)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4′-Hydroxy-4-biphenylcarboxylic acid (0.40 g, 1.9 mmol) was dissolved in thionyl chloride (10 mL) and heated at reflux for 1 h. The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (120 mg, 0.51 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (120 mg, 0.49 mmol) and triethylamine (100 μL, 0.74 mmol) in methylene chloride (20 mL) . After the addition the reaction was allowed to stir at ambient temperature for 15 min and was then washed with water. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/methanol/concentrated ammonium hydroxide (95:6:0.5) as the eluent. Yield: 95 mg (44%) of the title compound as white crystals: mp 261-262° C.; EIMS (70 eV) m/z (relative intensity) 441 (2, M+)
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]2C(=O)[C:18]3[C:13](=[CH:14]C=[CH:16][CH:17]=3)[C:12]2=[O:21])[S:2]1.Cl.C(Cl)(=O)C1C=CC=[N:26]C=1>C1(C)C=CC=CC=1.CO.C(N)CCC.O1CCCC1.C(N(CC)CC)C>[S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[N:26][CH:14]=2)[S:2]1
Reactant: O=C(Cl)c1cccnc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCC1CCSS1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCCCN
Solvent: CO
Product: O=C(NCCCCCC1CCSS1)c1cccnc1
Yield: 32.9 %

Procedure:
The reaction was carried out as described in Example 100, but using 3 ml of a solution of 1.6 mmol of 2-[5-(1,2-dithiolan-3-yl)pentyl]isoindoline-1,3-dione (prepared as described in Example 58) in toluene, 2 ml of methanol, 2 ml of butylamine, 5 ml of anhydrous tetrahydrofuran, 0.33 ml of triethylamine and 427 mg of nicotinoyl chloride hydrochloride. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 3:1 and 1:0 by volume mixtures of ethyl acetate and hexane and a 20:1 by volume mixture of ethyl acetate and methanol as the eluent. The solvent was removed from the eluate by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilised, to obtain 156 mg of the title compound as a yellow amorphous substance, melting at 41 to 44° C.