Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[C:4]1[CH:8]2[C:9]([CH3:11])=[CH:10][CH:5]1[C:6]([CH2:13][OH:14])([CH3:12])[CH2:7]2)([CH3:3])[CH3:2].N1C=CC=CC=1.[C:21](Cl)(=[O:23])[CH3:22]>CN(C1C=CN=CC=1)C.ClCCl.O>[C:1](=[C:4]1[CH:8]2[C:9]([CH3:11])=[CH:10][CH:5]1[C:6]([CH2:13][O:14][C:21](=[O:23])[CH3:22])([CH3:12])[CH2:7]2)([CH3:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC1=CC2C(=C(C)C)C1CC2(C)CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCC1(C)CC2C(C)=CC1C2=C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a solution of (7-Isopropylidene-2,5-dimethyl-bicyclo[2.2.1]hept-5-en-2-yl)-methanol (4.32 g, 22.5 mmol), pyridine (3.55 g, 45 mmol) and DMAP (50 mg) in dichloromethane (50 ml) was added acetyl chloride (2.47 g, 31.5 mmol) with cooling. The mixture was stirred at room temperature for 1 h and was then diluted with water and extracted with pentane (3×80 ml). the organic phase was washed with 1N HCl, water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel (hexane:MTBE=9:1) to yield 4.25 g of a colorless oil as a mixture of isomers. Odor description: cedarwood oil, carrot, verdyl, musky. 1H-NMR (CDCl3, 400 MHz): 5.93–5.72 (m, 1H), 3.94–3.73 (m, 2H), 3.10–2.78 (m, 2H), 2.09–2.03 (m, 3H), 1.85–1.53 (m, 9H1.50–1.15 (m, 2H), 1.09/0.97/0.92/0.89 (4s, 3H) ppm. GC/MS (EI): main isomer: 234 (M+, trace), 159 (3), 120 (100), 105 (46), 91 (11), 77 (7), 43 (15), IR (atr): 2927m, 2726w, 1741s, 1446m, 1369m, 1233vs, 1031s, 986m, 802m cm−1.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[O-2].[Mg+2].[Cl:10][C:11]1[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]>O.C1COCC1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[S:16]([C:14]1[S:15][C:11]([Cl:10])=[C:12]([N+:20]([O-:22])=[O:21])[CH:13]=1)(=[O:18])=[O:17]
Reactant: OCCNCCO
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)sc1Cl
Agent: [Mg+2]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cc(S(=O)(=O)N(CCO)CCO)sc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.2 %

Procedure:
To a stirred solution of diethanolamine (1.16 g, 11 mmol) in water (4 ml) was added at room temperature magnesium oxide (2.22 g, 55 mmol) and THF (16 ml). The suspension was stirred at room temperature for 30 min and a solution of 5-chloro-4-nitrothiophene-2-sulfonyl chloride (3.46 g, 13.2 mmol) in THF (4 ml) was added. The light yellow suspension was stirred at room temperature for 1 h and, after filtration on Dicalit, evaporated. Water (60 ml) was added and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (70 ml), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (heptane/ethyl acetate) to yield 5-chloro-4-nitro-thiophene-2-sulfonic acid bis-(2-hydroxy-ethyl)-amide (0.48 g, 13%) as a yellow solid. MS (ISP) 331.2 [(M+H)+], mp 113° C.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]=[C:7]([C:14]([CH3:16])=O)[C:8]([O:10][CH2:11][CH2:12][CH3:13])=[O:9])=[CH:4][CH:3]=1.[CH3:19][NH:20]/[C:21](/[CH3:29])=[CH:22]\[C:23]([O:25][CH2:26][CH2:27][CH3:28])=[O:24]>CC(O)CC>[Br:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]2[C:22]([C:23]([O:25][CH2:26][CH2:27][CH3:28])=[O:24])=[C:21]([CH3:29])[N:20]([CH3:19])[C:14]([CH3:16])=[C:7]2[C:8]([O:10][CH2:11][CH2:12][CH3:13])=[O:9])=[CH:4][CH:3]=1
Reactant: CCCOC(=O)C(=Cc1ccc(Br)cc1)C(C)=O
Reactant: CCCOC(=O)/C=C(/C)NC
Solvent: CCC(C)O
Product: CCCOC(=O)C1=C(C)N(C)C(C)=C(C(=O)OCCC)C1c1ccc(Br)cc1

Procedure:
A solution of 6.22 g (0.02 mol) of propyl 2-(4-bromobenzylidene)acetoacetate and 3.14 g (0.02 mol) of propyl 3-methylamino-crotonate in 25 ml of 2-butanol is stirred under reflux for 10 hours. The mixture is then concentrated in vacuo, and the precipitate formed in the cold is filtered off with suction. After recrystallization from propanol, 5.32 g (59.1% of theory) of melting point 97°-99° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18](OCC)=[O:19])[CH:8]=1)=[O:5].[CH2:34]([CH2:36][NH2:37])[OH:35].C(N(CC)C(C)C)(C)C>CO>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=[C:9]([C:18]([NH:37][CH2:36][CH2:34][OH:35])=[O:19])[CH:8]=1)=[O:5]
Reactant: CCOC(=O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Reactant: NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=C(NCCO)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Yield: 41.7 %

Procedure:
Ethyl 5-(2-chloro-5-(3-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylate (Example 113, 40 mg, 0.09 mmol), ethanolamine (15.7 mg, 0.26 mmol) and N,N-diisopropylethylamine (33.3 mg, 0.26 mmol) in methanol (1 mL) was heated at 50° C. in a sealed vial for 17 hours. The reaction was cooled and purified using reverse phase column chromatography eluting with 3-50% MeCN in water with 0.1% ammonia to afford the title compound as a white solid (18 mg, 44%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.[NH:14]1[CH2:19][CH2:18][C:17]2([CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[O:20]2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:14]3[CH2:19][CH2:18][C:17]4([CH2:23][C:22]5[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=5[O:20]4)[CH2:16][CH2:15]3)=[CH:7][CH:6]=2)[O:12][N:11]=1
Reactant: c1ccc2c(c1)CC1(CCNCC1)O2
Reactant: Cc1noc(-c2ccc(Cl)nn2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1noc(-c2ccc(N3CCC4(CC3)Cc3ccccc3O4)nn2)n1

Procedure:
The object product (201 mg, 87%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridazine (130 mg) obtained in Example 43(2), 3H-spiro[1-benzofuran-2,4′-piperidine] (150 mg) and potassium carbonate (110 mg).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:32]([OH:34])=O)[CH2:20][CH2:19][N:18]([C:21]([C:23]3([CH3:31])[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25][CH2:24]3)=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH:35][N:36]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.NO>CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:32]([NH:36][OH:35])=[O:34])[CH2:20][CH2:19][N:18]([C:21]([C:23]3([CH3:31])[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25][CH2:24]3)=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C(=O)C3(C)COC(C)(C)OC3)CC2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)NO)CCN(C(=O)C3(C)COC(C)(C)OC3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-[(2,2,5-trimethyl-1,3-dioxan-5-yl)carbonyl]-4-piperidinecarboxamide was prepared following the procedure Example 64 (step 6). Starting from 4-(4-but-2-ynyloxybenzenesulfonyl)-1-[(2,2,5-trimethyl-1,3-dioxan-5-yl)carbonyl]-4-piperidinecarboxylic acid (280 mg, 0.57 mmol) in dimethylformamide (6 ml), 1-hydroxybenzotriazole (92 mg, 0.57 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (153 mg, 0.80 mmol), N-methylmorpholine (0.094 ml, 0.85 mmol), and hydroxylamine (0.174 ml, 2.85 mmol), 180 mg (62%) of the product was isolated as a solid. HR-MS: m/z Calculated for C24H32N12O8S 531.1771; Found 531.1768.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:5]=1[C:11]#[N:12].Cl.[CH3:15][NH:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([N:16]([CH3:17])[CH3:15])[CH:7]=[CH:6][C:5]=1[C:11]#[N:12]
Reactant: COC(=O)c1cc(F)ccc1C#N
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cc(N(C)C)ccc1C#N
Temperature: 65 °C
Reaction time: 15 h
Yield: 89 %

Procedure:
To a stirred solution of 4.03 g (22.5 mmol) 21a and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 15 h at 65° C. in an autoclave and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 21b was obtained in 89.0% yield (4.09 g, 20.0 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:22])[NH:10][CH:11]=[C:12]3[C:17]=2[NH:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[S:13]3)=[CH:4][CH:3]=1.C(O)(=[O:25])C.C(OO)(=O)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:22])[NH:10][CH:11]=[C:12]3[C:17]=2[NH:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[S:13]3=[O:25])=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: O=c1[nH]cc2c(c1-c1ccc(Cl)cc1)Nc1ccccc1S2
Agent: CC(=O)OO
Solvent: O
Product: O=c1[nH]cc2c(c1-c1ccc(Cl)cc1)Nc1ccccc1S2=O

Procedure:
To 3 parts of the product of the process described in Example 14, 4-(4-chlorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one, suspended in 5 parts acetic acid is added and 1 part 40% peracetic acid. After ten minutes reaction time, water is added to the now homogeneous reaction mixture and the precipitate which forms is collected and recrystallized from aqueous DMF to yield white needles of 4-(4-chlorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one 10 oxide, melting above 310°.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].C(N(CC)CC)C.[C:16]([O:24][CH2:25][C:26]#[CH:27])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[C:16]([O:24][CH2:25][C:26]#[C:27][C:6](=[O:7])[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C#CCOC(=O)c1ccccc1
Reactant: O=C(Cl)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(OCC#CC(=O)c1cccs1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.4 %

Procedure:
A solution of 2-thiophenecarbonyl chloride (549 mg, 3.75 mmol) in anhydrous dioxane (15 mL) was bubbled with argon for 10 minutes. Triethylamine (1.31 mL, 9.36 mmol) was added and the bubbling was maintained for 5 minutes. Bis(triphenylphosphine)palladium(II) dichloride (88 mg, 0.12 mmol), copper iodide (48 mg, 0.25 mmol) and propargyl benzoate (0.45 mL, 3.12 mmol) were added, and the reaction mixture was stirred for 1 hour at room temperature, under argon atmosphere. The solution was filtered and water (20 mL) was added to the filtrate. Layers were separated, and the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic layers were washed with a saturated solution of sodium hydrogenocarbonate (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100/0 to 95/5) to provide 4-oxo-4-(thiophen-2-yl)but-2-yn-1-yl benzoate (3a) (333 mg, 1.23 mmol, 39%).
Reaction SMILES: [CH2:1]([N:5]([CH2:22][CH2:23][CH2:24][CH3:25])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[O:20])=[CH:16][CH:15]=2)=[C:8]([OH:21])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:26]([CH:28]1[O:30][CH2:29]1)Br.C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O.C(OCC)(=O)C>[CH2:22]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[O:20])=[CH:16][CH:15]=2)=[C:8]([O:21][CH2:26][CH:28]2[CH2:29][O:30]2)[CH:7]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(O)c1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(OCC2CO2)c1
Temperature: 60 °C
Yield: 35.2 %

Procedure:
In 15 ml of 1-methyl-2-pyrrolidone were dissolved 0.76 g (2.13 mmol) of 5-[2-(4-dibutylamino-2-hydroxyphenyl)vinyl]thiophene-2-carboaldehyde and 0.8 g (5.84 mmol) of epibromohydrin. To this mixture was added 0.59 g (4.27 mmol) of anhydrous potassium carbonate and the mixture was stirred with heating at 60° C. for 4 hours. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residual liquid was purified by silica gel column chromatography. From the earlier fraction, 0.31 g of 5-[2-[4-dibutylamino-2-(oxiranylmethoxy)phenyl]vinyl]thiophene-2-carboaldehyde was obtained. From the later fraction, 0.45 g of 5-[2-[2-(3-bromo-2-hydroxypropoxy)-4-dibutylaminophenyl]vinyl]thiophene-2-carboaldehyde was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[NH2:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34]([OH:36])=[O:35]>CN(C=O)C.C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:30][C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34]([OH:36])=[O:35])=[O:9])=[CH:10][CH:11]=1)#[N:2]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(=O)Nc2cccc(C(=O)O)c2)cc1
Yield: 70 %

Procedure:
4-Cyanobenzoic acid is activated with 2-chloro-4,6-dimethoxy-1,3,5-triazine and N-methylmorpholine analogously to Example 1 and subsequently reacted with 3-aminobenzoic acid in DMF/CH2Cl2. There is obtained m-(p-cyanobenzamido)benzoic acid in the form of colourless crystals. Yield: 70%, m.p. 267° C. (ethyl acetate/acetonitrile).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[N:18][CH:19]=1.[CH:22]1([CH:25]=[O:26])[CH2:24][CH2:23]1.[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH:22]1([CH:25]([C:15]2[C:14]([F:13])=[CH:19][N:18]=[C:17]([O:20][CH3:21])[CH:16]=2)[OH:26])[CH2:24][CH2:23]1
Reactant: COc1ccc(F)cn1
Reactant: O=CC1CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: COc1cc(C(O)C2CC2)c(F)cn1
Temperature: -15 °C
Reaction time: 0.08 h

Procedure:
Under a nitrogen atmosphere, a hexane solution (1.6 M, 29.5 mL) of n-butyllithium was added to a solution of diisopropylamine (6.60 mL) in THF (80 mL) at −15° C., and the mixture was stirred at −15° C. for 5 min. A solution of 5-fluoro-2-methoxypyridine (5.00 g) in THF (30 mL) was added dropwise to the reaction mixture at −78° C. over 15 min, and the mixture was stirred at −78° C. for 1.5 hr. A solution of cyclopropanecarbaldehyde (3.53 mL) in THF (15 mL) was added dropwise to the reaction mixture at −78° C. over 20 min, and the mixture was stirred at −78° C. for 30 min. To the reaction mixture was added saturated aqueous ammonium chloride solution at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product (8.87 g) of the title compound as a pale-yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: [S:1](Cl)([N:4]=C=O)(=[O:3])=[O:2].[CH2:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1.[Cl-].[Al+3].[Cl-].[Cl-]>[N+](CC)([O-])=O.O.C(OCC)(=O)C>[NH2:17][C:13]1[CH:12]=[C:11]2[C:16]([CH2:8][CH2:9][CH2:10]2)=[CH:15][C:14]=1[S:1]([NH2:4])(=[O:2])=[O:3].[NH2:17][C:13]1[CH:14]=[CH:15][C:16]2[CH2:8][CH2:9][CH2:10][C:11]=2[C:12]=1[S:1]([NH2:4])(=[O:2])=[O:3]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)CCC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC[N+](=O)[O-]
Product: Nc1cc2c(cc1S(N)(=O)=O)CCC2
Product: Nc1ccc2c(c1S(N)(=O)=O)CCC2
Temperature: -5 °C
Yield: 41.7 %

Procedure:
Sulfurisocyanatidic chloride (0.752 mL, 8.63 mmol) and anhydrous nitroethane (10 mL) were mixed, cooled to −5° C. (ice/salt-bath) and a solution of 2,3-dihydro-1H-inden-5-amine (1 g, 7.51 mmol) in anhydrous nitroethane (10 mL) was added dropwise under vigorous stirring. When the addition was completed, anhydrous aluminum chloride (1.251 g, 9.39 mmol) was added and the suspension was heated at 110° C. for 60 min. The solution was cooled to room temperature and diluted with water (50 mL) and ethyl acetate (50 mL). The mixture was filtered and the layers were separated. The organic phase was dried over magnesium sulfate and concentrated under vacuum. The residue was dissolved in sulfuric acid and water (1:1 30 mL) and heated at 140° C. for 90 min before it was allowed to reach room temperature and stirred over night. The mixture was neutralized using 15% sodium hydroxide and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated under vacuum to give 0.664 g (21% yield) of the title mixture.
Reaction SMILES: [CH:1](=[C:8]1[NH:12][C:11](=[O:13])[NH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])(=[O:18])[CH:16]=[CH2:17].[OH-].[K+].CN(C=O)C>C1(C)C=CC=CC=1>[CH:1](=[C:8]1[C:9](=[O:14])[N:10]([CH2:17][CH2:16][C:15]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18])[C:11](=[O:13])[NH:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)OCC(C)C
Reactant: O=C1NC(=O)C(=Cc2ccccc2)N1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)COC(=O)CCN1C(=O)NC(=Cc2ccccc2)C1=O
Temperature: 110 °C
Reaction time: 2 h
Yield: 81.1 %

Procedure:
20 g (0.106 mol) of benzalhydantoin, 14.9 g (0.117 mol) of isobutyl acrylate and 1.2 g (0.02 mol) of potassium hydroxide were added to 150 ml of DMF, and the mixture was stirred at 110° C. for 2 hours. After cooling, the reaction solution was added with 300 ml of toluene and crystallized. The crystals were filtered out and dried to obtain 27.2 g of isobutyl 4-benzylidene-2,5-dioxo-1-imidazolidinepropionate (yield: 81%).
Reaction SMILES: [C:1]([C:5]1[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:17]=[CH:16][C:6]=1[O:7][CH:8]([CH2:12][C:13](O)=[O:14])[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[CH2:34](O)[CH3:35]>O>[C:20]([C:18]1[CH:19]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]2[O:7][CH:8]([C:9]([O:11][CH2:34][CH3:35])=[O:10])[CH2:12][C:13](=[O:14])[C:16]=2[CH:17]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1ccc(OC(CC(=O)O)C(=O)O)c(C(C)(C)C)c1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C1CC(=O)c2cc(C(C)(C)C)cc(C(C)(C)C)c2O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 50 parts of 2,4-di-t-butylphenoxysuccinic acid and 100 parts of concentrated sulphuric acid was stirred at room temperature for three hours. The resulting solution was poured into water, excess sodium bicarbonate solution was added and the basic solution was extracted with ether. The aqueous extract was acidified with concentrated hydrochloric acid and the product was extracted into ether. The ether extract yielded a residue which was esterified by refluxing for three hours with 200 parts of a 3% v/v solution of ethanol containing concentrated sulphuric acid. After cooling, water was added and the esterified product was extracted into ether. The ether extract was washed with sodium bicarbonate solution and water, dried and the ether was removed by evaporation. Chromatography of the resulting residue on silica gel, elutingwith a 3:2 mixture of chloroform and light petroleum (b.p. 40°-60° C), gave 1 part of 6,8-di-t-butyl-2,3-dihydro-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester as a semi-solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[C:27](Cl)(=O)C.[NH2:31][CH2:32][CH:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[OH:34]>>[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][C@H:9]1[C:24]([NH:31][CH2:32][CH:33]([OH:34])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:26])(=[O:7])[CH3:27]
Reactant: NCC(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)O
Reactant: CC(=O)Cl
Product: CC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)NCC(O)c1ccccc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, acetyl chloride, and (1RS)-2-amino-1-phenylethanol the title compound was obtained in 48% purity by LC/MS. MS(ESI+): m/z=464.6.
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: Cc1ccc(NCCc2ccc(C(F)(F)F)nc2)cc1C
Reactant: O=C(O)Cc1ccccc1
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: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:61][CH3:62])=[C:10]([CH2:19][N:20]([CH3:60])[C:21]([C:23]3[CH:24]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[CH:35][C:36]([F:59])=[C:37]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]6[CH2:51][CH2:50][N:49](C(OC(C)(C)C)=O)[CH2:48][CH2:47]6)[CH:40]=5)[CH:38]=4)=[O:30])[CH:26]=[CH:27][CH:28]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:61][CH3:62])=[C:10]([CH2:19][N:20]([CH3:60])[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:38]=[C:37]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]6[CH2:47][CH2:48][NH:49][CH2:50][CH2:51]6)[CH:40]=5)[C:36]([F:59])=[CH:35][CH:34]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(C)C(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(C)C(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCNCC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
To a solution of 1,1-dimethylethyl 4-{[5′-({[(3-{[{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}(methyl)amino]carbonyl}phenyl) carbonyl]amino}methyl)-2′-fluoro-3-biphenylyl]methyl}-1-piperazinecarboxylate (0.056 g, 0.066 mmol) in DCM (0.25 mL) was added TFA (0.25 mL) which was then stirred at room temperature for 30 min before being diluted with DCM and basified with NaHCO3 (sat. aq.). The organic layer was separated, dried over Na2SO4, filtered, concentrated, purified using a Gilson HPLC (with TFA), and the final product was basified with an amine cartridge to afford 0.047 g (95%) of the title compound. LC-MS m/z 747 (M+H)+; 1H-NMR (400 MHz, CD3OD) δ ppm 1.39 (t, J=7.53 Hz, 3 H) 1.50 (t, J=7.28 Hz, 3 H) 1.79-1.92 (m, 2 H) 2.08-2.17 (m, J=12.80, 1.76 Hz, 2 H) 2.93 (s, 3 H) 3.15 (q, J=7.45 Hz, 2 H) 3.56 (s, 8 H) 3.62-3.71 (m, 2 H) 3.98-4.06 (m, J=8.66, 2.89 Hz, 2 H) 4.33-4.42 (m, 1 H) 4.45-4.54 (m, 4 H) 4.61 (s, 2 H) 7.17 (dd, J=10.54, 8.53 Hz, 1 H) 7.38-7.44 (m, J=5.52, 3.01 Hz, 1 H) 7.49-7.63 (m, 4 H) 7.64-7.70 (m, 2 H) 7.74 (s, 1 H) 7.97-8.03 (m, 2 H) 8.32 (s, 1 H).