Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-])([O-])=O.[Na+].[I:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.[Sn](Cl)Cl>O.Cl>[I:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][NH2:1])=[CH:9][CH:8]=1
Reactant: Nc1ccc(I)cc1
Reactant: O=[N+]([O-])[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(I)cc1
Temperature: 25 °C
Yield: 49.9 %

Procedure:
The title compound was synthesized in accordance with Reaction Scheme 2. The product obtained had the formula of compound (13), in which X and X1 represent C(CH3)2, R/R1 represent C22H14 /C45H29 and A represents Cl. 4-iodophenylhydrazine was prepared by the procedure of Blaikie et al., J. Chem. Soc., 313:296 (1924). Sodium nitrate (16.56 g, 0.24 mol, Aldrich) dissolved in water (100 ml) was added dropwise within 45 mins. to a solution of 4-iodoaniline (43.9 g, 0.20 mol, Aldrich) in ice-water (600 ml) and concentrated hydrochloric acid (200 ml) which was cooled to 0°-2° C. The reaction mixture was stirred for a further 30 minutess at 0°-2° C. then tin(II) chloride (151.68 g, 0.8 mol, Aldrich) in c.HCl (150 ml) was added dropwise over 90 mins. while maintaining the temp. of the reaction mixture between 0°-2° C. Following the addition, the resulting solution was warmed to room temperature and stirred for 3 hours. The yellow solid which had separated from the solution was then collected by filtration, placed in ice water (800 ml) and the pH adjusted to 10 with 25% aqueous potassium hydroxide solution. The resulting solid was collected by filtration, washed with a small amount of water and dried under vacuum. The product was then placed in toluene (400 ml) and filtered to remove insoluble impurities. Hexane (1200 ml) was added and upon cooling in the refrigerator yellow needles separated which were collected by filtration, washed with hexane (100 ml) and dried under high vacuum to give pure 4-Iodophenylhydrazine (23.36 g, 50%), m.p.=94° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[C:21]2[CH2:26][CH2:25][N:24](C)[CH2:23][CH2:22]2)[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1>ClC(Cl)Cl>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:21]2[CH2:22][CH2:23][N:24]([C:1]([O:2][CH2:3][CH3:4])=[O:5])[CH2:25][CH2:26]2)=[CH:10][CH:9]=1
Reactant: CN1CCC(=C(c2ccc(F)cc2)c2cccnc2)CC1
Reactant: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC(=C(c2ccc(F)cc2)c2cccnc2)CC1
Reaction time: 16 h
Yield: 75 %

Procedure:
To a stirred solution of 180 parts of ethyl carbonochloridate in 600 parts of trichloromethane was added dropwise a solution of 110 parts of 3-[(4-fluorophenyl)(1-methyl-4-piperidinylidene)methyl]pyridine in 600 parts of trichloromethane. Upon completion, the whole was heated till reflux and stirring at reflux was continued for 16 hours. The reaction mixture was evaporated. The residue was stirred in water and the whole was alkalized with a sodium hydroxide solution. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated, yielding 100 parts (75%) of ethyl 4-[(4-fluorophenyl)(3-pyridinyl)methylene]-1-piperidinecarboxylate as a residue (intermediate 20).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH:16]2[CH2:18][CH2:17]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:5]2[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:4]2[N:3]=1.[C:24]([C:27]1[S:28][C:29](B(O)O)=[CH:30][CH:31]=1)([OH:26])=[O:25].C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC.CCO>[C:11]([O:10][C:9]([N:8]([CH:16]1[CH2:18][CH2:17]1)[C:6]1[N:5]2[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:4]2[N:3]=[C:2]([C:29]2[S:28][C:27]([C:24]([OH:26])=[O:25])=[CH:31][CH:30]=2)[CH:7]=1)=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)c1ccc(B(O)O)s1
Reactant: CC(C)(C)OC(=O)N(c1cc(Cl)nc2c(C=O)cnn12)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)(C)OC(=O)N(c1cc(-c2ccc(C(=O)O)s2)nc2c(C=O)cnn12)C1CC1
Temperature: 95 °C
Reaction time: 3 h
Yield: 35.4 %

Procedure:
To tert-butyl 5-chloro-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (1 g, 2.97 mmol) in 30 mL of a 2:1 mixture of 1,2-dimethoxyethane/EtOH was added 2-carboxythiophene-5-boronic acid (766 mg, 4.45 mmol), tetrakis(triphenylphosphine)palladium(0) (171 mg, 0.148 mmol), and 2M aqueous solution of Na2CO3 (4.45 mL, 8.91 mmol). The mixture was stirred at 95° C. for 3 hours then cooled to room temperature and partitioned between 2N NaOH and ethyl acetate. The layers were separated and the aqueous layer was acidified to pH<3 with conc. HCl. The aqueous layer was extracted (3×) with methylene chloride. The combined organic layers was washed with brine, dried over MgSO4, filtered, and evaporated to dryness to provide 450 mg of 5-(7-(tert-butoxycarbonyl(cyclopropyl)amino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)thiophene-2-carboxylic acid. Some additional material which was in the first ethyl acetate layer was purified by silica gel chromatography (0%-20% MeOH/CH2Cl2) to provide another 550 mg of 5-(7-(tert-butoxycarbonyl(cyclopropyl)amino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)thiophene-2-carboxylic acid (79%). LCMS (M+1=429)
Reaction SMILES: [Zn:1].[Li+].[Cl-].I[CH2:5][CH2:6][C:7]#[N:8].[C:9]([O-:15])(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].[Li+]>C1COCC1>[C:9]([O-:15])(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].[C:7]([CH2:6][CH2:5][Zn+:1])#[N:8]
Reactant: [Zn]
Reactant: N#CCCI
Agent: CC(C)(C)C(=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CCC[Zn+]
Temperature: 22 °C
Reaction time: 2 h

Procedure:
Zinc powder (490 mg, 7.5 mmol) and LiCl (318 mg, 7.5 mmol) were placed in a Schlenk-flask, equipped with a magnetic stirrer and a septum, dried for 5 min at 400° C. (heat gun) in high vacuum and then dissolved in 7.0 mL of dry THF. 4 drops of 1,2-dibromoethane were added and the mixture was heated to boiling for the activation of the zinc dust. After cooling to 22° C. 3-iodopropionitrile (905 mg, 5.0 mmol) was added dropwise and the mixture was stirred for 2 h at 22° C. The stirring of the reaction mixture was stopped and the excess zinc dust was sedimented. The supernatant solution was transferred to another Schlenk-flask containing a solution of lithium pivalate (811 mg, 1.50 mmol) prepared as described above in 5.0 mL of dry THF. The mixture was stirred for 15 min at 22° C. and then the solvent was removed in vacuo. (2-cyanoethyl)zinc pivalate was obtained as a yellow solid (2.94 g). The content of active zinc species was determined by titration of 398 mg of the reagent with a stock solution of iodine (1.0 M in THF). A concentration of 1020 mg/mmol was determined which corresponds to a yield of 58%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([CH3:15])([CH3:14])[C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1.[Br:16]Br>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:12][C:11](=[O:13])[C:10]([CH3:15])([CH3:14])[CH2:9][S:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: BrBr
Reactant: CC(=O)C(C)(C)CSc1ccc(Cl)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(CSc1ccc(Cl)cc1)C(=O)CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
97 g (0.4 mol) of 1-(4-chlorophenylmercapto)-2,2-dimethyl-butan-3-one were dissolved in 400 ml of carbon tetrachloride, and 64 g (0.4 mol) of bromine were added dropwise in the course of 30 minutes. The mixture was subsequently stirred at room temperature for 1 hour and was then concentrated by distilling off the solvent. 127 g (99% of theory) of crude 1-bromo-4-(4-chlorophenylmercapto)-3,3-dimethyl-butan-2-one were obtained as a yellowish oil, which was further reacted directly.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][C@H:8]([OH:10])[CH:7]=[CH:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C>C(O)C.[Ni]>[C:1]([O:4][C@@H:5]1[CH2:6][CH2:7][C@H:8]([OH:10])[CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1C=C[C@@H](O)C1
Agent: [Ni]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H]1CC[C@H](O)C1
Reaction time: 0.33 h
Yield: 87.3 %

Procedure:
Dissolve (-)-cis-4-acetoxy-cyclopent-2-enol (11.0 g, 77.4 mmol, prepared in example 19) in ethanol (50 mL) and treat with Raney nickel (1.1 g, previously washed with water (2×50 mL) and ethanol (2×50 mL), Ra--Ni). Charge the atmosphere with hydrogen at 50 psi (344.74 kPa) and shake the mixture. After 20 minutes, filter the solution and treat the filtrate with triethylamine (1.0 mL, 7.2 mmol). After one hour concentrate the solution under vacuum and distill the residue by Kugelrohr distillation (60°-80° C., 1 mm Hg), to provide the title compound (9.74 g, 87%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[N:7]([CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][C:18]2[NH:19][CH:20]=[CH:21][N:22]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+].C(O)(=O)C.[CH3:43][N:44]1[CH:48]=[CH:47][N:46]=[C:45]1[CH:49]=O>CO>[C:1]([O:5][C:6](=[O:34])[N:7]([CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH2:28][CH2:29][CH3:30])[CH2:31][CH2:32][CH3:33])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]([CH2:17][C:18]2[NH:19][CH:20]=[CH:21][N:22]=2)[CH2:49][C:45]2[N:44]([CH3:43])[CH:48]=[CH:47][N:46]=2)=[CH:13][CH:14]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCN(CCC)CCCCN(Cc1ccc(CNCc2ncc[nH]2)cc1)C(=O)OC(C)(C)C
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCN(Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 144 h
Yield: 71.1 %

Procedure:
The compound (231 mg) obtained in Example 1-6 was dissolved in anhydrous methanol (5.0 ml) The solution was added with sodium cyanoborohydride (61.6 mg), acetic acid (2.00 ml), and 1-methyl-2-imidazole carboxaldehyde (80.9 mg) and the whole was stirred at room temperature for 6 days under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off. The resultant was then dissolved in chloroform and added with a saturated aqueous sodium hydrogen carbonate solution and the whole was stirred for a while. The solution was subjected to extraction with chloroform and the extract was then washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. Subsequently, the solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining the subject compound (197 mg) as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.[C:26](O)([CH3:29])([CH3:28])[CH3:27]>>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([O:8][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: CC(C)(C)O
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 76 %

Procedure:
4-Amino-5-chloro-2-methoxybenzoic acid (1.0 g, 4.96 mmol) was dissolved in t-butanol (20 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.05 g, 5.46 mmol) was added with stirring at room temperature, and the mixture was stirred at room temperature under a nitrogen atmosphere for 17 hours. After the reaction was completed, the reaction mixture was filtered, and the filtrate was washed with hexane. The resulting filtrate was recrystallized with ethanol to give the title compound (0.97 g; yield, 76%) as a white solid.
Reaction SMILES: Cl.[OH:2][C:3]([CH3:20])([CH3:19])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:18])[C@@H:12]([NH2:17])[CH2:13][CH:14]([CH3:16])[CH3:15])=[N:6]1.C(N(CC)C(C)C)(C)C.CC1(C)O[C@H](CN2C=CC(NC(=O)[C@@H](N3[CH2:53][C:52]([O:54][C:55]4[C:60]([F:61])=[CH:59][CH:58]=[C:57]([O:62][CH2:63][CH3:64])[C:56]=4[F:65])=[CH:51][C:50]3=[O:66])CC(C)C)=N2)CO1>C(#N)C>[OH:2][C:3]([CH3:20])([CH3:19])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:18])[C@@H:12]([N:17]2[CH2:53][C:52]([O:54][C:55]3[C:60]([F:61])=[CH:59][CH:58]=[C:57]([O:62][CH2:63][CH3:64])[C:56]=3[F:65])=[CH:51][C:50]2=[O:66])[CH2:13][CH:14]([CH3:15])[CH3:16])=[N:6]1
Reactant: CCOc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)c1F
Reactant: CC(C)C[C@H](N)C(=O)Nc1ccn(CC(C)(C)O)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(CC(C)(C)O)n3)C2)c1F
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 15.5 %

Procedure:
A suspension of (S)-2-amino-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]amide hydrochloride salt (2.0 g, 5.8 mmol) in acetonitrile (25 mL) was treated with N,N-diisopropylethylamine (4.0 mL) and stirred at 60° C. for 15 min. At this time N,N-diisopropylethylamine (2.5 mL) and a solution of (E)-4-bromo-3-(3-ethoxy-2,6-difluoro-phenoxy)-but-2-enoic acid ethyl ester (prepared in Example 116, 1.37 g, 3.75 mmol) in acetonitrile (10 mL) were added and the resulting solution refluxed for 48 h. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The layers were separated and the organic layer was dried over sodium sulfate. The mixture was filtered and concentrated in vacuo and the residue purified by ISCO flash chromatography (RediSep silica 40 g, 5% to 80% (10% methanol/dichloromethane)/hexanes) which afforded (S)-2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (295 mg, 16%): HR-ES-MS (m/z) calculated for C25H32F2N4O5 [M+H]+ 507.2414, observed 507.2414; 1H NMR (300 MHz, CDCl3) δ ppm 0.96 (br. s., 6H), 1.13 (br. s., 6H), 1.42 (br. s., 3H), 1.48-1.64 (m, 1H), 1.66-1.95 (m, 2H), 3.73 (br. s., 1H), 3.91 (br. s., 2H), 4.01-4.24 (m, 3H), 4.38 (d, J=17.8 Hz, 1H), 4.88 (br. s., 1H), 4.99 (br. s., 1H), 6.66 (br. s., 1H), 6.73-7.00 (m, 2H), 7.27 (br. s., 1H), 8.79 (br. s., 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:10])[CH3:9])=[C:4]([F:11])[CH:3]=1.[C:12](Cl)(=[O:15])[CH2:13][CH3:14].CCN(C(C)C)C(C)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:12](=[O:15])[CH2:13][CH3:14])[CH3:9])=[C:4]([F:11])[CH:3]=1
Reactant: CC(N)c1ccc(Br)cc1F
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)NC(C)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
61 mg (1 eq, 0.24 mmol) of 1-(4-bromo-2-fluorophenyl)ethanamine from Stage 1 were dissolved in 4 ml of dichloromethane, and 24 mg (1.1 eq, 23 μl, 0.264 mmol) of propanoyl chloride and 70 mg (2.2 eq, 90 μl) of Hünig's base were added. The mixture was stirred at room temperature for 5 h and then concentrated. The crude product was dissolved in ethyl acetate and washed 1× with 1M HCl, 1× with sat. sodium carbonate solution and then with water, and dried over magnesium sulphate. After concentrating under reduced pressure, the resulting crude product was purified by means of chromatography on silica gel (eluent: cyclohexane/ethyl acetate). 50 mg (67%) of N-[1-(4-bromo-2-fluorophenyl)ethyl]propanamide were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.CO.I[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH3:29])[C:24](=[O:30])[CH:23]=[CH:22]2>ClCCl>[CH3:29][N:25]1[C:26]2[C:21](=[CH:20][C:19]([O:18][CH2:17][CH2:16][CH2:15][NH:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]=[CH:7][CH:6]=[CH:5]4)=[CH:28][CH:27]=2)[CH:22]=[CH:23][C:24]1=[O:30]
Reactant: Cn1c(=O)ccc2cc(OCCCI)ccc21
Reactant: Nc1ccc2ncccc2c1
Solvent: ClCCl
Solvent: CO
Product: Cn1c(=O)ccc2cc(OCCCNc3ccc4ncccc4c3)ccc21
Temperature: 60 °C
Reaction time: 17 h
Yield: 48 %

Procedure:
6-Aminoquinoline (360 mg) was added to the methanol solution (10 ml) of 6-(3-iodopropoxy)-1-methyl-1H-quinolin-2-one (172 mg) and stirred at 60° C. for 17 hours. The reaction mixture was added to ice water, and extraction with dichloromethane was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:0→4:1). The purified product was condensed under reduced pressure to give the title compound (86.4 mg) as a yellow amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([N+:14]([O-])=O)[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:14][C:12]1[CH:11]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: [H][H]
Reactant: CCOC(=O)c1cc(OC)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(N)cc(OC)c1
Yield: 96.7 %

Procedure:
The compound (5.1 g, 23.1 mmol) prepared in step 2 was dissolved in ethyl acetate (50.0 ml), added with 10%-palladium (Pd) (100 mg). The resulting mixture was then stirred at room temperature for 24 hours in presence of hydrogen gas. After completion, 10%-palladium (Pd) was removed by celite-filter and the filtrate concentrated to dryness. The residue was purified by flash column chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (4.36 g, yield: 96.8%, white solid).
Reaction SMILES: Cl[C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]([O:16][CH3:17])=[O:15])[CH:8]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][NH2:36])=[CH:30][CH:29]=1>C(O)(C)C>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][NH:36][C:2]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:14]([O:16][CH3:17])=[O:15])[CH:8]=3)[N:3]=2)=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc2nc(Cl)n(C)c(=O)c2c1
Reactant: NCCc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC(=O)c1ccc2nc(NCCc3ccc(Cl)cc3)n(C)c(=O)c2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a suspension of methyl 2-chloro-3-methyl-4-oxo-3,4-dihydroquinazoline-6-carboxylate (77.0 mg, 0.30 mmol) in isopropyl alcohol (5 mL) was added N,N-diisopropylethylamine (0.11 mL, 0.64 mmol) and 2-(4-chlorophenyl)ethanamine (0.11 mL, 0.76 mmol). The reaction mixture was heated to 100° C. and stirred for 1 h. The mixture was then cooled to rt and concentrated. The residue was purified by flash silica gel chromatography (0% to 5% MeOH/DCM) to afford methyl 2-{[2-(4-chlorophenyl)ethyl]amino}-3-methyl-4-oxo-3,4-dihydroquinazoline-6-carboxylate (106 mg, 94%). LC-MS: (FA) ES+ 372.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:7][N:6]=[CH:5]2.CS(O)(=O)=O.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1>C(Cl)Cl.C1COCC1>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:7]([CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][O:21]1)[N:6]=[CH:5]2
Reactant: CCOC(=O)c1cc2[nH]ncc2cc1O
Reactant: C1=COCCC1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(cnn2C2CCCCO2)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a solution of ethyl 5-hydroxy-1H-indazole-6-carboxylate (15.5 g, 75 mmol) in DCM (100 mL) and THF (100 mL) containing methanesulfonic acid (721 mg, 7.5 mmol) is added a solution of 3,4-dihydro-2H-pyran (6.6 g, 79 mmol) in DCM (20 mL) dropwise at RT. The resulting solution is stirred at RT overnight. After the solvent is removed, EtOAc (500 mL), saturated aqueous sodium chloride (500 mL) and NaHCO3 (5 g) are added. The organic layer is separated, dried and concentrated. The residue is purified by silica gel column chromatography to afford the product (16.8 g, 77% yield). MS (m/z): 291.1 (M+H).
Reaction SMILES: C(O[C:5]([O:7][C@@H:8]1[CH2:13][N:12]([C:14]([O:16][CH3:17])=[O:15])[C@H:11]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)=[O:19])[C@@H:10]([C:32]([O:34][CH3:35])=[O:33])[CH2:9]1)=O)C=C.O1CC[CH2:38][CH2:37]1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH2:5]([O:7][C@@H:8]1[CH2:13][N:12]([C:14]([O:16][CH3:17])=[O:15])[C@H:11]([C:18]([N:20]2[CH2:21][CH2:22][N:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:24][CH2:25]2)=[O:19])[C@@H:10]([C:32]([O:34][CH3:35])=[O:33])[CH2:9]1)[CH:37]=[CH2:38]
Reactant: C=CCOC(=O)O[C@H]1C[C@H](C(=O)OC)[C@@H](C(=O)N2CCN(c3ccccc3)CC2)N(C(=O)OC)C1
Reactant: C1CCOC1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=CCO[C@H]1C[C@H](C(=O)OC)[C@@H](C(=O)N2CCN(c3ccccc3)CC2)N(C(=O)OC)C1

Procedure:
A mixture of dimethyl(2S,3S,5S)-5-[(allyloxy)carbonyl]oxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate (100 mg, 0.0002 mol) and tetrakis(triphenylphosphine)palladium(O) (24 mg, 0.000020 mol) in tetrahydrofuran (5.00 mL, 0.0616 mol) was refluxed for 2 h. The mixture was concentrated to dry and used directly in next step.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:21])[O:8][C@@:9]([C:14](=[O:20])[N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])([CH2:12][CH3:13])[C:10]=1[CH3:11])=[O:5])[CH3:2].C[C@H]1C[C@@H](OC(=O)C(=O)CC)[C@H](C(C)(C2C=CC=CC=2)C)CC1.[CH3:45][N:46]([CH:48](N(C)C)N(C)C)[CH3:47]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:21])[O:8][C@@:9]([C:14](=[O:20])[N:15]([CH2:16][CH3:17])[CH2:18][CH3:19])([CH2:12][CH3:13])[C:10]=1/[CH:11]=[CH:45]/[N:46]([CH3:48])[CH3:47])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(C)[C@@](CC)(C(=O)N(CC)CC)OC1=O
Reactant: CN(C)C(N(C)C)N(C)C
Agent: CCC(=O)C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)(C)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(/C=C/N(C)C)[C@@](CC)(C(=O)N(CC)CC)OC1=O

Procedure:
According to the procedure described in Example 6 1.22 0 g of compound (23) as obtained from example 17 (4.103 mmol) in 7.3 mL dimethyl formamide were treated with 7.55 mL tris(dimethylamino)methane (42.26 mmol, 10.3 eq) yielding the crude product as an orange oil (1.463 mg, 101% by weight).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:4][N:3]=1.[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20][NH2:21]>>[CH:14]([S:11]([C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH:21][CH2:20][CH2:19][N:18]([CH3:22])[CH3:17])=[N:3][CH:4]=1)(=[O:13])=[O:12])([CH3:16])[CH3:15]
Reactant: CC(C)S(=O)(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CN(C)CCN
Product: CC(C)S(=O)(=O)c1cnc(NCCN(C)C)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from 2-chloro-5-(isopropylsulfonyl)-3-nitropyridine (Step D of Example 22) and N,N-dimethylethylenediamine.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][CH3:5].[C:7]1([CH3:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OOC(C)(C)C)(C)(C)C>>[C:7]1([CH2:13][O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCCCCO
Reactant: Cc1ccccc1
Agent: CC(C)(C)OOC(C)(C)C
Product: CCCCCOCc1ccccc1
Temperature: 90 °C
Yield: 20 %

Procedure:
Into a pressure vessel 1-pentanol (109 μL, 1 mmol, 1 eq) was added and diluted with toluene (1.063 mL, 10 mmol, 10 eq). To this stirring solution was added 1 mol % of a stock solution of {[Cl2NN]Cu}2(benzene) from the catalyst stock solution described in Example 4 (200 μL=0.01 mmol). After adding of tert-butyl peroxide (220 μL, 1.2 mmol), the pressure vessel was sealed and heated to 90° C. for 24 hr. The catalyst was separated by exposing the mixture to air and filtering through Celite®. After removing toluene under vacuum, the residue was analyzed by 1H NMR and GC/MS to determine the yield and consumption of starting materials. 1H NMR Yield: 20%.