Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[C:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)#[N:23].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:27]2[CH:28]=[CH:29][C:24]([C:22]#[N:23])=[CH:25][CH:26]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(B(O)O)cc1
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: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)OC(C)(C)C
Yield: 68.2 %

Procedure:
To a solution of (S)-3-(4-Bromo-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester (70.1 mmol) in toluene (250 mL) was added 4-cyanobenzeneboronic acid (105 mmol), Pd(PPh3)4 (3.5 mmol), and 1N Na2CO3 solution (105 mL). The mixture was heated at reflux for 7 h. After completion of the reaction, the aqueous layer was drained. The organic was washed with 10% Na2CO3 and 1 N HCl. The organic was dried over sodium sulfate and concentrated under reduced pressure to afford the crude product. The residue was purified by column chromatography (hexanes-EtOAc) to provide (S)-2-tert-Butoxycarbonylamino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (18.2 g). LC-MS (m/z) 382.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6](OS(C(F)(F)F)(=O)=O)=[C:5]([CH3:20])[CH:4]=1)#[N:2].[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([C:34]([CH3:46])([CH3:45])[CH2:35][C:36]([C:41]([F:44])([F:43])[F:42])([OH:40])[CH2:37][C:38]#[CH:39])[C:28]2[O:32][CH2:31][CH2:30][C:29]=2[CH:33]=1)(=[O:24])=[O:23]>C1(C)C=CC=CC=1.C(N(CC)CC)C.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>[OH:40][C:36]([C:41]([F:43])([F:44])[F:42])([CH2:35][C:34]([C:27]1[C:28]2[O:32][CH2:31][CH2:30][C:29]=2[CH:33]=[C:25]([S:22]([CH3:21])(=[O:24])=[O:23])[CH:26]=1)([CH3:45])[CH3:46])[CH2:37][C:38]#[C:39][C:6]1[C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:20]
Reactant: Cc1cc(C#N)cc([N+](=O)[O-])c1OS(=O)(=O)C(F)(F)F
Reactant: C#CCC(O)(CC(C)(C)c1cc(S(C)(=O)=O)cc2c1OCC2)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(C#N)cc([N+](=O)[O-])c1C#CCC(O)(CC(C)(C)c1cc(S(C)(=O)=O)cc2c1OCC2)C(F)(F)F
Temperature: 60 °C
Yield: 42.8 %

Procedure:
A mixture of trifluoromethanesulfonic acid 4-cyano-2-methyl-6-nitrophenyl ester (217 mg, 0.7 mmol), dichlorobis(triphenylphosphine)palladium (II) (24.6 mg, 0.035 mmol), copper (I) iodide (13.3 mg, 0.7 mmol), and 6-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-6-methyl-4-trifluoromethylhept-1-yn-4-ol (273 mg, 0.7 mmol) in a mixture of 0.8 mL of anhydrous toluene and 0.3 mL of anhydrous triethylamine was heated in a microwave at 60° C. for 10 minutes. The reaction mixture was applied to a column of SiO2 (50% ethyl acetate in hexanes) to give 165 mg of the title product as a light yellow oil (43% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([O-])([OH:10])=[O:9]>O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])([O-:10])=[O:9]
Reactant: Clc1ccccc1
Reactant: O=[N+]([O-])O
Solvent: O
Product: O=[N+]([O-])c1ccccc1Cl

Procedure:
According to the equation of the process according to the invention, chlorobenzene is reacted with nitric acid to give nitrochlorobenzene and water. Thus, chlorobenzene and nitric acid are introduced into the process, and nitrochlorobenzene and water are discharged; the sulphuric acid/phosphoric acid/water mixture described being the reaction medium. Since, in the case of industrial implementation, it is advantageous to use water-containing nitric acids, the water of the water-containing nitric acid used has to be discharged in addition to the water of the reaction.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[F:23])[NH2:19].C(=O)(O)[O-].[Na+]>O>[Br:15][C:16]1[CH:17]=[C:18]([NH:19][C:3]([C:4]2[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=2)=[N:2][OH:1])[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: COCCNc1nonc1C(Cl)=NO
Reactant: Nc1ccc(F)c(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COCCNc1nonc1C(=NO)Nc1ccc(F)c(Br)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 98.6 %

Procedure:
N-Hydroxy-4-[(2-methoxyethyl)amino]-1,2,5-oxadiazole-3-carboximidoyl chloride (46.0 g, 0.208 mol) was mixed with water (300 mL). The mixture was heated to 60° C. 3-Bromo-4-fluoroaniline [Oakwood products, product #013091] (43.6 g, 0.229 mol) was added and stirred for 10 min. A warm sodium bicarbonate (26.3 g, 0.313 mol) solution (300 mL water) was added over 15 min. The reaction was stirred at 60° C. for 20 min. LCMS indicated reaction completion. The reaction solution was cooled to room temperature and extracted with ethyl acetate (2×300 mL). The combined ethyl acetate solution was dried over sodium sulfate and concentrated to give the desired product (76.7 g, 98%) as a crude brown solid. LCMS for C12H14BrFN5O3 (M+H)+: m/z=374.0, 376.0. 1H NMR (400 MHz, DMSO-d6): δ 11.55 (s, 1H), 8.85 (s, 1H), 7.16 (t, J=8.8 Hz, 1H), 7.08 (dd, J=6.1, 2.7 Hz, 1H), 6.75 (m, 1H), 6.14 (t, J=5.8 Hz, 1H), 3.48 (t, J=5.2 Hz, 2H), 3.35 (dd, J=10.8, 5.6 Hz, 2H), 3.22 (s, 3H).
Reaction SMILES: [H-].[H-].COCCO[Al+2]OCCOC.C1(C)C=CC=CC=1.[CH2:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C:28]([NH2:30])=O)[CH3:22].Cl>O>[NH2:30][CH2:28][C@@H:24]1[CH2:25][CH2:26][CH2:27][N:23]1[CH2:21][CH3:22]
Reactant: CCN1CCC[C@H]1C(N)=O
Agent: COCCO[Al+2]OCCOC
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCN1CCC[C@H]1CN
Temperature: 40 °C
Yield: 131.6 %

Procedure:
Bis (2-methoxyethoxy)aluminium dihydride (203.4 g, 0.70 mol, approx. 70% solution in toluene) and toluene (80 ml, dried over molecular sieves Å) were added to a three-necked round-bottomed flask. The temperature in the flask was increased to 40° C. and then (S)-1-ethyl-2-pyrrolidinecarboxamide (21.0 g, 0.147 mol, 95% purity on GC) was added spoonwise during 45 min. In order to maintain the temperature at approx. 40° C., cooling was necessary during the addition. The temperature was decreased below 10° C. 55 min after completed addition. Water (500 ml) was added during 15 min and the pH was adjusted to 1 by adding 115 ml concentrated HCl and 100 ml H2O. After extraction, the phases were separated and 200 ml CH2Cl2 were added to the water phase. The pH was subsequently adjusted to 13-14 by adding NaOH (40%, 50 ml). The organic phase was separated and the water phase was extracted with further portions of CH2Cl2 (200+100 ml). The combined organic phases were dried, filtered and concentrated under vacuo to afford 24.8 g crude title product (83%) in an optical purity of >99%.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([NH:12][C:13]([C:15]2[CH:45]=[CH:44][C:18]3[N:19]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[C:20]([C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[C:27]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:26]=[N:25]5)=[N:21][C:17]=3[CH:16]=2)=[O:14])[C:9]([OH:11])=[O:10])CCCC[CH2:2]1.N1(C(OCC2C3C(=CC=CC=3)C3C2=CC=CC=3)=O)C[C@H](O)C[C@H]1C(O)=[O:49]>>[CH:38]1([N:19]2[C:18]3[CH:44]=[CH:45][C:15]([C:13]([N:12]4[CH2:2][CH:1]([OH:49])[CH2:7][CH:8]4[C:9]([OH:11])=[O:10])=[O:14])=[CH:16][C:17]=3[N:21]=[C:20]2[C:22]2[CH:31]=[C:30]3[C:29](=[CH:24][CH:23]=2)[N:28]=[C:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:26]=[N:25]3)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: O=C(NC(CC1CCCCC1)C(=O)O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Product: O=C(O)C1CC(O)CN1C(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Yield: 50 %

Procedure:
The general procedure described for Compound 242 was used with Fmoc-Hyp Wang resin (143 mg, 0.7 mmol/g), producing 23 mg of the title compound (50% yield). MS: 560.23 (M−H+) HPLC Procedure A, retention time=11.58 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[CH3:2].[CH3:23][N:24]1[CH:28]([CH2:29][CH2:30]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:27][N:26]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=2)[C:25]1=[O:53].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:30][CH2:29][CH:28]2[CH2:27][N:26]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([C:49]([F:51])([F:52])[F:50])=[CH:45][CH:44]=3)[C:25](=[O:53])[N:24]2[CH3:23])[CH:8]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1
Reactant: CCOC(=O)C(C)(Cc1cccc(O)c1)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Cc1cccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)c1)Oc1ccccc1
Temperature: 55 °C

Procedure:
To a solution of 3-(3-Hydroxy-phenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (Isomer 2) (43 mg, 0.143 mmol,) and Toluene-4-sulfonic acid 2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethyl ester (Isomer 2) (72 mg, 0.157 mmol) in DMF (1 ml) at 23° C. is added Cs2CO3 (61 mg, 0.186 mmol) and the suspension heated at 55° C. for 7 hours. The mixture is cooled, filtered, and the filter cake washed with DMF (10 ml). The filtrate is poured into 1N HCl (35 ml) and extracted with ethyl acetate (2×20 ml). The combined organic extracts were washed with water (25 ml), brine (20 ml), dried (Na2SO4) and concentrated to an oil. Purification by flash chromatography on a Biotage silica cartridge (gradient elution, 4:1 hexanes:acetone to 1:1 hexanes:acetone) provided an oil, (72 mg, 87%) (diastereomer 4).
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].[ClH:6].[CH2:7]([OH:9])[CH3:8]>>[ClH:6].[C:1](=[NH:5])([O:9][CH2:7][CH3:8])[CH:2]([CH3:4])[CH3:3]
Reactant: CCO
Reactant: CC(C)C#N
Agent: Cl
Product: CCOC(=N)C(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 82 %

Procedure:
Isobutyronitrile (1 g, 14.5 mmol) was dissolved in anhydrous ethanol (30 mL) under an atmosphere of Ar. The solution was cooled to 0° C., saturated with HCl gas, stirred for 6 h, allowed to warm to RT, and stirred for 6 h. The solvent was removed in vacuo to afford ethyl isobutyrimidate hydrochloride (1.8 g, 82%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6): δ 11.78 (br s, 1H), 11.05 (br s, 1H), 4.40 (q, J=7.0 Hz, 2H), 2.93-2.92 (m, 1H), 1.33 (t, J=7.0 Hz, 3H), 1.16 (d, J=6.9 Hz, 6H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:14][C@H:15]2[CH2:20][CH2:19][CH2:18][O:17][CH2:16]2)(=O)=O)=CC=1.[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C.CCOC(C)=O>[N:29]([CH2:12][C@@H:13]([NH:21][C:22](=[O:23])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:14][C@H:15]1[CH2:20][CH2:19][CH2:18][O:17][CH2:16]1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](C[C@H]2CCCOC2)NC(=O)OC(C)(C)C)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])C[C@H]1CCCOC1
Temperature: 25 °C
Yield: 63.7 %

Procedure:
The solution of (S)-2-(tert-butoxycarbonylamino)-3-((R)-tetrahydro-2H-pyran-3-yl)propyl 4-methylbenzenesulfonate (132 mg, 0.32 mmol) and NaN3 (62 mg, 0.95 mmol) in anhydrous DMF was heated to 80° C. under N2 atmosphere for 1.5 hr, cooled to rt and diluted with EtOAc, and washed with H2O (3×20 mL), followed by brine, and dried over anhydrous Na2SO4, and filtered, and concentrated under reduced pressure. The resulted slurry was purified through flash chromatography on silica gel (eluted with gradient system: 0-30% EtOAc in hexane) to afford tert-butyl (S)-1-azido-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamate 58 mg, yield 64%. MS ESI+ve m/z 307 (M+Na).
Reaction SMILES: ClC1N=C([N:8]2[CH2:17][CH2:16][C:15]3[C:14]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:13][C:12]([C:24]4[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH2:34][CH3:35])=[O:32])=[CH:26][CH:25]=4)=[N:11][C:10]=3[CH2:9]2)C=C(C)N=1.C(NC(NC1C=CC(C2N=C(N3CCOCC3)C3CCNCC=3N=2)=CC=1)=O)C.Cl[C:66]1[N:71]=[C:70]([Cl:72])[CH:69]=[C:68]([CH3:73])[N:67]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[Cl:72][C:70]1[CH:69]=[C:68]([CH3:73])[N:67]=[C:66]([N:8]2[CH2:17][CH2:16][C:15]3[C:14]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:13][C:12]([C:24]4[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH2:34][CH3:35])=[O:32])=[CH:26][CH:25]=4)=[N:11][C:10]=3[CH2:9]2)[N:71]=1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2cc(C)nc(Cl)n2)C3)cc1
Reactant: Cc1cc(Cl)nc(Cl)n1
Agent: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2nc(C)cc(Cl)n2)C3)cc1

Procedure:
and 1-(4-(7-(2-chloro-6-methylpyrimidin-4-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)-3-ethylurea (vz2): 1-Ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0506 g, 0.132 mmol) and 2,4-Dichloro-6-methylpyrimidine (0.0360 g, 0.221 mmol) were combined then added dry N,N-Dimethylformamide (0.910 mL, 11.8 mmol) followed by N,N-Diisopropylethylamine (0.0456 mL, 0.262 mmol). The reaction was microwaved on 200 watts, 120° C. for 30 minutes on a CEM microwave. The reaction mixture was concentrated, chromatographed through silica gel (4 g, 0-100% EtOAc in heptane), and then purified by HPLC. 1-(4-(7-(4-chloro-6-methylpyrimidin-2-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)-3-ethylurea (vz1): 1H NMR (500 MHz, DMSO) δ 8.62 (s, 1H), 8.21 (d, J=8.8, 2H), 7.49 (d, J=8.8, 2H), 6.71 (s, 1H), 6.15 (t, J=5.6, 1H), 4.81 (s, 2H), 3.96 (s, 2H), 3.78-3.68 (m, 4H), 3.53-3.41 (m, 4H), 3.17-3.05 (m, 2H), 2.75 (t, J=5.2, 2H), 2.34 (s, 3H), 1.07 (t, J=7.2, 3H). LC/MS-m/z+509.2 (M+H)+; 1-(4-(7-(2-chloro-6-methylpyrimidin-4-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)-3-ethylurea (vz2): 1H NMR (500 MHz, DMSO) δ 8.63 (s, 1H), 8.21 (d, J=8.8, 2H), 7.49 (d, J=8.8, 2H), 6.88 (s, 1H), 6.16 (t, J=5.6, 1H), 4.69 (s, 2H), 3.86 (s, 2H), 3.78-3.69 (m, 4H), 3.56-3.43 (m, 4H), 3.18-3.04 (m, 2H), 2.77 (d, J=4.6, 2H), 2.29 (s, 3H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+509.2 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[CH:14][C:13](F)=[N:12][C:8]=2[N:9]=[CH:10][N:11]=1.Cl.CN.C[CH2:24][N:25](CC)CC>CCO>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[CH:14][C:13]([NH:25][CH3:24])=[N:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: Fc1ccc2c(Nc3cccc(Br)c3)ncnc2n1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: CCO
Product: CNc1ccc2c(Nc3cccc(Br)c3)ncnc2n1
Temperature: 100 °C

Procedure:
A solution of 4-(3-bromoanilino)-7-fluoropyrido[2,3-d]pyrimidine (see a previous experimental) (0.20 g, 0.63 mmol), methylamine hydrochloride (0.13 g, 1.88 mmol) and Et3N (0.30 mL) 2.19 mmol) in EtOH (15 mL) is heated at 100° C. in a pressure vessel for 18 h. The solvent is removed under reduced pressure, and the residue is partitioned between EtOAc and water. Workup of the organic layer gives 4-(3-bromoanilino)-7-(methylamino)pyrido[2,3-d]pyrimidine (0.16 g, 770.). 1H NMR (DMSO) δ 9.53 (1H, s), 8.54 (1H, s), 8.41 (1H, d, J=8.1 Hz), 8.17 (1H, t, J=1.8 Hz), 7.83 (1H, dd, J=8.0, 1.9 Hz), 7.66 (1H, brs), 7.32 (1H, t, J=8.0 Hz), 7.24 (1H, dd, J=8.0, 1.8 Hz), 6.77 (1H, d, J=8.1 Hz), 2.92 (3H, d, J=4.8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:16]([CH3:38])=[C:17]([CH3:37])[C:18]4[O:22][C:21]([CH2:24][N:25]5[CH2:34][CH2:33][C:28]6(OCC[O:29]6)[CH2:27][CH2:26]5)([CH3:23])[CH2:20][C:19]=4[C:35]=3[CH3:36])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.C(OCC)(=O)C.Cl.O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[C:16]([CH3:38])=[C:17]([CH3:37])[C:18]4[O:22][C:21]([CH2:24][N:25]5[CH2:34][CH2:33][C:28](=[O:29])[CH2:27][CH2:26]5)([CH3:23])[CH2:20][C:19]=4[C:35]=3[CH3:36])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(CN3CCC5(CC3)OCCO5)O4)CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(CN3CCC(=O)CC3)O4)CC2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
To a solution of ethyl acetate (2.0 mL) containing 8-({5-[4-(4-Methoxyphenyl)piperazin-1-yl]-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-2-yl}methyl)-1,4-dioxa-8-azaspiro[4.5]decane (55 mg, 0.105 mmol) synthesized in Example 115, a solution of 4N hydrochloric acid-ethyl acetate (2.0 mL) was added, and the mixture was stirred at room temperature for 5 hours and at 50° C. for 2 hours. After that, 6N hydrochloric acid was (1.0 mL) was added thereto, and the mixture was further stirred at 70° C. for 2 hours. After cooled to room temperature, the reaction solution was poured into saturated sodium bicarbonate water, and extraction was performed using ethyl acetate. The extract was washed saturated saline, and then dried using anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane-ethyl acetate 95:5-72:28) and crystallized from ethyl acetate-hexane to give 25 mg of the title compound (yield 50%). Melting point was 123 to 127° C.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Br[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:12]([O:11][C:9]([CH2:8][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[Cl:1])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Clc1ncc[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Cn1ccnc1Cl

Procedure:
The starting material was prepared by reaction of 2-chloroimidazole with t-butyl bromoacetate in CH2Cl2 /aqueous sodium hydroxide in presence of tetra-n-butyl ammonium hydrogen sulphate to give 1-t-butoxycarbonylmethyl-2-chloroimidazole. Reaction of this compound with trimlethyloxonium tetrafluoroborate in CH2Cl2 gave 1-t-butoxycarbonylmethyl-2-chloro-3-methylimidazolium tetrafluoroborate; n.m.r. in d6DMSO:-1.5(s, 9H); 3.9(s, 3H); 5.17(s, 2H); 7.81(d, 1H): 7.85(d, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:19])=[C:10]2[C:17]([CH3:18])=[N:16][S:15][C:11]2=[C:12](Br)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:19])=[C:10]2[C:17]([CH3:18])=[N:16][S:15][C:11]2=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2snc(C)c2c1O
Reactant: OB(O)c1ccccc1
Product: CCCCOC(=O)c1nc(-c2ccccc2)c2snc(C)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 7-Bromo-4-hydroxy-3-methyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid butyl ester and phenyl boronic acid: MS (m/z) 343.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[N:4]([C@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([Br:25])[CH:24]=1)[NH:21][CH2:20][CH2:19]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:21]2[C:22]3[C:18](=[CH:17][C:16]([Br:15])=[CH:24][C:23]=3[Br:25])[CH2:19][CH2:20]2)[C:3](=[O:14])[N:4]([C@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:5]=1
Reactant: Brc1cc(Br)c2c(c1)CCN2
Reactant: COC[C@@H](C)n1cc(Cl)nc(Cl)c1=O
Product: COC[C@@H](C)n1cc(Cl)nc(N2CCc3cc(Br)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-2-methoxy-1-methylethyl]-2(1H)-pyrazinone and 5,7-dibromoindoline as the starting materials. mp 119–120° C.; 1H NMR (300 MHz, CDCl3): δ 7.47 (d, J=1.8 Hz, 1 H), 7.27 (d, J=1.8 Hz, 1 H), 7.06 (s, 1 H), 5.14–5.09 (m, 1 H), 4.32 (t, J=7.9 Hz, 2 H), 3.62–3.52 (m, 2 H), 3.34 (s, 3 H), 3.11 (t, J=8.1 Hz, 2 H), 1.40 (d, J=7.0 Hz, 3 H); HRMS (CI) calcd for C16H16N3O2Br2Cl (M+H)+: 474.9298; found m/z 474.9285.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#N.CC(C[AlH]CC(C)C)C.C(O)(=[O:25])C.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:25]
Reactant: N#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: CC(=O)O
Agent: CC(C)C[AlH]CC(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(C(F)(F)F)cc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
2-Chloro-4-(trifluoromethyl)benzonitrile (500 mg, 2.43 mmol) was diluted with toluene (3 mL), placed under nitrogen and cooled to −78° C. DIBAL-H (4865 μL, 4.86 mmol) was added dropwise and the reaction was stirred for 1 hour. The reaction was warmed to 0° C. and acetic acid (2 mL) was added followed by 10 mL of water. After stirring for 2 hours, the reaction was extracted twice with ethyl acetate, washed with Rochelle's salt, dried over MgSO4, filtered and concentrated. The material was purified using a biotage 25 cartridge running a gradient, 100% hexanes to 20% DCM/hexanes to yield 2-chloro-4-(trifluoromethyl)benzaldehyde (400 mg, 1.92 mmol, 78.8% yield) as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH3:19])[CH:12]=1)([OH:10])[C:6]([O:8][CH3:9])=[O:7].[C@@:25]12(O)[N:32](C)[C@@H:29]([CH2:30][CH2:31]1)[CH2:28][CH:27]=[CH:26]2>>[CH3:19][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[O:17][CH3:18])[C:5]([C:4]1[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:2]([CH3:1])[CH:3]=1)([OH:10])[C:6]([O:8][C@@:9]12[N:32]([CH3:25])[C@@H:29]([CH2:30][CH2:31]1)[CH2:28][CH:27]=[CH:26]2)=[O:7]
Reactant: COC(=O)C(O)(c1ccc(OC)c(C)c1)c1ccc(OC)c(C)c1
Reactant: CN1[C@@H]2CC=C[C@@]1(O)CC2
Product: COc1ccc(C(O)(C(=O)O[C@]23C=CC[C@H](CC2)N3C)c2ccc(OC)c(C)c2)cc1C

Procedure:
4.17 is prepared analogously to the method according to II.1; the product is purified by recrystallizing from diethylether. Yield: 2.30 g (35% of theory) starting from 5.0 g (0.015 mol) of 3h and 4.21 g (0.03 mol) of tropenol; melting point: 126° C.
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:10][CH:11]=2)[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:5]=1.C(N(CC)CC)C.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH2:42][CH:41]([C:45](O)=[O:46])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:2][S:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([N:13]3[CH2:14][CH2:15][N:16]([C:45]([CH:41]4[CH2:42][CH2:43][CH2:44][N:39]([C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH2:40]4)=[O:46])[CH2:17][CH2:18]3)=[CH:10][CH:11]=2)[N:6]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:5]=1
Reactant: CSc1nn(-c2ccccc2)c2cc(N3CCNCC3)ccc12
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1nn(-c2ccccc2)c2cc(N3CCN(C(=O)C4CCCN(C(=O)OC(C)(C)C)C4)CC3)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(methylthio)-1-phenyl-6-(piperazin-1-yl)-1H-indazole hydrochloride (from Example 1, 80 mg, 0.22 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL), triethylamine (50 mg, 0.50 mmol, 2.10 equiv), 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (60 mg, 0.26 mmol, 1.20 equiv), HATU (250 mg, 0.66 mmol, 3.00 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1) to yield tert-butyl 3-(1-(3-(methylthio)-1-phenyl-1H-indazol-6-yl)piperazine-4-carbonyl)piperidine-1-carboxylate as yellow oil. MS: 536 (MH+)