Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[C:14]3[N:15]=[C:16]([NH2:18])[S:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH:32]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.O.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>[C:36]([O:35][C:33]([N:30]1[CH2:29][CH:28]=[C:27]([C:2]2[CH:3]=[C:4]([O:8][C:9]3[C:14]4[N:15]=[C:16]([NH2:18])[S:17][C:13]=4[CH:12]=[CH:11][CH:10]=3)[N:5]=[CH:6][N:7]=2)[CH2:32][CH2:31]1)=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: Nc1nc2c(Oc3cc(I)ncn3)cccc2s1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(Oc3cccc4sc(N)nc34)ncn2)CC1
Temperature: 120 °C

Procedure:
A mixture of 4-(6-iodo-pyrimidin-4-yloxy)-benzothiazol-2-ylamine, (Example 129(b)), (200 mg, 0.54 mmol), 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate (200 mg, 0.65 mmol, prepared according Eastwood, P. R. Tetrahedron Lett. 2000, 41, 3705–3708), PdCl2(PPh3)2 (38 mg, 0.050 mmol, Aldrich), and Na2CO3 (86 mg, 0.81 mmol) in DME/EtOH/H2O (2:1:2, 2.0 mL) was stirred and heated by microwave synthesizer at 120° C. for 15 min. The reaction mixture was concentrated in vacuum to dryness. Purification by silica gel chromatography (gradient: 0% to 5.0% MeOH/CH2Cl2) provided the title compound as a light-yellow solid. Mp: 188° C. (decomp.). MS (ESI, pos. ion) m/z: 426 (M+1).
Reaction SMILES: [CH3:1][NH:2][S:3](/[CH:6]=[CH:7]/[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[C:17]1[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH:22]=1)(=[O:5])=[O:4].[ClH:24]>CN(C=O)C.[Pd]=O>[ClH:24].[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:17]1[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)/C=C/c1ccc2[nH]cc(C3=CCN(C)CC3)c2c1
Agent: O=[Pd]
Agent: Cl
Solvent: CN(C)C=O
Product: CNS(=O)(=O)CCc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Reaction time: 21 h

Procedure:
A mixture of (E)-N-methyl-2-[3-(1,2,3,6tetrahydro-1-methyl-4-pyridinyl)-1H-indol-5-yl]ethenesulphonamide (8.6 kg) and 10% palladium oxide on charcoal (2.58 kg, 50% wet paste) in DMF (86L) and 2N hydrochloric acid (12.3 kg) was hydrogenated at atmospheric pressure over 21 h. The catalyst was removed by filtration. The filter cake was washed with DMF/water (1:1; 30L). The combined washings and filtrate were then treated with decolourising charcoal (0.86 kg) at 75°-80° for 2 h. The suspension was filtered and the residue washed with DMF/water (2×30L). The filtrates from two hydrogenations could be combined for work-up. Thus the combined solutions were treated with 2M hydrochloric acid (1.72L) then concentrated in vacuo to approximately 52L. Ethyl acetate (120L) was added, the resulting suspension cooled to 30 and aged for 1 h. The product was collected by filtration, washed with ethyl acetate (2×26L) and dried in vacuo at 40°-50° overnight (15.96 kg, 83% of theory). Recrystallisation from hot IMS/water (7:1; 206L) gave fine, off-white crystals (13.02 kg, 84% of theory).
Reaction SMILES: CC(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([N:13]([CH3:15])[CH3:14])[CH2:9]1)(C)C.[ClH:17]>O1CCOCC1>[ClH:17].[ClH:17].[CH3:14][N:13]([C@H:10]1[CH2:11][CH2:12][C@H:8]([NH2:7])[CH2:9]1)[CH3:15]
Reactant: CN(C)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)[C@H]1CC[C@H](N)C1
Reaction time: 0.83 h

Procedure:
(1S-trans)-[3-(N,N-Dimethylamino)cyclopentyl]carbamic acid 1,1-dimethylethyl ester (0.537 g, 2.35 mmol) in 1,4-dioxan (4 ml) was treated with a saturated solution of hydrogen chloride in 1,4-dioxan (15 ml) and additional 1,4-dioxan (8 ml). After 50 minutes at 21° C., another portion of a saturated solution of hydrogen chloride in 1,4-dioxan (5 ml) was added, and after a further 2.5h, the opaque solution was concentrated by evaporation to give the title compound as a beige solid, which was used without characterisation.
Reaction SMILES: [CH2:1]=CC(=C)C.CN(C)C(=O)C(C)C.C(N(CC)CC)C.[CH3:21][C:22]1([CH3:30])[C:25](C)([CH:26]=[CH2:27])[CH2:24][C:23]1=[O:29]>C(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[CH3:30][C:22]1([CH3:21])[CH:25]([C:26]([CH3:27])=[CH2:1])[CH2:24][C:23]1=[O:29]
Reactant: C=CC(=C)C
Reactant: C=CC1(C)CC(=O)C1(C)C
Agent: CC(C)C(=O)N(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C1CC(=O)C1(C)C

Procedure:
34.0 g (0.5 mol) of isoprene and then, at 0°-10° C., 75.0 g (0.55 mol) of zinc chloride were added to 350 ml of the solution, prepared according to Example 1, of the amide chloride is isobutyric acid dimethylamide in methylene chloride, while cooling and stirring. Thereafter, 50.0 g (0.5 mol) of triethylamine were added dropwise at the same temperature and, after warming to 20°-25° C., the mixture was heated to reflux and worked up according to Example 2. This gave 40.4 g (58%, relative to isobutyric acid dimethylamide employed) of the ketone of boiling point 109°-110° C./100 mm Hg and nD20 of 1.4518 (contaminated to the extent of about 10% by 2,2,3-trimethyl-3-vinyl-cyclobutanone).
Reaction SMILES: C(N(CC)CC)C.O=C1C2NC=CC=2C2C=C(S(=O)(=O)NC3C=CC=CC=3)C=CC=2N1.C(C([O-])=O)C.[CH3:37][NH:38][CH2:39][C:40]([NH2:42])=[O:41].Cl[S:44]([C:47]1[CH:56]=[CH:55][C:54]2[NH:53][C:52](=[O:57])[C:51]3[NH:58][CH:59]=[C:60]([C:61]([OH:63])=[O:62])[C:50]=3[C:49]=2[CH:48]=1)(=[O:46])=[O:45]>ClCCl.CN(C)C=O>[C:40]([CH2:39][N:38]([CH3:37])[S:44]([C:47]1[CH:56]=[CH:55][C:54]2[NH:53][C:52](=[O:57])[C:51]3[NH:58][CH:59]=[C:60]([C:61]([OH:63])=[O:62])[C:50]=3[C:49]=2[CH:48]=1)(=[O:46])=[O:45])(=[O:41])[NH2:42]
Reactant: CNCC(N)=O
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Agent: CCC(=O)[O-]
Agent: O=c1[nH]c2ccc(S(=O)(=O)Nc3ccccc3)cc2c2cc[nH]c12
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CC(N)=O)S(=O)(=O)c1ccc2[nH]c(=O)c3[nH]cc(C(=O)O)c3c2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 53 %

Procedure:
584 μL (3 mmol) of triethylamine and 208 mg (1.68 mmol) of 2 methylamino-acetamide are added to 456 mg (1.4 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid suspended in 4 mL of anhydrous dichloromethane and 1 mL of anhydrous dimethylformamide. The reaction mixture is stirred for 3 days at room temperature. The solvents are evaporated then the residue is taken up in methanol. The solid is filtered, rinsed with methanol then diisopropyl ether and dried under vacuum to give 279 mg (53%) of 8-(carbamoylmethyl-methyl-sulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]1[CH2:11][CH:10]=[CH:9][CH2:8][CH:7]([NH:12]C(OC(C)(C)C)=O)[C:6]1=[O:20].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]1[CH2:11][CH:10]=[CH:9][CH2:8][CH:7]([NH2:12])[C:6]1=[O:20]
Reactant: COC(=O)CN1CC=CCC(NC(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CN1CC=CCC(N)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution containing (3-tert-butoxycarbonylamino-2-oxo-2,3,4,7-tetrahydroazepin-1-yl) acetic acid methyl ester, 2, (0.57 g, 2.0 mmol) in 10 mL of CH2Cl2 is treated with 2.5 mL of wet TFA and stirred at room temperature for 30 minutes. The solution is concentrated in vacuo and treated with saturated NaHCO3. Solid NaCl is added to the resulting aqueous solution and the solution is extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated in vacuo to afford the desired intermediate which can be used without further purification.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-])=O)[CH:8]=2)[N:3]=1.[CH3:15][CH:16]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24]([NH2:25])[C:18]=2[O:17]1.[CH:26]([N:29]=[C:30]=[O:31])([CH3:28])[CH3:27]>>[CH:26]([NH:29][C:30]([NH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:25][C:24]1[C:18]3[O:17][CH:16]([CH3:15])[CH2:20][C:19]=3[CH:21]=[CH:22][CH:23]=1)[CH:11]=[CH:10]2)=[O:31])([CH3:28])[CH3:27]
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Reactant: CC1Cc2cccc(N)c2O1
Reactant: CC(C)N=C=O
Product: CC(C)NC(=O)Nc1ccc2nc(Nc3cccc4c3OC(C)C4)ccc2c1

Procedure:
The title compound, MS: m/e=377.4 (M+H+), was prepared in accordance with the general method of example 14 from 2-chloro-6-nitro-quinoline, 2,3-dihydro-2-methyl-7-benzofuranamine (CAS 26210-74-2) and isopropyl isocyanate.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[NH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)C(C)C)(C)C>CC(O)C.ClCCl>[Cl:9][C:6]1[N:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:7]=1[NH2:8]
Reactant: NC1CCOCC1
Reactant: Cc1nc(Cl)c(N)c(Cl)n1
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Cl)c(N)c(NC2CCOCC2)n1
Temperature: 25 °C

Procedure:
Heat a solution of 4,6-Dichloro-2-methyl-pyrimidin-5-ylamine (0.008 mol, 1.5 g, 1.0 equiv.), 4-amino tetrahydropyran (0.012 mol, 1.27 g, 1.5 equiv.), and N,N-diisopropylethylamine (0.0092 mol, 1.1 g, 1.1 equiv.) in 2-propanol (80 mL) at 150° C. in a sealed tube for 16 hours. Cool the reaction mixture to room temperature and remove the 2-propanol under reduced pressure to give the residue. Dissolve the residue in dichloromethane and wash with water and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue on silica gel column eluting with dichloromethane: methanol 96:4 to give the title compound. MS (m/z): 243.41 (M+1).
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][C:13]2=[C:16]([C:19]#[N:20])[C:17]#[N:18])=[CH:8][CH:7]=1>C1COCC1.[Cu]I>[CH3:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][C:13]2([CH:16]([C:19]#[N:20])[C:17]#[N:18])[CH3:1])=[CH:8][CH:7]=1
Reactant: C[Mg]Br
Reactant: COc1ccc2c(c1)C(=C(C#N)C#N)CCC2
Agent: [Cu]I
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(C)(C(C#N)C#N)CCC2
Yield: 66.6 %

Procedure:
To a solution of methylmagnesium bromide (3.0 M in diethyl ether (12.0 mL, 36.0 mmol)) and copper(I) iodide (6.86 g, 36.0 mmol) in THF (100 mL) was added 48.1 (6.73 g, 30.0 mmol) at room temperature. The resulting mixture was refluxed for 4 hours. The mixture was then cooled in an ice-bath, quenched with aqueous NH4Cl (200 mL), extracted with ether, concentrated, and purified by silica gel column chromatography to give 48.2 (4.8 g, 66% yield). MS ESI (pos.) M/E: 241 (M+H).
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[I:23]N1C(=O)CCC1=O.O>CN(C=O)C>[OH:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[C:10]([I:23])[C:3]=12
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1nc[nH]c2nccc1-2
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Oc1nc[nH]c2ncc(I)c1-2
Temperature: 40 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a solution of 1.0 g of 4-hydroxypyrrolo [2,3-d]pyrimidine in 20 ml of DMF, 3.3 g (2.2 eq) of bis(trimethylsilyl)acetamide was added, and the resulting solution was stirred at 40° C. in an oil bath for about 2 h. Completeness of silylation was indicated by NMR analysis of an aliquot showing disappearance of the N-3 proton signal. The reaction was cooled to ambient temperature and 1.6 g (1.2 eq) of N-iodosuccinimide (NIS), was added in one portion. The reaction mixture was protected from light and stirred at ambient temperature until completion was indicated by NMR analysis (disappearance of pyrrole C-H doublets and emergence of a single, finely split doublet at δ7.17, about 2 h). The mixture was poured into 50 mL of water with stirring. After 1-2 hours, the product was collected by filtration, washed with water, dried, and reslurried in 10 volumes of 10% methanol in chloroform. Filtration and drying gave 1.7 g of 4-hydroxy- 5-iodopyrrolo[2,3-d]pyrimidine (88% yield), mp 248°-253° C. (dec). 1H NMR (300 MHz, DMSO-d6) δ7.17 (d, J=2.4 Hz, 1 H), 7.80 (d, J=2.3 Hz, 1 H), 11.82 (s, 1 H), 12.14 (s, 1 H). 13C NMR (75.5 MHz, DMSO-d6) δ53.8, 107.3, 125.5, 143.6, 147.9, 157.8. Anal. Calcd for C6H4IN3O: C, 27.61; H, 1.54; N, 16.10. Found: C, 27.71; H, 1.48; N, 15.85.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][S:7][C:6](=[O:9])[C@@H:5]2[CH2:10][CH2:11][CH2:12][N:4]2[C:3]1=[O:13].CN(C)C=[O:17]>[OH-].[Na+]>[SH:7][CH2:8][CH:2]([CH3:1])[C:3]([N:4]1[CH2:12][CH2:11][CH2:10][C@H:5]1[C:6]([OH:17])=[O:9])=[O:13]
Reactant: CC1CSC(=O)[C@@H]2CCCN2C1=O
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Product: CC(CS)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (4RS-9aS)-hexahydro-4-methyl-1H,5H-pyrrolo[2,1-c][1,4]thiazepine-1,5-dione (2 g) in dimethylformamide (100 ml), normal sodium hydroxide (20 ml) is added. The mixture is stirred for four hours at room temperature under argon. The solvent is removed in vacuo, the residue is dissolved in ethyl acetate and washed with 10% potassium bisulfate and water. The organic layer is dried and concentrated to yield the title compound.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C([O-])(=O)C.[Na+].Cl.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27]N)=[CH:23][CH:22]=1.O>C(O)(=O)C>[CH2:11]([O:10][C:8]([CH:5]1[CH2:6][C:7]2[C:25]3[C:24](=[CH:23][CH:22]=[C:21]([O:20][CH3:19])[CH:26]=3)[NH:27][C:2]=2[CH2:3][CH2:4]1)=[O:9])[CH3:12]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: COc1ccc(NN)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C1CCc2[nH]c3ccc(OC)cc3c2C1
Yield: 68.4 %

Procedure:
A solution of ethyl 4-oxocyclohexanecarboxylate (3 g, 17.6 mmol) and sodium acetate (1.59 g, 19.4 mmol) in glacial acetic acid (36 mL) was degassed with nitrogen prior to addition of 4-methoxyphenylhydrazine hydrochloride (3.38 g, 19.4 mmol). The mixture was heated at reflux for 2 hours then cooled, poured into water and extracted with tert-butylmethyl ether. The organic phase was washed with 5% K2CO3, then water and finally brine. The organic layer was dried over sodium sulphate then solvent removed under reduced pressure and the residue purified by column chromatography to afford 3.29 g of the title compound.
Reaction SMILES: C(OC[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13](C)C)=[C:8]([O:16]COCC)[C:7]=1C)C.Cl.O>CO>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][C:8]=1[OH:16]
Reactant: CCOCOc1ccc(OC(C)C)c(OCOCC)c1C
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccc(O)cc1O
Yield: 127.9 %

Procedure:
A solution of 5c (157 mg, 0.53 mmol) in MeOH (4.40 mL) at room temperature was treated dropwise with 3 M HCl (1.40 mL, 4.21 mmol), then heated to reflux for one hour. Water (5 mL) was added and the solution was extracted with EtOAc (3×10 mL). Combined organic fractions were washed with saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated to afford 6c as a red amorphous solid (95 mg, 99%): 1H NMR (CDCl3, 500 MHz) 6.54 (d, J=8.7 Hz, 1H), 6.21 (d, J=8.7 Hz, 1H), 5.78 (s, 1H), 4.37-4.32 (m, 1H), 2.09 (s, 3H), 1.25 (d, J=6.1 Hz, 6H); 13C NMR (CDCl3, 125 MHz) δ 147.7, 144.9, 137.5, 110.8, 109.8, 104.0, 71.7, 21.3 (2C); IR (film) νmax 3526, 2974, 2924, 2853, 1717, 1607, 1475, 1238, 1113, 1067, 928, 887, 791 cm−1.
Reaction SMILES: F[C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[C:22]1[S:26][CH:25]=[N:24][CH:23]=1.[NH:27]1[CH2:31][C@H:30]([OH:32])[C@@H:29]([OH:33])[CH2:28]1>CS(C)=O>[OH:33][C@@H:29]1[C@@H:30]([OH:32])[CH2:31][N:27]([C:2]2[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)=[O:7])=[CH:4][C:3]=2[C:22]2[S:26][CH:25]=[N:24][CH:23]=2)[CH2:28]1
Reactant: O[C@H]1CNC[C@@H]1O
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(F)c(-c2cncs2)c1
Solvent: CS(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(-c2cncs2)c1

Procedure:
A solution of 4-fluoro-3-(thiazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.1, 60 mg, 0.13 mmol), (3S,4S)-pyrrolidine-3,4-diol (28.2 mg. 0.273 mmol) and TEA (76 μL, 0.546 mmol) in DMSO (103 μL) was stirred at 105° C. for 90 h. The solvent was evaporated off under reduced pressure and the crude product was purified by preparative SFC (Column Diol, from 22% to 27% in 10 min) to afford the title compound as a yellow powder. UPLC-MS (Condition 1) tR=2.18 min, m/z=466.0 [M+H]+, m/z=464.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.86 (d, J=10.51 Hz, 2H) 3.36 (dd, J=10.51, 3.67 Hz, 2H) 3.90 (br. s, 2H) 5.05 (br. s, 2H) 6.93 (d, J=8.80 Hz, 1H) 7.33 (d, J=8.56 Hz, 2H) 7.78-7.98 (m, 5H) 9.16 (s, 1H) 10.12 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[N:4][CH:3]=1.C1C(=O)N([Cl:22])C(=O)C1.C(=O)(O)[O-].[Na+]>Cl>[Cl:22][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[C:14]2=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cncc2[nH]c3ccccc3c12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cncc2[nH]c3ccc(Cl)cc3c12
Temperature: 25 °C
Yield: 93.7 %

Procedure:
4-methyl-9H-β-carboline (97 mg, 0.532 mmol) was dissolved in HCl (1N, 4 ml) and stirred at RT. NCS (85 mg, 0.637 mmol) was added thereto and the reaction mixture was stirred for 5 hr. Saturated sodium bicarbonate solution (20 ml) was added thereto and the reaction mixture was extracted twice with EtOAc (100 ml). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give 6-chloro-4-methyl-9H-β-carboline (108 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([C:10]#N)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C1(C)C=CC=CC=1.[H-].C([NH2+]CC(C)C)C(C)C.Cl.[OH2:31]>ClCCl>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:10]=[O:31])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Cl)c(C)c1C#N
Reactant: O
Agent: CC(C)C[NH2+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ncc(Cl)c(C)c1C=O
Temperature: -78 °C
Reaction time: 72 h

Procedure:
2.47 g (13.5 mmol) of 5-chloro-3-cyano-4-methyl-2-methoxypyridine was dissolved in 50 ml of anhydrous dichloromethane, the solution was cooled to −78° C., and 20.3 ml (20.3 mmol) of a toluene solution of 1M diisobutylammonium hydride was dropwise added slowly. After stirring at −78° C. for two and a half hours, the temperature was gradually increased to room temperature, and stirring was carried out at the same temperature for three days. The obtained solution was cooled in an ice bath, and 30 ml of water was slowly added to terminate the reaction. The reaction mixture was poured into 150 ml of 1N hydrochloric acid, followed by extraction with 100 ml of dichloromethane twice. The dichloromethane solution was washed with 100 ml of a saturated sodium chloride solution and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain crude 5-chloro-3-formyl-4-methyl-2-methoxypyridine. 1H-NMR (400 MHz, CDCl3): δ(ppm) 2.65 (s, 3H), 4.03 (s, 3H), 8.25 (s, 1H), 10.48 (s, 1H)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Cl[C:10]1[CH:15]=[C:14](Cl)[N:13]=[CH:12][N:11]=1.[IH:17]>>[I:17][C:10]1[CH:15]=[C:14]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[N:13]=[CH:12][N:11]=1
Reactant: OB(O)c1ccsc1
Reactant: I
Reactant: Clc1cc(Cl)ncn1
Product: Ic1cc(-c2ccsc2)ncn1

Procedure:
The compound was prepared according to Example 1 using thiophene-3-boronic acid and 4,6-dichloropyrimidine. The resultant chloro compound was converted to iodo with hydroiodic acid as described in the general procedure.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[OH:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32]N)=[CH:28][CH:27]=1>>[OH:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:28][CH:27]=1
Reactant: NNc1ccc(O)cc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccc(O)cc3)n2)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and 4-hydroxy-phenylhydrazine according to the method described for example 43. MS: M=409.1 (M+H)+
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[CH:8]2)(=[O:3])[CH3:2].[N+:14]([O-])([OH:16])=[O:15]>>[N+:14]([C:6]1[C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[N:9][NH:10]2)([O-:16])=[O:15]
Reactant: CC(=O)Nc1ccc2[nH]ncc2c1
Reactant: O=[N+]([O-])O
Product: CC(=O)Nc1ccc2[nH]ncc2c1[N+](=O)[O-]
Yield: 91.6 %

Procedure:
By referring to the Step 4 of Example 1, 5-acetylaminoindazole (6 g, 34.2 mmol), HNO3 (2.0 mL, 48 mmol), were used to obtain a product (6.9 g, 91.7%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[CH:7]=[C:8]([C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9](=[O:16])CC(OCC)=O)([O-:3])=[O:2].[O:28]1[CH2:33][CH2:32][N:31]([CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:30][CH2:29]1.[CH2:40]([OH:42])[CH3:41]>>[O:28]1[CH2:33][CH2:32][N:31]([C:34]23[O:24][C:17]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[C:8]([C:9]([O:42][CH2:40][CH3:41])=[O:16])[CH:7]([C:6]4[CH:25]=[CH:26][CH:27]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)[CH:39]2[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH2:30][CH2:29]1
Reactant: CCOC(=O)CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)c1ccccc1
Reactant: C1CCC(N2CCOCC2)CC1
Reactant: CCO
Product: CCOC(=O)C1=C(c2ccccc2)OC2(N3CCOCC3)CCCCC2C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 10.9 g (0.033 mole) of ethyl 3-nitrobenzylidenebenzoylacetoacetate and 5.6 g (0.033 mole) of morpholinocyclohexane in 80 ml of ethanol is boiled under reflux for 4 hours. The solution is concentrated and the residue is triturated with ether, filtered off with suction and recrystallized from ethanol.
Reaction SMILES: S(Cl)(C)(=O)=O.[CH2:6]([O:8][C:9](=[O:42])[C@H:10]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[N:35]([CH2:39]CO)[CH2:36][CH2:37]O)[CH:26]=2)[CH:20]=1)[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH3:7].O.[Cl-:44].[Li+].[CH2:46]([Cl:48])Cl>CO>[CH2:6]([O:8][C:9](=[O:42])[C@H:10]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[N:35]([CH2:39][CH2:46][Cl:48])[CH2:36][CH2:37][Cl:44])[CH:26]=2)[CH:20]=1)[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH3:7]
Reactant: CCOC(=O)[C@H](Cc1cccc(-c2ccc3c(N(CCO)CCO)cccc3c2)c1)NC(=O)C(F)(F)F
Reactant: [Cl-]
Reactant: ClCCl
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Product: CCOC(=O)[C@H](Cc1cccc(-c2ccc3c(N(CCCl)CCCl)cccc3c2)c1)NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
A solution of mesyl chloride (172 mg, 1.50 mmol) in methylene chloride (1 ml) was added to a solution of 3-[5-bis[2-(hydroxy)ethyl]amino-naphth-2-yl]-N-trifluoroacetyl-L-phenylalanine ethyl ester (268 mg, 0.50 mmol) in methylene chloride (9 ml) and the mixture was stirred at room temperature for 3 hrs. To the mixture was added water and the mixture was extracted with methylene chloride. The extract was washed with water and dried. The solvent was distilled off under reduced pressure. To the residue were added methanol (10 ml) and lithium chloride (638 mg, 15 mmol) and the mixture was stirred at room temperature for 1 hr. and heated under reflux for 5 hrs. After the mixture was cooled to room temperature, silica gel (3 g) was added thereto and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=5) to give 3-[5-bis[2-(chloro)ethyl]amino-naphth-2-yl]-N-trifluoroacetyl-L-phenylalanine ethyl ester (207 mg, 72%) as a pale yellow oil.