Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[NH:8][N:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])[CH3:2].CS(O[CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)(=O)=O>>[CH:27]1([CH2:26][N:8]2[C:7](=[O:20])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][C:10]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)=[N:9]2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CS(=O)(=O)OCC1CCCC1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Product: CCOC(=O)c1cc(-c2ccc(OC)cc2)nn(CC2CCCC2)c1=O
Yield: 88.5 %

Procedure:
Using 4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and cyclopentylmethyl methanesulfonate as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 88.5%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[Br:11]Br.O>C(O)(=O)C.ClCCl>[Br:11][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([F:1])[C:9]=1[OH:10])[CH:5]=[O:6]
Reactant: BrBr
Reactant: O=Cc1ccc(O)c(F)c1
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=Cc1cc(F)c(O)c(Br)c1
Temperature: 20 °C
Reaction time: 7 h
Yield: 63.9 %

Procedure:
To a mixture of 3-fluoro-4-hydroxybenzaldehyde (700 mg, 5.0 mmol) in acetic acid (5 mL) and dichloromethane (5 mL) was added bromine (0.5 mL, 9.8 mmol) at 0° C. The resulting mixture was stirred at 20° C. for 7 hours and then it was poured into water (50 mL), filtrated, the filtered cake was dried to give Intermediate 77 (700 mg, yield 64%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=O)=[CH:11][CH:12]=2)[CH:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:6][CH:5]1[CH3:30])(=[O:3])[CH3:2].Cl.C1C=CC2N(O)N=NC=2C=1.O.Cl.[CH3:44][O:45][NH2:46].C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:46][O:45][CH3:44])=[O:16])=[CH:11][CH:12]=2)[CH:7]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[CH:22][CH:23]=2)[CH2:6][CH:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CON
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2C(Nc2ccc(N3CCOCC3)cc2)CC1C
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CONC(=O)c1ccc2c(c1)C(Nc1ccc(N3CCOCC3)cc1)CC(C)N2C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
74 mg of 1-acetyl-4-[(4-morpholinophenyl)amino]-2-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (compound of Step 3 of Example 111), 52 mg of WSCD.HCl, 37 mg of HOBt-H2O, and 45 mg of methoxyamine hydrochloride were dissolved in 2 mL of dichloromethane, and 76 μL of triethylamine was added to the solution. The mixture was stirred overnight at room temperature. After completion of the reaction, a saturated aqueous solution of sodium hydrogen carbonate was added to the mixture, and the mixture was extracted three times with chloroform. The extraction product was washed with saturated brine, dehydrated over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (methanol:chloroform=1:10), and thus 57 mg (cis:trans=4:1, 72%) of the title compound was obtained as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[C:16](Br)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](C2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].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>[CH2:1]([N:8]1[CH:17]=[C:16]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[C:27]([O:28][CH3:29])[CH:26]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C2OC(C)(C)C(C)(C)O2)cc1OC
Reactant: O=c1c2ccccc2c(Br)cn1Cc1ccccc1
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+]
Product: COc1ccc(-c2cn(Cc3ccccc3)c(=O)c3ccccc23)cc1OC
Temperature: 90 °C
Reaction time: 16 h
Yield: 86.4 %

Procedure:
A mixture of 2-benzyl-4-bromoisoquinolin-1(2H)-one (0.377 g, 1.20 mmol), 2-(3,4-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3-dioxolane (0.380 g, 1.44 mmol) and Na2CO3 (0.382 g, 3.60 mmol) was degassed under nitrogen. Toluene (20 mL), ethanol (20 mL) and water (2 mL) were then added. The reaction mixture was degassed again and Pd(PPh3)4 (0.139 g, 0.12 mmol) was added. The reaction was stirred at 90° C. for 16 h under nitrogen. After that time, the mixture was cooled to rt and concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (2×100 mL). The organic phase was washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 70:30 hexanes/ethyl acetate to 60:40 hexanes/ethyl acetate) to give 2-benzyl-4-(3,4-dimethoxyphenyl)isoquinolin-1(2H)-one (0.385 g, 86%) as a pale yellow solid: mp 174-176° C.; 1H NMR (400 MHz, CDCl3): δ 8.57 (d, J=7.81 Hz, 1H), 7.47-7.66 (m, 3H), 7.24-7.42 (m, 5H), 7.06 (s, 1H), 6.85-6.98 (m, 3H), 5.27 (s, 2H), 3.93 (s, 3H), 3.87 (s, 3H). ESI MS m/z 372 [M+H]+.
Reaction SMILES: C(OC([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=O)(C)(C)C.CCOCC.[ClH:42]>CCOC(C)=O>[ClH:42].[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc2ccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(C)[Si](Oc1ccc2cccc(N)c2c1)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
A solution of 1-(tert-butoxycarbonylamino)-7-(tert-butyldiphenylsilyloxy)naphthalene, as described above in Step B, (1.54 g, 3.09 mmol) in EtOAc (80 mL) and Et2O (20 mL) at ambient temperature was saturated with HCl (g). After 1 hr, the mixture was concentrated in vacuo to yield the desired product as a pale solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][C:17]#N.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.CC[O:38]CC>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][CH:17]=[O:38]
Reactant: COc1ccc(OC)c(C2CCCC2CC#N)c1
Reactant: CCOCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: COc1ccc(OC)c(C2CCCC2CC=O)c1
Temperature: -10 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Dissolve [2-(2,5-dimethoxy-phenyl)-cyclopentyl]-acetonitrile (3.9 g, 16 mmol) in ether (85 ml), cool to −10° C., add diisobutylaluminum hydride 1.5M in toluene (19 ml, 29 mmol), and stir at −10° C. for 1 hour. Quench with 1N hydrochloric acid, and add ethyl acetate. Separate layers, wash organic with brine, dry, and concentrate to give the title compound (3 g, 76%): 1H NMR (CDCl3) δ 9.50-9.49 (m, 1H), 6.77-6.69 (m, 3H), 3.77 (s, 3H), 3.76 (s, 3H), 3.58-3.54 (m, 1H), 2.88-2.83 (m, 1H), 2.08-1.87 (m, 5H), 1.74-1.65 (m, 2H), 1.44-1.39 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([C@H:32]2[CH2:36][CH2:35][C@@H:34]([NH:37]C(OC(C)(C)C)=O)[CH2:33]2)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([C@H:32]2[CH2:36][CH2:35][C@@H:34]([NH2:37])[CH2:33]2)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](C(=O)N[C@H](Cc2ccc(Cl)cc2)C(=O)N2CCC(c3ccccc3NS(C)(=O)=O)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Nc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@H]2CC[C@@H](N)C2)CC1
Reaction time: 0.5 h

Procedure:
The title compound was prepared according to the procedure described in Example 3 Step (b) from N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)-amino]phenyl}-piperidyl)-2-oxoethyl]{(1S,3R)-3-[(tert-butoxy)carbonylamino]-cyclopentyl}-carboxamide (Step a) (323 mg, 0.5 mmol) and a 50% soln of TFA in CH2Cl2 (20 mL). Purification by preparative HPLC [Phenomenex; 5 μm 250×21.2 mm, 5% to 95% CH3CN (0.1% TFA) in H2O (0.1% TFA) over 30 min, then 100% CH3CN (0.1% TFA) for 2 min]provided the title compound (TFA salt) as a white foam (113 mg). MS (ESI, pos. ion) m/z: 547 (M+1); (ESI, neg. ion) m/z: 545 (M-1). Calc'd for C27H35ClN4O4S: 546.21.
Reaction SMILES: [CH2:1]([C:5]([CH3:19])([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4].Br[CH2:21][CH2:22][O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH2:1]([C:5]([CH3:19])([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:21][CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[CH:16][CH:17]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: BrCCOC1CCCCO1
Reactant: CCCCC(C)(Cc1ccc(O)cc1)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCCCC(C)(Cc1ccc(OCCOC2CCCCO2)cc1)C(=O)OCC
Yield: 95.4 %

Procedure:
In a similar manner to that described in Reference example 3(e), a reaction was carried out using ethyl 2-butyl-3-(4-hydroxyphenyl)-2-methylpropionate (2.95 g), which is the product of Reference example 10(b), 2-(2-bromoethoxy)tetrahydropyran (4.66 g) and potassium carbonate (4.62 g) in dimethylacetamide and the reaction mixture was treated to afford the desired compound (4.18 g) as a syrup.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[CH2:17]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)[CH3:18]>>[CH2:17]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]2[C:8]3[NH:9][C:10]4[C:15]([C:7]=3[CH2:6][CH:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:21][CH:20]=1)[CH3:18]
Reactant: CCc1ccc(C=O)cc1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Product: CCc1ccc(C2NC(C(=O)OC)Cc3c2[nH]c2ccccc32)cc1

Procedure:
The same method but starting from racemic tryptophan methyl ester and 4-ethylbenzaldehyde gave the cis and trans isomer of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:15])[S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1.Cl.[F:24][C:25]1[CH:26]=[N:27][C:28]([C@@H:31]([NH2:33])[CH3:32])=[N:29][CH:30]=1.CCN(C(C)C)C(C)C>CCCCO>[F:24][C:25]1[CH:26]=[N:27][C:28]([C@@H:31]([NH:33][C:2]2[N:7]=[C:6]([N:8]([CH3:15])[S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:5]=[C:4]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=3)[N:3]=2)[CH3:32])=[N:29][CH:30]=1
Reactant: Cc1cc(Nc2cc(N(C)S(=O)(=O)N(C)C)nc(Cl)n2)n[nH]1
Reactant: C[C@H](N)c1ncc(F)cn1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2cc(N(C)S(=O)(=O)N(C)C)nc(N[C@@H](C)c3ncc(F)cn3)n2)n[nH]1
Temperature: 180 °C
Yield: 70.1 %

Procedure:
A microwave reaction vessel was charged with N-{2-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N,N′,N′-trimethylsulfamide (Method 30, 51.9 mg, 0.150 mmol), (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 53.3 mg, 0.301 mmol), and DIPEA (0.079 ml, 0.449 mmol). Anhydrous n-BuOH (1 ml) was added, and the tube was sealed and heated in a microwave reactor at 180° C. for 4 hours. The reaction mixture was purified by silica gel chromatography (by ISCO Combiflash with gradient EtOAc and hexanes) to afford the title compound as a white solid (47.4 mg, 70%). LC-MS, 451 (M+1). 1H NMR (DMSO-d6, 400 MHz, 80° C.) δ 11.61 (s, 1H), 8.95 (s, 1H), 8.77 (s, 2H), 5.84-6.89 (m, 3H), 5.17-5.23 (m, 1H), 3.17 (s, 3H), 2.74 (s, 6H), 2.18 (s, 3H), 1.54 (d, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])[CH:3]=1.C([Li])CCC.CN([CH:22]=[O:23])C.Cl>C1COCC1>[CH3:13][O:12][CH2:11][CH2:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:22]=[O:23]
Reactant: COCCCCc1cccc(Br)c1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCCCc1cccc(C=O)c1
Temperature: -72 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the title C compound, 1-bromo-3-(4-methoxy-butyl)-benzene (11 g, 45.24 mmol) in 200 mL of THF is added drop wise n-butyl lithium (31.1 mL, 49.76 mmol, 1.6 M solution in hexane) over 30 min at −72° C. The reaction mixture is further stirred 5 min at −72° C. before the addition of a THF solution (50 mL) of DMF (7.67 mL, 99.52 mmol) over 45 min. The reaction mixture is further stirred for 15 min at −72° C., 1 h at room and poured into aqueous 2 M HCl solution. The aqueous layer is extracted twice with ether and the combined organic extracts are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (hexane/EtOAc 9/1) to afford the title compound as a yellow oil: MS 210.0 [M+18]; Rt (HPLC, Nucleosil C18, 10:90-100:0 CH3CN/H2O+0.1% TFA within 5 min, then 100% CH3CN+0.1% TFA): 5.35 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[CH:6]2.Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([C:27]([C:29]2[CH:39]=[C:38]([CH3:40])[C:32]3[N:33]([CH3:37])[C:34](=[O:36])[O:35][C:31]=3[CH:30]=2)=[O:28])[CH:22]=1.O>CN(C=O)C>[CH3:37][N:33]1[C:32]2[C:38]([CH3:40])=[CH:39][C:29]([C:27]([C:23]3[N:24]=[CH:25][N:26]=[C:21]([N:17]4[CH2:18][CH2:19][CH:14]([C:7]5[C:8](=[O:13])[NH:9][C:10]6[C:5]([CH:6]=5)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=6)[CH2:15][CH2:16]4)[CH:22]=3)=[O:28])=[CH:30][C:31]=2[O:35][C:34]1=[O:36]
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Reactant: COc1ccc2[nH]c(=O)c(C3CCNCC3)cc2c1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2[nH]c(=O)c(C3CCN(c4cc(C(=O)c5cc(C)c6c(c5)oc(=O)n6C)ncn4)CC3)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
30 mg (0.087 mmol) 6-methoxy-3-piperidin-4-yl-1H-quinoline-2-one, 30 mg (0.10 mmol) 6-(6-chloro-pyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 50 μl (0.36 mmol) TEA were combined in 3 mL DMF and stirred overnight at RT. Then the reaction mixture was added to water, the precipitate formed was suction filtered and washed with MeOH. Next, the precipitate was boiled in DMF/MeOH and the precipitate was suction filtered.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][S:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(Cl)(Cl)(Cl)Cl>[Cl:1][CH:11]([S:10][CH3:9])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)CSC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Cl)SC
Temperature: 25 °C
Reaction time: 17 h
Yield: 42.7 %

Procedure:
N-Chlorosuccinimide (5.97 g, 44.71 mmol) was added portionwise to ethyl (methylthio)acetate (6.00 g, 44.71 mmol) in carbon tetrachloride (30 mL) at 0° C. under argon and the reaction was allowed to warm to room temperature and stirred for 17 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The oil was purified by distillation to give 3.22 g (43%) of ethyl chloro(methylthio)acetate as an oil. 1H NMR (400 MHz, d6-DMSO): δ 6.10 (s, 1H), 4.20 (q, J=7 Hz, 2H), 2.24 (s, 3H), 1.22 (t, J=7 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([C@H:5]1[C@H:12]2[C@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[CH:7]=[CH:6]1)[OH:4]>CO.[Pd]>[NH2:1][CH2:2][C@H:3]([C@H:5]1[C@H:12]2[C@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[CH2:7][CH2:6]1)[OH:4]
Reactant: CC1(C)O[C@H]2[C@H]([C@H](O)CN)C=C[C@H]2O1
Agent: [Pd]
Solvent: CO
Product: CC1(C)O[C@H]2[C@H]([C@H](O)CN)CC[C@H]2O1
Reaction time: 2 h

Procedure:
(S)-2-amino-1-((3aS,4S,6aR)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ethanol (2-5) (3.22 g, 16.2 mmol, 1.0 equiv) was dissolved in MeOH (150 mL) and 10% Pd/C (1.72 g, 16.2 mmol, 1.0 equiv) was carefully added. The resulting mixture stirred for 2 hours under a H2 atmosphere. The reaction mixture was filtered through a plug of celite, and the solids were washed with MeOH (4×50 mL). The filtrate was concentrated to afford desired (S)-2-amino-1-((3aS,4S,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ethanol (2-6) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 4.65 (s, 1H); 4.35 (s, 1H); 3.67 (s, 2H); 3.50 (s, 1H); 3.04 (t, J=7.3 Hz, 1H); 2.91 (d, J=27.3 Hz, 1H); 2.70 (d, J=11.1 Hz, 1H); 2.26-2.21 (m, 1H); 1.96 (d, J=14.6 Hz, 2H); 1.89 (d, J=20.3 Hz, 1H); 1.77 (s, 1H); 1.52-1.41 (m, 3H); 1.35-1.26 (m, 3H).
Reaction SMILES: [CH3:1][C:2](=[CH2:17])[CH2:3][Sn](CCCC)(CCCC)CCCC.Br[C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH2:21][CH2:22][C:23]2=[O:28].CN(C)C=O.[F-].[K+]>O.[Pd].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:3][C:2](=[CH2:1])[CH2:17][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH2:21][CH2:22][C:23]2=[O:28]
Reactant: C=C(C)C[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1CCc2c(Br)cccc21
Agent: [Pd]
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)Cc1cccc2c1CCC2=O
Reaction time: 0.08 h

Procedure:
9 g of (2-methyl-2-propenyl)-tributyl stannane, 5.25 g of 4-bromo indanone, 50 ml of dimethylformamide and 300 g of tetrakis phenyl phosphine palladium are heated to 125° C. under agitation for 45 minutes. After cooling, the mixture is poured into an iced solution of 7.5 g of potassium fluoride in 300 ml of water, agitated for 5 minutes and filtered on celite. The filtrate is extracted with isopropyl ether, dried and concentrated to dryness under reduced pressure. The residue is chromatographed on silica, eluting with a hexane-ethyl acetate mixture (8-2) and 4 g of expected product is recovered.
Reaction SMILES: [Br:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][CH:3]=1.[Li]CCCC.CCCCCC.[CH2:22]([CH:24]([C:27]1[C:28]2[N:29]([C:34](I)=[C:35]([CH3:37])[N:36]=2)[N:30]=[C:31]([CH3:33])[CH:32]=1)[CH2:25][CH3:26])[CH3:23]>C1COCC1.[Cl-].[Cl-].[Zn+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[Br:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[C:34]1[N:29]2[N:30]=[C:31]([CH3:33])[CH:32]=[C:27]([CH:24]([CH2:22][CH3:23])[CH2:25][CH3:26])[C:28]2=[N:36][C:35]=1[CH3:37]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: Brc1csc2cccnc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc4cccnc4c3Br)c(C)nc12
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 22.1 %

Procedure:
428 mg of 3-Bromo-thieno[3,2-b]pyridine (2.0 mmol) is dissolved in 2.0 ml of dry THF and cooled to −78° C. and 0.88 ml of n-BuLi 2.5M in hexane (2.2 mmol) is added slowly and the mixture is stirred at −78° C. for 15 min. 4.4 ml of ZnCl2 0.5M in THF (2.2 mmol) is added and stirred at room temperature for 20 min. 617 mg of 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (1.8 mmol) and 66 mg of PdCl2(dppf) (0.08 mmol) are added. The reaction vial is capped with a Teflon cap and heated at 80° C. overnight. Water and CH2Cl2 are added, and the separated CH2Cl2 layer is dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt=5:1) to produce the title compound 171 mg (22%), mass spectrum (m/e): 430; 1H-NMR (CDCl3): 8.84 (dd, 1H, J=4.5 Hz, 1.4 Hz), 8.20 (dd, 1H, J=8.4 Hz, 1.4 Hz), 7.37 (dd, 1H, J=8.4 Hz, 4.5 Hz), 6.75 (s, 1H), 3.34 (m, 1H), 2.56 (s, 3H), 2.51 (s, 3H), 1.85 (m, 4H), 0.89 (t, 6H, J=7.4 Hz) ppm.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH:30]=[CH:29][S:28][CH:27]=3)[CH:21]=2)[CH:13]=1)[CH2:9][CH3:10].C=O.[C:35]([BH3-])#N.[Na+]>C(#N)C>[CH3:32][C:2]([CH3:31])([CH3:1])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH:30]=[CH:29][S:28][CH:27]=3)[CH:21]=2)[CH3:35])[CH:13]=1)[CH2:9][CH3:10]
Reactant: [BH3-]C#N
Reactant: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(NCc2cccc(-c3ccsc3)c2)c1
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(N(C)Cc2cccc(-c3ccsc3)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
100 mg of the (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[3-(3-thienyl)benzylamino]benzylamine obtained in Example 175 was dissolved in 3 ml of acetonitrile. 0.1 ml of a 35% aqueous solution of formaldehyde and 22.7 mg of sodium cyanoborohydride were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was evaporated under reduced pressure. The residue was dissolved in a mixture of ethyl acetate and water. The organic layer was separated, and dried over anhydrous magnesium sulfate. The desiccant was separated by filtration, and the solvent was evaporated. The residue was purified by silica gel column chromatography [Wakogel C-200, 5 g; eluting solvent: hexane/ethyl acetate=10/1→6/1] to give 55 mg (yield 53%) of the captioned compound as a pale yellow crystalline solid, m.p. 51°-52° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[F-].[Cs+].Cl[C:17]1[CH:25]=[C:24]2[C:20]([C:21]([NH:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[N:22][N:23]2[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])=[CH:19][CH:18]=1>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]([NH:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[N:22][N:23]3[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:31])[CH3:32])=[CH:19][CH:18]=2)=[CH:5][CH:4]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)ccc12
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(C(F)(F)F)cc3)ccc12
Yield: 77 %

Procedure:
775 mg of 4-trifluoromethylphenylboronic acid, 1.24 g of caesium fluoride, 13.5 mg of palladium acetate and finally 31 mg of 2-dicyclohexylphosphine-2-(N,N-dimethylamino)biphenyl are added to 1 g of N-[6-chloro-1-[[2-(trimethylsilyl)-ethoxy]methyl]-1H-indazol-3-yl]butanamide, described in Example 25, in 30 cm3 of dioxane. The mixture is then refluxed for 18 hours, the temperature is then allowed to return to room temperature and the reaction medium is diluted with 75 cm3 of ethyl acetate, filtered through a sinter funnel packed with Celite and concentrated to dryness under reduced pressure (2 kPa; 50° C.). The work-up and the purification are performed by analogy with Example 41. 1 g of N-[6-[4-(trifluoromethyl)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide is thus obtained in the form of a yellow oil in a purity of 95%.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].[S:11](Cl)(=[O:14])(=[O:13])[NH2:12]>>[C:4]([C:3]1[C:6]([Cl:10])=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][S:11]([NH2:12])(=[O:14])=[O:13])#[N:5]
Reactant: N#Cc1c(N)cccc1Cl
Reactant: NS(=O)(=O)Cl
Product: N#Cc1c(Cl)cccc1NS(N)(=O)=O

Procedure:
Prepared as in Example 77a from 2-amino-6-chlorobenzonitrile and sulfamoyl chloride.