Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]=[C:6]1[CH2:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:9]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:8]=2[NH:7]1)[CH3:2].[N:26]([O-])=[O:27].[Na+]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:25])[C:5](=[N:26][OH:27])[C:6]1[CH2:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:9]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:8]=2[N:7]=1)[CH3:2]
Reactant: CCOC(=O)C=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C(=NO)C1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1
Reaction time: 0.08 h

Procedure:
The crude 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylideneacetic acid ethyl ester obtained by reduction of 10 g. of the end produce of Example 15 as described above was dissolved in 40 ml. of glacial acetic acid. Sodium nitrite, 2.45 g., was added with stirring over a period of 5 minutes. Following the addition the mixture was stirred at room temperature for 15 minutes. The product started to crystallize and was further precipitated by addition of 50 ml. of water. The crystals were collected, washed with water, ethanol and ether to yield the end product. The analytical sample was recrystallized from tetrahydrofuran/ethanol to give pale yellow crystals with mp 230°-233°.
Reaction SMILES: NC1C2C[C:9](C)(C)[O:10]C=2C(C(OC)=O)=CC=1.N[C:18]1[C:23]2[CH2:24][C:25]([CH3:28])([CH3:27])[O:26][C:22]=2[C:21]([C:29]([OH:31])=[O:30])=[CH:20][C:19]=1[Cl:32]>>[Cl:32][C:19]1[CH:20]=[C:21]([C:29]([OH:31])=[O:30])[C:22]2[O:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]=2[C:18]=1[O:10][CH3:9]
Reactant: COC(=O)c1ccc(N)c2c1OC(C)(C)C2
Reactant: CC1(C)Cc2c(N)c(Cl)cc(C(=O)O)c2O1
Product: COc1c(Cl)cc(C(=O)O)c2c1CC(C)(C)O2

Procedure:
Following the same procedure, 19.9 g of methyl 4-amino-2,2-dimethyl-2,3-dihydro-7-benzofurancarboxylate was transformed into 20.1 g of 4-amino-5-chloro-2, 2-dimethyl-2,3-dihydro-7-benzofurancarboxylic acid, m.p. 176°-178° C.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[C:7]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:6](=[O:28])[NH:5]1)([CH3:3])[CH3:2].CC([O:32][CH2:33][C@H:34]1[O:39][C@H:38](Br)[C@H:37]([O:41]C(C)=O)[C@@H:36]([O:45]C(C)=O)[C@@H:35]1[O:49]C(C)=O)=O.[OH-].[Na+]>ClCCl>[C@@H:38]1([O:28][C:6]2[C:7]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=3[O:26][CH3:27])=[C:8]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=2)[O:39][C@H:34]([CH2:33][OH:32])[C@@H:35]([OH:49])[C@H:36]([OH:45])[C@H:37]1[OH:41]
Reactant: COc1ccc(-c2c(Cc3ccc(OC)cc3OC)c(=O)[nH]n2C(C)C)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(-c2c(Cc3ccc(OC)cc3OC)c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn2C(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.7 %

Procedure:
To a suspension of 1-isopropyl-5-(4-methoxypheny)-4-[(2,4-dimethoxyphenyl)methyl]-1,2-dihydro-3H-pyrazole-3-one (0.090 g), acetobromo-α-D-glucose (0.48 g) and benzyl-(n-tributyl)ammonium chloride (0.037 g) in dichloromethane (2 mL) was added sodium hydroxide (5 mol/L, 0.47 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by column chromatography on aminopropylated silica gel (eluent:tetrahydrofuran). The obtained semi purified 1-isopropyl-5-(4-methoxyphenyl)-4-[(2,4-dimethylphenyl)-methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole was dissolved in methanol (5 mL), and sodium methoxide (28% methanol solution, 0.45 mL) was added to the solution. The mixture was stirred at room temperature overnight. The solvent of the reaction mixture was removed, and methanol (0.5 mL) and 10% citric acid aqueous solution (5 mL) were added to the residue. The mixture was purified by solid phase extraction on ODS (washing solvent:water, eluent:methanol). Further purification by preparative reverse phase column chromatography (Shiseido CAPSELLPAC C18 UG80, 5μM, 20×50 mm, flow rate 30 mL/min linear gradient, water/methanol=90/10-10/90) gave the title compound (0.065 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:15][C:16]1[S:17][C:18]([CH2:21][OH:22])=[N:19][N:20]=1.Cl>N1C=CC=CC=1>[OH:22][CH2:21][C:18]1[S:17][C:16]([NH:15][S:11]([C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)(=[O:13])=[O:12])=[N:20][N:19]=1
Reactant: Nc1nnc(CO)s1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(CO)s2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 82 %

Procedure:
To a solution of p-acetamidobenzenesulfonyl chloride (510 mg, 2.18 mmol) in pyridine (6 mL) was added 2-amino-5-hydroxymethyl-1,3,4-thiadiazole (260 mg, 1.98 mmol). The reaction mixture was stirred at room temperature for 4.5 h, then 2 M HCl (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (4×50 mL). The organic extracts were washed with water (40 mL), brine (40 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel (70-230 mesh) eluted with CH2Cl2:methanol 9:1 to give the product as a solid, mp 101-102° C., in 82% yield (533 mg, 1.62 mmol); 1H NMR (300 MHz, DMSO-d6) δ 2.07 (s, 3H), 4.56 (d, 2H, J=5.1 Hz), 6.09 (t, 1H, J=4.8 Hz), 7.73 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 24.8, 59.1, 119.3, 127.7, 136.2, 143.5, 161.7, 168.1, 169.6; MS (LCQ, ESI+) Calcd for C11H13N4O4S2 329.0, found 329.1 (M+H)+; HRMS (ESI+, m/z) Calcd for C11H13N4O4S2 329.0378, found 329.0376 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[CH2:5][CH:6]([OH:9])[CH2:7][CH:8]=1)[CH2:2][CH3:3].CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(Cl)=O.C(C1CC(O)CC=1C)C.[Cl:31]/[C:32](/[C:42]([F:45])([F:44])[F:43])=[CH:33]\[C@@H:34]1[C@H:36]([C:37](Cl)=[O:38])[C:35]1([CH3:41])[CH3:40]>>[Cl:31]/[C:32](/[C:42]([F:43])([F:44])[F:45])=[CH:33]\[C@@H:34]1[C@H:36]([C:37]([O:9][CH:6]2[CH2:7][CH:8]=[C:4]([CH2:1][CH2:2][CH3:3])[CH2:5]2)=[O:38])[C:35]1([CH3:41])[CH3:40]
Reactant: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Reactant: CCCC1=CCC(O)C1
Agent: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Agent: CCC1=C(C)CC(O)C1
Product: CCCC1=CCC(OC(=O)[C@H]2[C@@H](/C=C(\Cl)C(F)(F)F)C2(C)C)C1
Yield: 91 %

Procedure:
(RS)-3-propyl-3-cyclopenten-1-ol (500 mg) and (1RS)-cis-2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropanecarbonyl chloride (902 mg) were respectively used instead of (RS)-3-ethyl-4-methyl-3-cyclopenten-1-ol and (1RS)-cis-3-(Z-2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride used in Example 1 above and the reaction procedures were carried out in the same manner as in Example 1 to afford 1150 mg of (RS)-3-propyl-3-cyclopentenyl (1RS)-cis-3-(Z-2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate (Compound No. 130). Yield 91% nD24 1.5038
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:10]=[C:11]([S:14](O)(=[O:16])=[O:15])[S:12][CH:13]=2)=[O:8])=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[NH4+:24].[OH-]>C(Cl)Cl.CC(C)=O>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:10]=[C:11]([S:14]([NH2:24])(=[O:16])=[O:15])[S:12][CH:13]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: [NH4+]
Reactant: COc1ccc(C(=O)c2csc(S(=O)(=O)O)c2)cc1
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CC(C)=O
Product: COc1ccc(C(=O)c2csc(S(N)(=O)=O)c2)cc1

Procedure:
To 2.98 g (0.01 mol) of product from Step B suspended in 75 ml CH2Cl2 was added excess thionyl chloride and the resulting suspension was stirred, and heated at reflux for 1.5 hours to give a homogeneous solution. The thionyl chloride was evaporated and the residue was extracted with CHCl3 after ice had been added. The organic extract was washed with brine, dried and the solvent evaporated to give a yellow oil. This was taken up in acetone and treated with 5 ml of concentrated NH4OH dropwise. After stirring for 15 minutes, this was extracted with chloroform and the extract was dried. Filtration and evaporation of the solvent gave the desired product as a yellow solid, m.p. 173°-175° C.
Reaction SMILES: [N:1]1([CH2:5][C:6]2[N:10]([CH3:11])[N:9]=[C:8]([NH2:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.Br[C:14]1[C:15](=[O:22])[N:16]([CH3:21])[N:17]=[C:18]([Cl:20])[CH:19]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.ClCCl.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:1]1([CH2:5][C:6]2[N:10]([CH3:11])[N:9]=[C:8]([NH:12][C:14]3[C:15](=[O:22])[N:16]([CH3:21])[N:17]=[C:18]([Cl:20])[CH:19]=3)[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Reactant: Cn1nc(N)cc1CN1CCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: Cn1nc(Nc2cc(Cl)nn(C)c2=O)cc1CN1CCC1
Temperature: 90 °C
Yield: 50.1 %

Procedure:
A solution of 5-(azetidin-1-ylmethyl)-1-methyl-1H-pyrazol-3-amine (292 mg, 1.76 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (393 mg, 1.76 mmol) cesium carbonate (2.00 g, 6.15 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethlxanthene (152 mg, 0.26 mmol) in dioxane (10 ml) was flushed with argon before tris(dibenzylideneacetone)dipalladium(0) (121 mg, 0.13 mmol) was added and the resulting solution was heated at 90° C. for 18 h. The mixture was cooled to room temperature and diluted with dichloromethane (50 mL) and water. The layers were separated and the aqueous layer was extracted with dichloromethane (2×25 mL).The organic layers were combined, dried over magnesium sulfate. The resulting mixture was filtered and concentrated in vacuo. The precipitate formed was isolated by filtration, washed with ether and dried under vacuum to give 4-(5-(azetidin-1-ylmethyl)-1-methyl-1H-pyrazol-3-ylamino)-6-chloro-2-methylpyridazin-3(2H)-one (272 mg, 50%) as a light yellow solid. (M+H)+=309 m/e.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[N:5]=[C:4]([N:16]2[CH2:20][CH2:19][CH2:18][CH:17]2[CH3:21])[N:3]=1.[CH3:22][C:23]1[C:24]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[N:25][CH:26]=[C:27]([N+:29]([O-])=O)[CH:28]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]([N:16]3[CH2:20][CH2:19][CH2:18][CH:17]3[CH3:21])[N:3]=[C:2]([N:35]3[CH2:36][CH2:37][N:32]([C:24]4[N:25]=[CH:26][C:27]([NH2:29])=[CH:28][C:23]=4[CH3:22])[CH2:33][CH2:34]3)[CH:7]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: CC1CCCN1c1nc(Cl)cc(-c2ccc(F)c(Cl)c2)n1
Reactant: Cc1cc([N+](=O)[O-])cnc1N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1cc(N)cnc1N1CCN(c2cc(-c3ccc(F)c(Cl)c3)nc(N3CCCC3C)n2)CC1
Temperature: 25 °C

Procedure:
Heat a mixture of 4-chloro-6-(3-chloro-4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidine (210 mg), 1-(3-Methyl-5-nitro-pyridin-2-yl)-piperazine, and DIEA (185 mg, 1.44 mmol) in DMA at 120° C. for 16 h. Cool to room temperature and partition between EtOAc and 1N NaOH. Wash with water, dry the solution (Na2SO4), and concentrate under reduced pressure. Purify the residue by flash column eluting with EtOAc to afford the title compound as a light-yellow solid. 1H NMR (400 MHz, CDCl3): δ 1.30 (t, 3H, J=6.4 Hz, CH3); 1.69 (m, 1H, CH2CH2); 1.91 (m, 1H, CH2CH2); 2.06 (m, 2H, CH2CH2); 2.28 (s, 3H, Ar—CH3); 3.10 (m, 4H); 3.47 (br, 2H, NH2); 3.68 (m, 4H); 3.77 (m, 4H); 4.34 (m, 1H); 6.25 (s, 1H, Ar—H); 6.88 (d, J=2.0 Hz, 1H); 7.18 (m, 1H); 7.70 (d, 1H, J=3.2 Hz); 7.89 (m, 1H); 8.07 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([F:11])[C:5]=1[F:12].Cl.[CH3:15][NH:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([N:16]([CH3:17])[CH3:15])=[C:6]([F:11])[C:5]=1[F:12]
Reactant: COC(=O)c1ccc(F)c(F)c1F
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N(C)C)c(F)c1F
Temperature: 55 °C
Reaction time: 5 h
Yield: 69 %

Procedure:
To a stirred solution of 4.28 g (22.5 mmol) 2.3.4-Trifluoro-benzoic acid methyl ester (Apollo) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 5 h at 55° C. in an autoclave and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 5a was obtained in 69% yield (3.34 g, 15.5 mmol).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][C:14]1[CH:15]=[C:16]([O:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH3:34])(=[O:33])=[O:32])(=[O:24])=[O:23])[CH:17]=[C:18]([OH:20])[CH:19]=1.[CH2:35](O)[CH2:36][CH2:37][OH:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCCCCC>[CH3:13][C:14]1[CH:15]=[C:16]([O:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH3:34])(=[O:33])=[O:32])(=[O:24])=[O:23])[CH:17]=[C:18]([CH:19]=1)[O:20][CH2:35][CH2:36][CH2:37][OH:38]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Reactant: OCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Diethyl azodicarboxylate (0.46 mL, 2.9 mmol) was added slowly to a solution of 1.0 g (2.9 mmol) of 5-methyl-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenol, as prepared in the preceding step, 0.21 mL (2.9 mmol) of 1,3-propanediol, and 760 mg (2.9 mmol) of triphenylphosphine in anhydrous tetrahydrofuran (25 mL). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was evaporated to dryness. The residue was triturated with hexane under sonification, and the solvent was decanted (4 times). The residue was dissolved in dichloromethane and diluted with hexane to produce a crystalline material which was discarded. The filtrate was diluted with hexane to give an oil, and the solvent was decanted. The oil was dissolved in a minimum of methanol and diluted with water to initiate crystallization. The solid was collected by filtration to afford the title compound (1.16 g, quantitative yield). 1H-NMR (300 MHz, CDCl3) δ 8.45 (dd, 1H, J=1.3, 7.8 Hz), 8.12 (dd, 1H, J=1.2, 7.8 Hz), 7.88 (td, 1H, J=1.3, 7.7 Hz), 7.74 (td, 1H, J=1.3, 7.7 Hz), 6.61-6.56 (m, 3H), 4.00 (t, 2H, J=6 Hz), 3.81 (t, 3H, J=5.9 Hz), 3.45 (s, 3H), 2.24 (s, 3H), and 1.97 (pentet, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C17H20O7S2 : 423.1 (M+Na). Found: 423.1.
Reaction SMILES: [C:1]([NH:22][C@@H:23]([CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=1)[C:24]([O:26]C)=[O:25])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20].[OH-].[Na+].Cl>C1COCC1>[C:1]([NH:22][C@@H:23]([CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=1)[C:24]([OH:26])=[O:25])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)N[C@@H](CCCCNC(=O)c1cccnc1)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)N[C@@H](CCCCNC(=O)c1cccnc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.7 %

Procedure:
(S)-methyl 2-((5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenamido)-6-(nicotinamido)hexanoate (140 mg, 0.225 mmol) was taken up in 2 mL of THF along with an aqueous solution of NaOH (35 mg in 2 mL of H2O). The resulting reaction mixture was stirred at room temperature for 2 h. It was then acidified to pH 4 with 2 N HCl and then extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford 31 mg of (S)-2-((5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenamido)-6-(nicotinamido)hexanoic acid. MS calculated for C34H47N3O4: 561.36. Found: [M+H]+ 562. MS calculated for C32H45N3O4: 535.34. Found: [M+H]+ 536.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][CH:7]=1)=[O:5])C.[ClH:13]>[OH-].[Na+].C(O)C>[Cl:13][C:7]1[S:8][C:9]([CH2:11][CH3:12])=[CH:10][C:6]=1[C:4]([OH:3])=[O:5]
Reactant: Cl
Reactant: CCOC(=O)c1csc(CC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(C(=O)O)c(Cl)s1
Temperature: 140 °C

Procedure:
5-Ethyl-thiophene-3-carboxylic acid ethyl ester (0.83 g, 3.8 mmol) was dissolved in a solution of aqueous sodium hydroxide (1 M, 6 mL) and ethanol (4 mL). The mixture was then heated to 140° C. for 10 minutes using microwave irradiation. The reaction mixture was acidified with 1 N hydrochloric acid and the resulting precipitate was isolated by filtration, washed with water and then dried under vacuum to give the title compound (0.53 g). 1H NMR (400 MHz, DMSO-d6): δ 7.05 (s, 1H), 2.75 (q, 2H), 1.4 (t, 3H), 1.2 (t, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([S:29]([CH3:31])=[O:30])[CH:4]=1)#[N:2].[C:32](C1C=CC([C@@H]2C(C#N)=C(C)N(C3C=CC=C(C(F)(F)F)C=3)C(=O)N2)=C([S@](C)=O)C=1)#N.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].IC>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[CH3:32])=[C:5]([S@:29]([CH3:31])=[O:30])[CH:4]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2[S@](C)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2[S@](C)=O)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 88 %

Procedure:
The reaction was carried out under argon. The diastereomer mixture of (RS,4S)-4-[4-cyano-2-(methylsulfinyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile and (SS,4S)-4-[4-cyano-2-(methylsulfinyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (535 mg, 1.2 mmol) was initially charged in absolute THF (12 ml), and a 1 M solution of lithium hexamethyldisilazide (LiHMDS) in THF (1.45 ml; 1.2 eq.) was added at −78° C. After 20 min of stirring at −78° C., iodomethane (854 mg; 5 eq.) was added and the mixture was stirred for 16 h with gradual warming from −78° C. to RT. The reaction mixture was then concentrated under reduced pressure, saturated ammonium chloride solution (50 ml) was added and the mixture was then extracted with ethyl acetate (3×30 ml). The combined organic phases were dried over solid sodium sulfate, filtered and concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compound as a solid (488 mg, 88% of theory).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:4]=2[S:5][C:6]=1[C:7]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:8].[CH3:23][Al](C)C.C(O)C.Cl>COCCOC.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:4]2[S:5][C:6]([C:7]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[O:8])=[C:2]([CH3:23])[C:3]=2[CH:18]=1
Reactant: C[Al](C)C
Reactant: COc1cc2sc(C(=O)N3CCOCC3)c(Cl)c2cc1OC
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: COc1cc2sc(C(=O)N3CCOCC3)c(C)c2cc1OC

Procedure:
(3-Chloro-5,6-dimethoxybenzo[b]thiophen-2-yl)morpholin-4-yl-methanone (3.0 g) from Example 8, trimethylaluminum (3.2 g) and [1,3-bis(diphenylphosphino)propane]dichloronickel (II) (1.2 g) in 1,2-dimethoxyethane (100 ml) were refluxed under argon for 10 hours. To the cold mixture ethanol (50 ml), water and HCl were added respectively and the mixture was extracted with ethyl acetate. Ethyl acetate was dried and evaporated to dryness. The crude product was purified by flash chromatography eluting with heptane-ethyl acetate (5:5).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[N:24]([S:27]([C:30]5[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=5)(=[O:29])=[O:28])[CH:25]=[CH:26][C:19]=34)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.Cl.[CH2:38]1[C:43]2([CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:42][CH2:41][CH2:40][N:39]1[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50].C(N(C(C)C)CC)(C)C>C(O)CCCC>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([N:46]4[CH2:45][CH2:44][C:43]5([CH2:38][N:39]([C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[CH2:40][CH2:41][CH2:42]5)[CH2:48][CH2:47]4)=[N:7][N:6]3[C:8]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[N:24]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[CH:25]=[CH:26][C:19]=23)=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(-c5ccc(F)cc5)nc5ccc(Cl)nn45)ccnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC2(CCNCC2)C1
Agent: Cl
Solvent: CCCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(-c5ccc(F)cc5)nc5ccc(N6CCC7(CCCN(C(=O)OC(C)(C)C)C7)CC6)nn45)ccnc32)cc1
Temperature: 140 °C
Yield: 0.1 %

Procedure:
A mixture of 0.15 g (0.29 mmol) of 6-chloro-2-(4-fluorophenyl)-3-[1-(4-methylphenylsulphonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]imidazo[1,2-b]pyridazine, prepared according to the method described in step 3.2 of Example 3, 0.337 g (1.15 mmol) of tert-butyl 2,9-diazaspiro[5.5]undecane-2-carboxylate hydrochloride (1:1) (CAS 1023301-88-3) and 0.224 g (1.7 mmol) of diisopropylethylamine in 2 ml of pentanol is heated under reflux for 40 hours at 140° C. The solvent is then evaporated under reduced pressure and the residue is purified by chromatography on a silica gel column by eluting with a gradient of dichloromethane, methanol and aqueous ammonia (of 100/0/0 to 90/10/1) in order to give 0.190 mg of tert-butyl 9-{2-(4-fluorophenyl)-3-[1-(4-methylphenylsulphonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]imidazo[1,2-b]pyridazin-6-yl}-2,9-diazaspiro[5.5]undecane-2-carboxylate after crystallization in methanol.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9]Cl)[C:5]([CH:11]=[CH2:12])=[CH:4][N:3]=1.[C:13](=[S:16])([S-:15])[S-:14].[Na+:17].[Na+]>O.CO>[C:13](=[S:14])([S-:16])[S:15][CH2:9][C:6]1[C:5]([CH:11]=[CH2:12])=[CH:4][N:3]=[C:2]([CH3:1])[C:7]=1[OH:8].[Na+:17]
Reactant: C=Cc1cnc(C)c(O)c1CCl
Reactant: S=C([S-])[S-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=Cc1cnc(C)c(O)c1CSC(=S)[S-]
Temperature: 50 °C
Reaction time: 4 h

Procedure:
2-Methyl-3-hydroxy-4-chloromethyl-5-vinylpyridine (20 g.) is suspended in water/methanol (100:25 v/v) and treated with disodium trithiocarbonate (33%) (45 g.). The mixture is stirred at b 50° C. for 4 hours under nitrogen and adjusted to pH 6.2-6.5 with dilute acid. The precipitate is recrystallized from DMF/water to give sodium (2-methyl-3-hydroxy-5-vinyl-4-pyridinyl)methyl trithiocarbonate.