Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([O:25][CH2:26][CH2:27][N:12]4[CH:11]=2)[CH:15]=[C:16]([C:21]#[C:22][CH2:23]O)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1.[H][H]>[Pt].C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([O:25][CH2:26][CH2:27][N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][CH2:22][CH3:23])[CH:17]=3)=[O:9])=[CH:28][CH:29]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cn2c3c(cc(C#CCO)cc3c1=O)OCC2
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1cc2c3c(c1)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn3CCO2
Yield: 34 %

Procedure:
A mixture of 50 mg of N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide of Example 2 and 20 mg of 5% platinum on carbon in 2 mL of 1:1 THF-methanol is stirred vigorously under 1 atmosphere of hydrogen gas for 3 hours, then filtered through diatomaceous earth. The filtrate is concentrated under reduced pressure, and the residue chromatographed on silica using 2-3% methanol in dichloromethane. Following concentration under reduced pressure, the upper eluting fractions provide 16.5 mg of N-(4-chlorobenzyl)-7-oxo-9-propyl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide (3B); the lower eluting fractions similarly afford 27.5 mg of N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide (3A).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([OH:14])=O)([CH3:3])[CH3:2].S(Cl)([Cl:17])=O>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([Cl:17])=[O:14])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)c1ccccc1CCC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)c1ccccc1CCC(=O)Cl

Procedure:
A mixture of 3-(2-isopropylphenyl)propanoic acid (prepared in 3 steps from 1-isopropyl-2-iodobenzene, 2.01 g, 10.5 mmole), thionyl chloride (4.30 ml, 59.0 mmole) and toluene (40 ml) was refluxed for 2 hours. Concentration in vacuo gave 3-(2-isopropylphenyl)propanoyl chloride which was taken up in methylene chloride and used in the next step as a crude. Step 2:
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([CH3:13])[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:19]N(C=O)C.[H-].[Na+].CI>[Cl-].[Na+].O>[Br:1][C:2]1[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([CH3:13])[N:5]([CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1c(C)[nH]c(-c2ccccc2)c1Br
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCOC(=O)c1c(Br)c(-c2ccccc2)n(C)c1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 115 %

Procedure:
Ethyl 4-bromo-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate (3.31 g, 11.4 mmol) was dissolved into anhydrous DMF (50 mL). After stirring at 0° C. for 15 min, to this solution was added NaH (60%, 0.55 g, 13.7 mmol). The mixture was held at 0° C. for 10 min and then MeI (2.13 mL, 34.2 mmol) was added to the mixture. The reaction mixture was gradually warmed to RT and stirred overnight. The mixture was poured into brine (100 mL) and extracted with ethyl acetate (200 mL). The organic phase was dried over MgSO4 and evaporated under vacuum. The residue was further purified by flash column chromatography to provide the crude intermediate ethyl 4-bromo-1,2-dimethyl-5-phenyl-1H-pyrrole-3-carboxylate (4.23 g, 13.1 mmol, 115%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([C:9]1[C:10]([CH3:31])=[C:11]([S:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[C:12](=[O:22])[N:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:14]=1)(=[O:8])[CH3:7].O>N1C=CC=CC=1>[C:6]([C:9]1[C:10]([CH3:31])=[C:11]([S:23][C:24]2[CH:25]=[CH:26][C:27]([NH:30][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:28][CH:29]=2)[C:12](=[O:22])[N:13]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[N:14]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)c1nn(-c2ccc(F)cc2)c(=O)c(Sc2ccc(N)cc2)c1C
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)c1nn(-c2ccc(F)cc2)c(=O)c(Sc2ccc(NS(C)(=O)=O)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.1 ml) was added to a solution of 6-acetyl-4-(4-aminophenylthio)-2-(4-fluorophenyl)-5-methyl-3(2H)-pyridazinone (185 mg) in pyridine (2 ml) at 5° C., followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. After washing with a saturated aqueous sodium hydrogen carbonate solution and a brine, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1), and was crystallized from ether to obtain 6-acetyl-2-(4-fluorophenyl)-5-methyl-4-(4-methylsulfonylaminophenylthio)-3(2H)-pyridazinone (180 mg) (Compound No. 4-01).
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][C:7]1[C:15]([CH3:17])([CH3:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH+:8]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH:27][C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=O)=[CH:22][CH:21]=1>>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N+:8]3[C:9]4[C:14]([C:15]([CH3:17])([CH3:16])[C:7]=3[CH:6]=2)=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:22][CH:21]=1
Reactant: COc1ccc(C=CC(=O)c2ccccc2)cc1
Reactant: CC1=[NH+]c2ccccc2C1(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: COc1ccc(-c2cc(-c3ccccc3)[n+]3c(c2)C(C)(C)c2ccccc2-3)cc1

Procedure:
2,3,3-Trimethyl-3H-indolium perchlorate (5 g.) and 3-(4-methoxyphenyl)-1-phenyl-prop-2-ene-1-one (10 g.) were heated together on a steam bath for three hours. The cooled mixture was purified by recrystallization from acetonitrile. The melting point is 258°C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:13])([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[S-:14][C:15]#[N:16].[K+]>>[CH3:12][C:6]([CH3:13])([CH2:5][CH2:4][CH2:3][CH2:2][S:14][C:15]#[N:16])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: N#C[S-]
Reactant: CCOC(=O)C(C)(C)CCCCBr
Agent: [K+]
Product: CCOC(=O)C(C)(C)CCCCSC#N

Procedure:
Using ethyl 6-bromo-2,2-dimethylhexanate as obtained in Reference Example 7and potassium thiocyanate, the title compound was produced in the same manner as in Reference Example 11.
Reaction SMILES: [N+](C1C=CC(S([N:13]([C@H:20]2[CH2:24][CH2:23][N:22]([C:25]3[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=3)[CH2:21]2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=O)=O)=CC=1)([O-])=O.[OH-].[Li+].C(O)(=O)CS>CN(C=O)C>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C@H:20]1[CH2:24][CH2:23][N:22]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:27][CH:26]=2)[CH2:21]1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CC[C@H](N(c3ccccn3)S(=O)(=O)c3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=C(O)CS
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(N2CC[C@H](Nc3ccccn3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.2 %

Procedure:
To a solution of compound 12 (1.41 g, 2.68 mmol) in DMF (13 mL), were successively added lithium hydroxide (382 mg, 9.09 mmol) and thioglycolic acid (274 μL, 3.94 mmol). The mixture was stirred for 18 h at r.t., the solvent was removed in vacuo at 80° C. and the residue was partitioned between EtOAc and H2O. The organic layer was collected, washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography using EtOAc/Hexanes (40:60) as an eluent, to afford the title compound 13 (511 mg, 47% yield) as a light yellow oil. 1H NMR: (DMSO-d6) d(ppm): 7.98 (dd, J=5.5, 1.6 Hz, 1H), 7.68 (d, J=8.8 Hz, 2H), 7.35 (td, J=7.0, 2.0 Hz, 1H), 6.80 (d, J=6.3 Hz, 1H), 6.52 (d, J=9.0 Hz, 2H), 6.49-6.46 (m, 2H), 4.52-4.49 (m, 1H), 3.64 (dd, J=10.5, 6.5 Hz, 1H), 3.48-3.44 (m, 1H), 3.39-3.33 (m, 1H), 3.16 (dd, J=10.0, 4.5 Hz, 1H), 2.30-2.24 (m, 1H), 2.00-2.19 (m, 1H), 1.48 (s, 9H). LRMS (ESI): (calc.) 339.19 (found) 340.1 (MH)+
Reaction SMILES: Br[C:2]1[CH:29]=[CH:28][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:18]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=5[F:26])[N:17]=[C:16]([NH2:27])[N:15]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:30][C:31]([OH:48])([CH3:47])[CH2:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1>>[NH2:27][C:16]1[N:15]=[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:36]5[CH:35]=[N:34][N:33]([CH2:32][C:31]([CH3:47])([OH:48])[CH3:30])[CH:37]=5)[CH:29]=[CH:28][C:5]=4[C:6]=3[N:7]=2)[N:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[N:17]=1
Reactant: Nc1nc(-c2nc3c(s2)CCOc2cc(Br)ccc2-3)n(-c2ccc(F)cc2F)n1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4nc(N)nn4-c4ccc(F)cc4F)nc2-3)cn1

Procedure:
Similarly to as described in General Procedure C, 5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-1-(2,4-difluoro-phenyl)-1H-[1,2,4]triazol-3-ylamine was reacted with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol. Purification of the crude reaction mixture by reverse phase HPLC gave 366. LCMS: 536.1.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])[C:5]=12.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][CH2:30]O)[CH:23]=1.N1CCCCC1>C(O)C>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][CH:30]=[C:18]2[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6]3[C:5]4[N:4]([CH:3]=[CH:2][N:1]=4)[CH:9]=[CH:8][CH:7]=3)[C:19]2=[O:20])[CH:23]=1
Reactant: O=C1CSC(=O)N1CCCCOc1cccn2ccnc12
Reactant: OCCCc1cccnc1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1SC(=CCCc2cccnc2)C(=O)N1CCCCOc1cccn2ccnc12

Procedure:
To a solution of 1.53 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-8-yloxy)butyl]thiazolidine-2,4-dione and 676 mg (5.0 mmol) of 3-(3-pyridyl)-1-propanol in 20 ml of ethanol, 43 mg (0.5 mmol) of piperidine was added, followed by refluxing for 3.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with purified water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform/methanol=50/1→25/1) to yield 0.49 g (23.0%, yellow oily substance) of the desired product.
Reaction SMILES: [CH2:1]([N:3]([CH2:45][CH3:46])[CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([NH:15][C:16](=[O:36])[CH2:17][N:18]([CH2:26][CH2:27][O:28]CC3C=CC=CC=3)CC3C=CC=CC=3)=[C:10]3[O:37][C:38]4[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][C:39]=4[C:8]([C:9]=23)=[N:7]1)[CH3:2].[H][H].[ClH:49].O>C(O)(=O)C.[OH-].[OH-].[Pd+2]>[ClH:49].[CH2:45]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([NH:15][C:16](=[O:36])[CH2:17][NH:18][CH2:26][CH2:27][OH:28])=[C:10]3[O:37][C:38]4[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][C:39]=4[C:8]([C:9]=23)=[N:7]1)[CH3:46]
Reactant: CCN(CC)CCn1nc2c3c(c(NC(=O)CN(CCOCc4ccccc4)Cc4ccccc4)ccc31)Oc1ccc(O)cc1-2
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCN(CC)CCn1nc2c3c(c(NC(=O)CNCCO)ccc31)Oc1ccc(O)cc1-2

Procedure:
A mixture of 1.3 g of the above acetamide and 0.10 g of 20% palladium hydroxide on carbon in 50 ml of glacial acetic acid stirred under hydrogen at atmospheric pressure until the hydrogen uptake measured 100 ml. The reaction mixture was filtered and coevaporated several times with methanol. The residue was dissolved in methanol and acidified with a solution of hydrogen chloride in 2-propanol. Further dilution with 2-propanol and cooling caused precipitation of a crystalline solid. The solid was isolated and dried to give 0.976 g of the product as a yellow crystalline solid with 2.5 equivalents of hydrogen chloride and 1.5 equivalents of water, mp 285° C. with decomposition.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[H-].[Na+].[CH2:8]=[C:9]1[O:13][C:11](=[O:12])[CH2:10]1.Cl>O1CCCC1>[NH2:4][C:3]1[O:13][C:9]([CH3:8])=[CH:10][C:11](=[O:12])[C:2]=1[C:1]#[N:5]
Reactant: C=C1CC(=O)O1
Reactant: N#CCC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(=O)c(C#N)c(N)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of malononitrile (3.3 g, 50 mmol) in anhydrous tetrahydrofuran (100 mL) was added sodium hydride (60%, 2.2 g, 55 mmol) at −10° C. The resulting reaction mixture was stirred for 2 hours. Then diketene (4.2 g, 50 mmol) was added dropwise to the solution. The reaction mixture was allowed to warmed to room temperature and continued to stir for 30 minutes. The mixture was neutralized with hydrochloric acid, and then concentrated in vacuo to give crude product as red solid, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[I:12]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[C:10]([I:12])=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: Clc1nc(Cl)c2c(I)c[nH]c2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 55.7 %

Procedure:
To a suspension of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (3.00 g, 16.0 mmol) in CH2Cl2 (30 mL), N-iodosuccinimide (3.60 g, 16.0 mmol) was added. It was stirred at room temperature for 20 h. The fine precipitate was collected, dried on vacuum to give 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (2.80 g). MS 314.1 and 316.1 (M+H)
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:10][OH:11])([CH2:7][CH:8]=[CH2:9])[C:4]([OH:6])=[O:5].[C:12]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[OH:1][CH2:2][C:3]([CH2:10][OH:11])([CH2:7][CH:8]=[CH2:9])[C:4]([O:6][CH3:12])=[O:5]
Reactant: C=CCC(CO)(CO)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: C=CCC(CO)(CO)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
A mixture of crude 2,2-bis(hydroxymethyl)pent-4-enoic acid (1 eq., 8.72 g), K2CO3 (3 eq., 22.9 g) and acetone (109 ml) was stirred at room temperature for 30 min. MeI (6 eq., 46.4 g) was added at 0° C. The mixture was stirred at room temperature for 2 days and concentrated. Water and EtOAc were added. The aqueous layer was extracted with 3×EtOAc. The organic layers were dried over MgSO4. Silica gel chromatography using 4-40% ACN (containing 5% MeOH)-DCM yields the title compound as colorless oil (2.2 g, 23% for two steps).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH2:25][CH3:26])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:30][C@H:31]([OH:34])[CH2:32][OH:33]>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:30][C@H:31]([OH:34])[CH2:32][OH:33])=[C:19]([CH2:25][CH3:26])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OC[C@@H](O)CCl
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OC[C@H](O)CO
Temperature: 60 °C
Reaction time: 15 h
Yield: 99.4 %

Procedure:
A mixture of 4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (250 mg, 659 μmol), (R)-3-chloro-1,2-propanediol (609 mg, 6.59 mmol) in isopropanol (8 mL) and 3 M aq. NaOH (2 mL) is stirred at 60° C. for 15 h. The mixture is diluted with EA and washed with brine, 1 M aq. NaOH and again with brine. The org. extract is dried over Na2SO4, filtered and concentrated. The crude product is purified on prep. TLC plates using DCM containing 10% of methanol to give the title compound (297 mg) as a pale yellow oil; LC-MS**: tR=0.87 min, [M+H]+=454.26.
Reaction SMILES: [C:1]([O:9][C@H:10]([CH2:15][C:16]1[C:17]([CH2:26]O)=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[NH:21][N:20]=[CH:19]2)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:28]CCl.C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=O>>[C:1]([O:9][C@H:10]([CH2:15][C:16]1[C:17]([CH2:26][Cl:28])=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[NH:21][N:20]=[CH:19]2)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: COC(=O)[C@@H](Cc1cc(Cl)c2[nH]ncc2c1CO)OC(=O)c1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](Cc1cc(Cl)c2[nH]ncc2c1CCl)OC(=O)c1ccccc1
Reaction time: 2 h

Procedure:
(R)-3-(7-chloro-4-(hydroxymethyl)-1H-indazol-5-yl)-1-methoxy-1-oxopropan-2-yl benzoate (6.5 g, 16.72 mmol) in dichloromethane (100.0 ml, 1554 mmol) was added Diisopropylethyl amine (2.59 g, 20.06 mmol) followed by methanesulfonyl chloride (1.433 ml, 18.39 mmol). After 2 h, the reaction mixture was quenched with aqueous NaHCO3, dried (Na2SO4) and the solvent was removed. MS (ESI) 407 (M+H); Rf=1.69.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([N:14]=CN(C)C)[C:11]([C:19]#[N:20])=[N:10][C:9]=1[C:21]1[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH:28]([CH3:30])[CH3:29])[N:22]=1.[OH-].[Na+]>O.Cl.O1CCOCC1>[NH2:14][C:12]1[C:11]([C:19]#[N:20])=[N:10][C:9]([C:21]2[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH:28]([CH3:30])[CH3:29])[N:22]=2)=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[N:13]=1
Reactant: CC(C)n1nc(-c2nc(C#N)c(N=CN(C)C)nc2-c2ccccc2Br)ccc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1nc(-c2nc(C#N)c(N)nc2-c2ccccc2Br)ccc1=O
Temperature: 22.5 °C
Reaction time: 18 h
Yield: 64.9 %

Procedure:
A solution of N′-[6-(2-bromophenyl)-3-cyano-5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinyl]-N,N-dimethylimidoformamide (285 mg) in a mixture of water (2 ml) and 4N hydrogen chloride in dioxane (6 ml) was stirred at 20-25° C. for 18 hours. After addition of water (18 ml), the mixture was neutralized with 1N aq. NaOH to give a solid. The solid was collected by filtration and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (50:50 v/v) to give 3-amino-5-(2-bromophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinecarbonitrile as a solid (163 mg).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:10](=[O:12])[CH:9]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][N:14]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:3]=1.[H-].[Na+].[CH2:31](Br)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].O>CN(C=O)C>[CH2:31]([O:19][C:16]1[CH:17]=[CH:18][C:13]([CH:9]2[C:10](=[O:12])[C:11]3[C:2]([F:1])=[N:3][C:4]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:5][C:6]=3[CH2:7][CH2:8]2)=[N:14][CH:15]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCOc1cc2c(c(F)n1)C(=O)C(c1ccc(O)cn1)CC2
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCOc1ccc(C2CCc3cc(OCCCCCCCC)nc(F)c3C2=O)nc1
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
10 mmol of 1-fluoro-7-(5-hydroxypyridin-2-yl)-3-octyloxy-6,7-dihydro-5H-isoquinolin-8-one are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1-octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo and the residue is chromatographed on silica gel, giving 7.55 mmol of 7-[5-(octyloxy)pyridin-2-yl]-1-fluoro-3-octyloxy-6,7-dihydro-5H-isoquinolin-8-one.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[C:21]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:23])[CH3:22]>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([C:21](=[O:23])[CH3:22])[CH:29]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: CC(=O)c1cccc(B(O)O)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3cccc(C(C)=O)c3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 3-acetyl-phenylboronic acid (53 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound. Yield: 11 mg, 10%; LC/MS tr 1.46 min; MS(ES+) m/z 378 (M+H)
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11]([CH3:13])([OH:12])[CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18](=[O:21])[NH:17][N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:22]#[N:23])[CH:8]=2)[O:3]1.[C:25]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:1][C:2]1([CH3:24])[C:11]([CH3:13])([OH:12])[CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH3:25])[N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:22]#[N:23])[CH:8]=2)[O:3]1
Reactant: CC1(C)Oc2ccc(C#N)cc2C(Oc2ccc(=O)[nH]n2)C1(C)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: Cn1nc(OC2c3cc(C#N)ccc3OC(C)(C)C2(C)O)ccc1=O

Procedure:
A mixture of 327 mg of 2,2,3-trimethyl-4-(1,6-dihydro-6-oxo-3-pyridazinyl-oxy)-6-cyano-chroman-3-ol, 20 ml of acetone, 400 mg of K2CO3 and 0.2 ml of dimethyl sulfate is refluxed for 2 hours. The mixture is filtered, concentrated and chromatographed on silica gel. There is obtained with ethyl acetate/methanol (9:1) 2,2,3-trimethyl-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl-oxy)-6-cyano-chroman-3-ol, m.p. 197°-199°.
Reaction SMILES: [CH:1]1([S:4]([N:7]2[CH2:11][C@@H:10]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=4[CH3:27])[CH2:16][CH2:15]3)=[O:13])[NH:9][C:8]2=[O:28])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:9]1[C@H:10]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=3[CH3:27])[CH2:16][CH2:15]2)=[O:13])[CH2:11][N:7]([S:4]([CH:1]2[CH2:3][CH2:2]2)(=[O:5])=[O:6])[C:8]1=[O:28])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(S(=O)(=O)C4CC4)C(=O)N3)CC2)c1
Reactant: BrCc1ccccc1
Product: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(S(=O)(=O)C4CC4)C(=O)N3Cc3ccccc3)CC2)c1

Procedure:
In analogy to example 66, step 4, from (S)-1-cyclopropanesulfonyl-4-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-imidazolidin-2-one and benzyl bromide was prepared