Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[CH3:2].[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>>[CH2:1]([O:3][C:4]([CH:5]1[CH2:6][CH2:7][N:8]([C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([F:12])=[CH:14][CH:15]=2)[CH2:9][CH2:10]1)=[O:11])[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CCOC(=O)C1CCN(C(=O)c2ccc(F)cc2)CC1

Procedure:
The method described in Referential Example 492 was performed by use of isonipecotic acid ethyl ester and p-fluorobenzoyl chloride, whereby the title compound was obtained.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O.Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([N+:25]([O-:27])=[O:26])[CH:19]=1)=[O:17]>CO>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]([C:15]2[O:3][C:4]3[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:5]=3[CH:6]=2)=[O:17])=[CH:19][C:20]=1[N+:25]([O-:27])=[O:26]
Reactant: COc1cccc(C=O)c1O
Reactant: O=C(CBr)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc2cc(C(=O)c3ccc(Cl)c([N+](=O)[O-])c3)oc12
Reaction time: 8 h

Procedure:
2 g KOH are dissolved in 50 ml methanol, a solution of 5.4 g 2-hydroxy-3-methoxybenzaldehyde is added and subsequently a suspension of 10 g 2-bromo-4'-chloro-3'-nitroacetophenone in 75 ml methanol. The batch is refluxed for 6 hours, agitation is continued overnight at room temperature, and the crystals are suction-filtered. M.p. 136° C. (from ethyl acetate).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.CC(C)([O-])C.[Na+]>>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:3][CH:4]=1)#[N:9]
Reactant: C1COCCN1
Reactant: N#Cc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: N#Cc1ccc(N2CCOCC2)cc1
Yield: 78.7 %

Procedure:
According to the general to procedure B, 4-chlorocyanobenzene (71 mg, 0.52 mmol) reacted with morpholine (53 mg, 0.61 mmol) using 1 mol % of catalyst and sodium tert-butoxide (58 mg, 0.60 mmol) at 45° C. for 27 h to give the title compound (77 mg, 82%) as a solid: 1H-NMR (400 MHz, CDCl3): δ 7.49 (d, 2H, J=8.0 Hz), 6.85 (d, 2H, J=8.8 Hz), 3.84 (t, 4H, J=4.8 Hz), 3.27 (t, 4H, J=4.8 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 153.36, 133.36, 119.76, 113.93, 100.69, 66.31, 47.15. GC/MS(EI): m/z 188 (M+).
Reaction SMILES: S(O[CH2:6][CH2:7][C:8]1([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)[CH2:13][N:12]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[C:11](=[O:29])[CH2:10][CH2:9]1)(C)(=O)=O.C([O-])([O-])=O.[K+].[K+].[C:44]1([CH:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.Cl>C(#N)C.CCOCC.CN(C=O)C>[ClH:36].[F:23][C:21]([F:24])([F:22])[C:19]1[CH:20]=[C:15]([CH:16]=[C:17]([C:25]([F:27])([F:28])[F:26])[CH:18]=1)[CH2:14][N:12]1[CH2:13][C:8]([CH2:7][CH2:6][N:53]2[CH2:54][CH2:55][CH:50]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:51][CH2:52]2)([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)[CH2:9][CH2:10][C:11]1=[O:29]
Reactant: CS(=O)(=O)OCCC1(c2ccc(Cl)c(Cl)c2)CCC(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C1CCC(CCN2CCC(c3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)CN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 22.3 %

Procedure:
2.79 g of 5-(2-mesyloxyethyl)-5-(3,4-dichlorophenyl)-1-[3,5-bis(trifluoromethyl)benzyl]piperid-2-one prepared in Example 1, step B, 1.95 g of K2CO3 and 0.91 g of 4-phenylpiperidine are mixed in 6 ml of acetonitrile and 6 ml of DMF and the mixture is heated at 80° C. for 4 hours. After evaporation of the solvents, the residue is extracted with ethyl acetate and the extract is washed with water and then with saturated NaCl solution. It is dried over MgSO4 and concentrated and the residue is then chromatographed on silica using DCM/MeOH (100/1; v/v) as the eluent. A sample of the product obtained is taken up with a solution of hydrochloric acid in ether and the solvent is evaporated off to give 0.365 g of the expected product, which crystallizes from a pentane/ether mixture. M.p.=170° C.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5](=[O:20])[CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([S:17]C#N)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1>CO>[CH3:3][O:4][C:5](=[O:20])[CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([SH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1
Reactant: COC(=O)CCN1CCc2cc(SC#N)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCN1CCc2cc(S)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
Sodium borohydride (0.6 g) was added to a solution of compound 21B (0.65 g) in 20 mL of MeOH at 0° C. by portion in 15 minutes period. The mixture was stirred for another 30 minutes at RT, quenched with 50 mL of water and 50 mL of ether. The organic layer was separated, washed with water, brine, dried (MgSO4), concentrated to afford compound 21C (0.42 g). MS: 236 (M−1)+. Preparation of 3-{5-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-2,3-dihydro-indol-1-yl}-propionic acid methyl ester (Compound 21D)
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][OH:18]>C(#N)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:16][CH2:17][OH:18])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCNCC1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCN(CCO)CC1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
1-Ethylpiperazine (5.0 g, 43.8 mmol) was dissolved in 90 mL of acetonitrile, followed by the addition of powdered potassium carbonate (18.2 g, 131 mmol), and 2-bromoethanol (10.9 g, 87.6 mmol). This mixture was warmed to reflux for 16 hours, cooled to ambient temperature, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (10% MeOH/DCM/0.5% NH4OH) to give 5.4 g (78%) of 2-(4-ethylpiperazin-1-yl)ethanol as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.Br[C:44]1[N:49]=[CH:48][CH:47]=[CH:46][N:45]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.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]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:28]2[CH:29]=[CH:30][C:31]([C:44]3[N:49]=[CH:48][CH:47]=[CH:46][N:45]=3)=[CH:32][CH:33]=2)=[CH:6][CH:7]=1
Reactant: Brc1ncccn1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cnn4-c4cccc(S(C)(=O)=O)c4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ncccn5)cc4)nc32)c1
Temperature: 100 °C

Procedure:
A solution of 5-(4-chloro-phenyl)-1-(3-methanesulfonyl-phenyl)-6-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]-pyrimidin-4-one (prepared as described in example 51, 0.500 g, 0.829 mmol) in N,N-dimethylformamide (30 mL) is degassed with argon for 0.5 h. Then 2-bromopyrimidine (0.197 g, 1.24 mmol), cesium carbonate (0.540 g, 1.66 mmol), Pd(dppf)2Cl2 (0.06 g, 0.082 mmol) is added and the resulted mixture is degassed with argon for 0.5 h. The reaction mixture is heated to 100° C. for 2 h. The reaction mixture is diluted with water and extracted with ethyl acetate (3×). The combined organic layer is washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography over silica gel (60-120 mesh) to afford 5-(4-chloro-phenyl)-1-(3-methanesulfonyl-phenyl)-6-(4-pyrimidin-2-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one. 1H NMR (CDCl3 400 MHz) δ 8.89 (m, 3H), 8.60 (m, 1H), 8.46 (m, 2H), 8.38 (s, 1H), 7.92-7.95 (m, 1H), 7.74 (m, 1H), 7.54 (m, 2H), 7.33-7.36 (m, 3H), 7.13-7.17 (m, 2H); LC-MS calculated for C28H19ClN6O3S (M+H+) 555.1, found 554.9.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15](Cl)=O>>[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][N:9]=1
Reactant: O=C(Cl)c1ccco1
Reactant: NCCc1ccccc1
Product: c1coc(C2=NCCc3ccccc32)c1

Procedure:
1-(Furan-2-yl)-3,4-dihydroisoquinoline was prepared by reacting phenethylamine with 2-furanoyl chloride followed by reflux with polyphosphoric acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[CH:3]1[CH2:9][CH2:10][C:11](O)=[O:12]>[Fe]>[CH3:1][C:2]1([CH3:14])[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[CH:3]1[CH2:9][CH2:10][C:11](=[O:12])[CH2:10][CH2:9][CH:3]1[C:2]([CH3:14])([CH3:1])[CH:7]2[CH2:8][CH:4]1[CH2:5][CH2:6]2
Reactant: CC1(C)C2CCC(C2)C1CCC(=O)O
Agent: [Fe]
Product: CC1(C)C2CCC(C2)C1CCC(=O)CCC1C2CCC(C2)C1(C)C
Temperature: 290 °C

Procedure:
3-(3,3-Dimethylnorborn-2-yl)propionic acid (392 g., 2.0 moles) and iron (hydrogen reduced, 61.5 g., 1.1 moles) is heated for 1.5 hours at 195° C. under a nitrogen atmosphere. After that time, the temperature is increased to 290° C. and maintained at that temperature for 3 hours. The cooled reaction mass was extracted well with ether, filtered through Celite, and the ethereal extracts concentrated under vacuum. The residual oil is distilled under vacuum to leave the product as a liquid, b.p. 172° C.-173° C./0.05-0.1 mm.
Reaction SMILES: [NH2:1][C:2]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]C)=O)=[S:3].[OH-].[Na+].Cl.[C:17]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24](=[O:36])[O:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][NH:34][CH3:35])[CH2:28][CH2:27]1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CO>[C:17]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24](=[O:36])[O:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][N:34]([C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][NH:4][C:2]([NH2:1])=[S:3])[CH3:35])[CH2:28][CH2:27]1
Reactant: COC(=O)CCCCCNC(N)=S
Reactant: CNCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNC(N)=S
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.8 %

Procedure:
Methyl 6-[(aminocarbonothioyl)amino]hexanoate (335 mg, 1.64 mmol) was dissolved in methanol (10 mL), a 1 N aqueous sodium hydroxide solution (2.46 mL, 2.46 mmol) was added, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, 1 N hydrochloric acid (2.46 mL, 2.46 mmol) was added, and then the solvent was evaporated under reduced pressure. The resulting residue was dissolved in dichloromethane, 1-[2-(methylamino)ethyl]piperidin-4-yl biphenyl-2-ylcarbamate (578 mg, 1.64 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (469 mg, 2.46 mmol) and triethylamine (0.342 mL, 2.46 mmol) were added, and the mixture was stirred overnight at room temperature. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added, the mixture was extracted 3 times with methylene chloride, and the resulting organic layer was dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (elution solvents, n-hexane:ethyl acetate:methanol=1:1:0→0:10:0→0:9:1, v/v/v) to give the title compound (291 mg; yield, 34%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].Br[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=1[OH:10])(=[O:12])[CH3:13]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
A mixture of 1.42 g of 2,4-dihydroxy-3-propylacetophenone, 2 g of ethyl 4-bromobutyrate, 1.5 g of potassium carbonate, and 10 ml of N,N-dimethylformamide was stirred overnight at room temperature. After addition of 100 ml of water to the reaction mixture, the product was extracted with 30 ml of toluene. The extract was washed with water, dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue thus formed was applied to silica gel column chromatography and eluted with toluene to provide 1.5 g of ethyl 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butyrate as an oily product. In a solution of 2 g of potassium hydroxide dissolved in 40 ml of 80% methanol was dissolved 1.3 g of the oily product and the solution was allowed to stand for one hour. To the reaction mixture was added 20 ml of water and methanol was distilled off under reduced pressure. The aqueous solution thus obtained was acidified by 5% hydrochloric acid and extracted by ethyl acetate. The extract thus formed was washed with water, dried over anhydrous magnesium sulfate. The solvent was distilled off to provide 1.1 g of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butyric acid.
Reaction SMILES: [O:1]=[CH:2][C:3]#[C:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.[N-:13]=[N+:14]=[N-:15].[Na+]>CS(C)=O>[CH:2]([C:3]1[C:4]([C:5]2[CH:6]=[CH:7][C:8]([C:9]#[N:10])=[CH:11][CH:12]=2)=[N:13][NH:14][N:15]=1)=[O:1]
Reactant: N#Cc1ccc(C#CC=O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1ccc(-c2n[nH]nc2C=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.4 %

Procedure:
To a solution of 4-(3-oxoprop-1-ynyl)benzonitrile (500 mg, 3.22 mmol, 1.00 equiv) in DMSO (15 mL) was added NaN3 (314 mg, 4.83 mmol, 1.50 equiv) in portions. The resulting solution was stirred at room temperature for 1 h and then quenched by the addition of 1 mL of water. The resulting mixture was concentrated under vacuum and the residue was purified on a C18 flash column eluted with 0-15% of acetonitrile in water to give 130 mg (20%) of 4-(5-formyl-2H-1,2,3-triazol-4-yl)benzonitrile as a light yellow solid. LCMS (method C, ESI), RT=0.93 min, m/z=199.0 [M+1]+
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:24]3[C:16](=[CH:17][N:18]=[C:19]4[C:23]=3[CH:22]=[CH:21][NH:20]4)[N:15]=[N:14]2)[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.O>C(Cl)Cl>[N:13]1([C@H:10]2[CH2:11][CH2:12][C@H:8]([NH2:7])[CH2:9]2)[C:24]2[C:16](=[CH:17][N:18]=[C:19]3[C:23]=2[CH:22]=[CH:21][NH:20]3)[N:15]=[N:14]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](n2nnc3cnc4[nH]ccc4c32)C1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: N[C@H]1CC[C@H](n2nnc3cnc4[nH]ccc4c32)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
A mixture of racemic trans [3-(6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentyl]-carbamic acid tert-butyl ester (900 mg, 2.63 mmol), trifluoroacetic acid (5 mL), water (50.0 μL) and DCM (10 mL) was stirred at ambient temperature for 5 hours. The solvents were removed in vacuo and the resulting residue purified by column chromatography (SCX-2, gradient: methanol to 2M NH3 in methanol) to give 586 mg (92%) of racemic trans 3-(6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentylamine as a white foam solid. LCMS (Method B, ESI): RT=0.36 & 1.05 min, m+H=243.3; 1H NMR (400 MHz, DMSO) δ: 12.35 (br s, 1H), 8.98 (s, 1H), 7.59 (d, 1H), 6.98 (d, 1H), 5.67 (m, 1H), 3.67 (m, 1H), 2.52 (m, 1H, partially obscured by DMSO), 2.40 (m, 1H), 2.25-2.03 (m, 3H), 1.54 (m, 1H).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:11][C:12]1[CH:13]=[C:14]2[C:19](=[N:20][C:21]=1[CH:22]([O:25][CH3:26])[O:23][CH3:24])[N:18]([C:27]([O:29]C1C=CC=CC=1)=O)[CH2:17][CH2:16][CH2:15]2.[NH2:36][C:37]1[CH:44]=[C:43]([NH:45][CH2:46][CH2:47][O:48][CH3:49])[C:40]([C:41]#[N:42])=[CH:39][N:38]=1>C1COCC1>[Br:11][C:12]1[CH:13]=[C:14]2[C:19](=[N:20][C:21]=1[CH:22]([O:23][CH3:24])[O:25][CH3:26])[N:18]([C:27]([NH:36][C:37]1[CH:44]=[C:43]([NH:45][CH2:46][CH2:47][O:48][CH3:49])[C:40]([C:41]#[N:42])=[CH:39][N:38]=1)=[O:29])[CH2:17][CH2:16][CH2:15]2
Reactant: COCCNc1cc(N)ncc1C#N
Reactant: COC(OC)c1nc2c(cc1Br)CCCN2C(=O)Oc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCNc1cc(NC(=O)N2CCCc3cc(Br)c(C(OC)OC)nc32)ncc1C#N
Temperature: -25 °C
Reaction time: 0.58 h

Procedure:
LHMDS (1M in THF, 0.36 mL, 0.360 mmol) was added to a solution of phenyl 6-bromo-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (intermediate 11, 148 mg, 0.345 mmol) and 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile (intermediate 75, 70 mg, 0.346 mmol) in THF (3 ml) at −70° C. and stirred for 35 min. The reaction mixture was allowed to warm to −25° C., stirred for 5 min and cooled to −70° C. while stirring for 30 min. The reaction mixture was allowed to warm to −15° C., stirred for 10 min, cooled to −70° C. and quenched with saturated aqueous NH4Cl. The reaction mixture was diluted with water and ethyl acetate, layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, dried using Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with a gradient ethyl acetate (90-100%) in heptane. Product fractions were combined, evaporated and dried to yield the title compound as a yellow solid. (UPLC-MS 3) tR 1.16 min, ESI-MS 505.1 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 8.23 (s, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 5.68 (s, 1H), 5.26-5.21 (m, 1H), 4.06-4.00 (m, 2H), 3.62 (t, 2H), 3.51-3.44 (m, 8H), 3.40 (s, 3H), 2.84 (t, 2H), 2.03-1.96 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[CH2:10])=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:18][SiH:19]([CH3:21])[Cl:20]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][Si:19]([CH3:21])([CH3:18])[Cl:20])=[CH:4][C:3]=1[O:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C=CCc1ccc(F)c(Oc2ccccc2)c1
Reactant: C[SiH](C)Cl
Solvent: C1CCOC1
Product: C[Si](C)(Cl)CCCc1ccc(F)c(Oc2ccccc2)c1
Reaction time: 8 h

Procedure:
To a stirred mixture of 4.1 g (0.018 mole) of 3-(4-fluoro-3-phenoxyphenyl)-1-propene and 0.060 g (0.00015 mole) of hydrogen hexachloroplatinate hydrate in 15 mL of tetrahydrofuran was added slowly 2.0 g (0.021 mole) of dimethylchlorosilane. Upon completion of addition the reaction mixture was stirred overnight and then was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([O:10]CC)=[O:9])=[CH:4][N:5]=[N:6][CH:7]=1.[OH-].[Na+].Cl>O.C1COCC1>[CH3:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[CH:4][N:5]=[N:6][CH:7]=1
Reactant: CCOC(=O)c1cnncc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnncc1C(=O)O
Temperature: 60 °C
Reaction time: 1 h
Yield: 185.1 %

Procedure:
To a solution of ethyl 5-methylpyridazine-4-carboxylate (240 mg, 1.4 mmol) in H2O/THF was added 7.5 N aq. NaOH (1.25 eq, 0.25 mL) and the mixture was stirred for 1 hour at 60° C. Concentrated HCl was added to pH 2 and subsequently the volatiles were removed in vacuo. The residue was first stirred with EtOAc and the solids were collected by filtration. Then stirred with THF and the solids were again collected by filtration. The solids were extracted with MeOH and removal of the volatiles afforded 5-methylpyridazine-4-carboxylic acid (358 mg) as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.Cl.[OH:35][CH:36]1[CH2:39][NH:38][CH2:37]1.C(N(CC)CC)C>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20]([N:38]4[CH2:39][CH:36]([OH:35])[CH2:37]4)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: OC1CNC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)N4CC(O)C4)c3)n2)n1
Yield: 55.8 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example 1.2) (0.200 g, 0.409 mmol) by treatment with commercially available 3-hydroxyazetidine hydrochloride [CAS-no. 18621-18-6](0.224 mg, 2.05 mmol) and triethylamine (0.57 ml, 4.1 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.120 g, 55%) as a white solid. MS (ISP) 526.3 [(M+H)+]; mp 205° C.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[NH2:7][CH2:8][CH:9]1[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1.C(N(CC)CC)C.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[NH:11]1[CH2:12][CH:9]([CH2:8][NH:7][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])[CH2:10]1.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CC(CN)C1
Reactant: O=C(Cl)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC1CNC1)C1CC1
Reaction time: 2 h

Procedure:
Cyclopropanecarbonyl chloride (315 mg, 3.0 mmol) was added into a solution of tert-butyl 3-(aminomethyl)azetidine-1-carboxylate (372 mg, 2.0 mmol) and triethylamine (1 mL) in CH2Cl2 (20 mL) at r.t. After 2 h, the reaction mixture was condensed. The residue was dissolved in CH2Cl2 (10 mL) and treated with TFA (10 mL) at r.t for 1 hr. Evaporation of solvents provided the desired product as its TFA salt, which was used in Step A directly.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([NH:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:16]1)=[O:13].[C:25]1([O:31][CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]/[C:37]2[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][CH2:45]Br)=[CH:39][CH:38]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:24][O:23][C:21]([CH:17]1[CH2:18][CH2:19][CH2:20][CH:15]([NH:14][C:12]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=2[O:1][CH2:45][CH2:44][CH2:43][C:40]2[CH:41]=[CH:42][C:37](/[CH:36]=[CH:35]/[CH2:34][CH2:33][CH2:32][O:31][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:38][CH:39]=2)[C:6]([O:8][CH3:9])=[O:7])=[O:13])[CH2:16]1)=[O:22]
Reactant: COC(=O)c1ccc(O)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Reactant: BrCCCc1ccc(/C=C/CCCOc2ccccc2)cc1
Product: COC(=O)c1ccc(OCCCc2ccc(/C=C/CCCOc3ccccc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1

Procedure:
Preparation takes place in analogy to Example 22 from the (+)-B-enantiomer of methyl 4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate (see Example IX, method 2) and (4E)-5-[4-(3-bromopropyl)phenyl]pent-4-en-1-yl phenyl ether.