Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][CH2:6]Br)[CH3:2].[NH2:9][C:10]1[N:11]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH:26]3[CH2:28][CH2:27]3)=[CH:18][CH:17]=2)[C:12]([SH:15])=[N:13][N:14]=1>CN(C=O)C>[NH2:9][C:10]1[N:11]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH:26]3[CH2:28][CH2:27]3)=[CH:18][CH:17]=2)[C:12]([S:15][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:8])=[N:13][N:14]=1
Reactant: CCOC(=O)CCBr
Reactant: Nc1nnc(S)n1-c1ccc(C2CC2)c2ccccc12
Solvent: CN(C)C=O
Product: CCOC(=O)CCSc1nnc(N)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 60 °C

Procedure:
3-Bromo-propionic acid ethyl ester (158 μL, 224 mg; 1.239 mmol) was added to a solution of 5-Amino-4-(4-cyclopropyl-naphthalen-1-yl)-4H-[1,2,4]triazole-3-thiol (0.35 g, 1.239 mmol) in DMF (2.5 mL). The resulting mixture was heated to 60° C. for 20 hours. The reaction mixture was concentrated and sonicated with ethyl ether several times, decanting the ethyl ether layer. The resulting light yellow oil was placed on high vacuum to afford crude ethyl 3-(5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)propanoate as a light brown oily foam which was used directly in the next step (0.409 g, 87%).
Reaction SMILES: [C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=3)[N:14]=2)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:33]([N:35]1[C:39](=[O:40])[CH2:38][S:37][C:36]1=[O:41])[CH3:34].C(O)(=O)C.N1CCCCC1>C(O)C>[CH2:33]([N:35]1[C:39](=[O:40])[C:38](=[CH:21][C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:13]3[N:14]=[C:15]4[C:7]([C:1](=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4])=[CH:8][N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:10]4=[N:11][CH:12]=3)=[CH:24][CH:23]=2)[S:37][C:36]1=[O:41])[CH3:34]
Reactant: CCN1C(=O)CSC1=O
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cc3)nc12
Solvent: C1CCNCC1
Solvent: CCO
Solvent: CC(=O)O
Product: CCN1C(=O)SC(=Cc2ccc(Nc3cnc4c(n3)c(C(=O)C(C)(C)C)cn4COCC[Si](C)(C)C)cc2)C1=O
Yield: 52.5 %

Procedure:
To a 50 ml three necked round bottom flask, 4-(7-pivaloyl-5-((2-(trimethylsilyl)-ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-2-ylamino)benzaldehyde (0.104 g, 0.00023 mole) and 3-ethylthiazolidine-2,4-dione (0.067 g, 0.00046 mole) was taken in ethanol (3 ml). Piperidine acetate (3.3 M solution in water) (0.1 ml) was added dropwise at RT. The reaction mixture was refluxed for 6 hrs. After completion of the reaction, ethanol was distilled out and water was added to residue. Aq. layer was extracted with ethyl acetate, the combined organic layers were dried over Na2SO4, filtered and concentrated to afford crude product which was purified by triturated with n-pentane. The solid was filtered and dried under vacuum to yield 0.070 g of 3-ethyl-5-(4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)benzylidene)thiazolidine-2,4-dione which was converted to the title compounds as described in Example 6 above.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:16])=O.CN(C)C=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([Cl:16])=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)/C=C/c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (2E)-3-(4-chlorophenyl)prop-2-enoic acid (2.0 g, 11 mmol) in 50 mL methylene chloride was added oxalyl chloride (1.05 mL, 12.1 mmol) and N,N-dimethylformamide (0.05 mL, 0.6 mmol). The resulting mixture was stirred at r.t. for 6 h. The solvent was removed under vacuum. The resulting solid was diluted with hexanes and the solvent removed under vacuum to provide an off-white solid which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([OH:12])[C:4]=2[N+:3]=1[O-:13].[O:14]=[C:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:24]#[N:25])[CH:21]=2)[NH:16]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[C:24]([C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:14])[CH:23]2[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([OH:12])[C:4]=2[N+:3]=1[O-:13])#[N:25]
Reactant: [O-][n+]1c(Cl)ccc2c1C(O)CCC2
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)C(c1ccc3c([n+]1[O-])C(O)CCC3)C(=O)N2

Procedure:
The title compound was prepared as described for Example 3.3 using 2-chloro-8-hydroxy-5,6,7,8-tetrahydroquinoline 1-oxide (100 mg, 0.501 mmol), 2-oxoindoline-5-carbonitrile (83 mg, 0.526 mmol), tetrahydrofuran (2.5 mL), and a 1.0 M solution of sodium bis(trimethylsilyl)amide (1.668 μL, 1.668 mmol). The reaction was quenched by addition of methanol (2.5 mL). The resulting solution was evaporated to dryness. The crude was used in the following reaction step without further purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH:15]=[CH:14][N:13](C(=O)C(C)(C)C)[CH:12]=[C:11]1[CH:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S]>C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[CH:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCCC1C1=CN(C(=O)C(C)(C)C)C=CC1COCc1ccccc1
Agent: [S]
Solvent: Cc1ccccc1
Product: CN1CCCC1c1cnccc1COCc1ccccc1
Yield: 59 %

Procedure:
A solution of 1-[4-benzyloxymethyl-3-(1-methylpyrrolidin-2-yl)-4H-pyridin-1-yl]-2,2-dimethyl-propan-1-one (0.176 g, 0.48 mmol), sulfur (0.015 g. 0.48 mmol) and toluene (5 mL) was refluxed for 3 days. After filtration of the mixture through a pad of Celite and evaporation of the solvent under reduced pressure, the crude material was purified by radial PLC (hexanes) to afford 0.08 g (60%) of 4-benzyloxymethyl-3-(1-methylpyrrolidin-2-yl) -pyridine as a yellow oil. IR (thin film, neat, NaCl) 3436, 1637, 1090 cm−1; 1H NMR (CDCl3, 300 MHz) δ 8.74 (s, 1 H), 8.47 (d, 1 H, J=4.8 Hz), 7.40-7.27 (m, 6 H), 4.62 (d, 2 H,J=13. 2 Hz), 3.34-3.18 (m, 2 H), 2.28-2.18 (m, 2 H), 2.15 (s, 3 H), 2.11-1.09 (m, 5 H); 13C NMR (CDCl3, 75 MHz) δ 149.31, 148.37, 145.16, 137.86, 128.67, 128.06, 127.98, 122.14, 72.92, 68.19, 65.88, 57.07, 40.75, 34.28, 27.83, 22.91; HRMS Calcd for C18H22N2O: 283.1810 [M+H]+. Found: 283.1800 [M+H]+. [α]D24−75.9 (c 2.5, CH2Cl2).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[F:11].[CH3:12][Si](C=[N+]=[N-])(C)C>CO.ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[CH:4][C:3]=1[F:11]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(Br)c(F)c1

Procedure:
A solution of 4-bromo-3-fluorobenzoic acid (117 mg, 0.50 mmol) in methanol (1 mL) and dichloromethane (2 mL) at room temperature was slowly treated with 2M trimethylsilyldiazomethane in hexanes until the solution became light yellow. The mixture was concentrated to provide the desired product.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22].C(N(CC)CC)C.Br[C:34]1[CH:39]=[C:38]([S:40]([C:43]2[CH:48]=[CH:47][C:46]([S:49]([CH3:52])(=[O:51])=[O:50])=[CH:45][CH:44]=2)(=[O:42])=[O:41])[CH:37]=[CH:36][C:35]=1[NH:53][C:54](=[O:62])[C@:55]([OH:61])([CH3:60])[C:56]([F:59])([F:58])[F:57]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(OCC)(=O)C>[CH3:20][Si:21]([CH3:23])([CH3:22])[C:24]#[C:25][C:34]1[CH:39]=[C:38]([S:40]([C:43]2[CH:44]=[CH:45][C:46]([S:49]([CH3:52])(=[O:51])=[O:50])=[CH:47][CH:48]=2)(=[O:42])=[O:41])[CH:37]=[CH:36][C:35]=1[NH:53][C:54](=[O:62])[C@:55]([OH:61])([CH3:60])[C:56]([F:58])([F:59])[F:57]
Reactant: C#C[Si](C)(C)C
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)c2ccc(S(C)(=O)=O)cc2)cc1Br)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)c2ccc(S(C)(=O)=O)cc2)cc1C#C[Si](C)(C)C)C(F)(F)F
Temperature: 50 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
Bis(triphenylphosphine)palladium(II) chloride (0.01 g), triphenylphosphine (0.0038 g), trimethylsilylacetylene (0.17 ml), triethylamine (0.16 ml) and copper(I) iodide (0.0013 g) were added to a solution of (R)-N-[2-bromo-4-(4-mesylphenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 140) (0.311 g) in anhydrous THF (10 ml) under argon. The mixture was heated at 50° C. for 3 hours then more bis(triphenylphosphine) palladium(II) chloride (0.01 g) and trimethylsilylacetylene (0.17 ml) were added and heating was continued for a further 3 hours. The reaction mixture was allowed to cool, ethyl acetate (50 ml) was added and the mixture was filtered through a pad of diatomaceous earth which was washed with ethyl acetate (3×20 ml). The filtrates were combined and volatile material was removed by evaporation. The residue was purified by chromatography eluting with 10-40% ethyl acetate/iso-hexane to give the title compound (in 89% yield) as a solid. NMR (CDCl3): 0.29 (s, 9H), 1.74 (s, 3H), 3.05 (s, 3H), 3.69 (s, 1H), 7.88-7.92 (m, 1H), 8.02 (d, 1H), 8.05-8.13 (m, 4H), 8.61 (d, 1H), 9.46 (s, 1H); MS (ESP−): 546.
Reaction SMILES: [Br:1][C:2](=[CH:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH2:3][NH:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][N:7]1[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38])[C:31](Cl)=[O:32].C(N(CC)CC)C.C(O)(C(F)(F)F)=O>C(#N)C>[Br:1][C:2](=[CH:18][C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[CH2:3][N:4]([CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][N:7]1[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:31](=[O:32])[C:30]1[CH:29]=[C:28]([O:27][CH3:26])[C:36]([O:37][CH3:38])=[C:35]([O:39][CH3:40])[CH:34]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: Fc1ccc(C=C(Br)CNCC2CCCN2CC2CCCCC2)cc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1cc(C(=O)N(CC(Br)=Cc2ccc(F)cc2)CC2CCCN2CC2CCCCC2)cc(OC)c1OC

Procedure:
Experimental condition analogous to Example 12 were used with [2-bromo-3-(4-fluoro-phenyl)-allyl]-(1-cyclohexylmethyl-pyrrolidin-2-ylmethyl)-amine 0.15 g (0.36 mmol), 3,4,5-trimethoxy-benzoylchloride 0.1 g (0.47 mmol), and triethylamine 0.08 ml. Reverse phase high pressure liquid chromatography with a gradient of 20-80% acetonitrile phase lead to 120 mg of white powder as a TFA salt.
Reaction SMILES: [OH:1][C:2]([CH3:28])([CH3:27])[CH2:3][N:4]1[CH2:8][C@H:7]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]([CH2:16][C:17]([OH:19])=O)[C:11](=[O:20])[CH:10]=2)[C@H:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5]1.Cl.Cl.[NH2:31][CH2:32][C:33]1[CH:34]=[C:35]2[C:39](=[N:40][CH:41]=1)[NH:38][CH:37]=[C:36]2[F:42].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C>[OH:1][C:2]([CH3:27])([CH3:28])[CH2:3][N:4]1[CH2:8][C@H:7]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]([CH2:16][C:17]([NH:31][CH2:32][C:33]3[CH:34]=[C:35]4[C:39](=[N:40][CH:41]=3)[NH:38][CH:37]=[C:36]4[F:42])=[O:19])[C:11](=[O:20])[CH:10]=2)[C@H:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5]1
Reactant: NCc1cnc2[nH]cc(F)c2c1
Reactant: Cc1cc([C@H]2CN(CC(C)(C)O)C[C@H]2c2ccccc2)cc(=O)n1CC(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([C@H]2CN(CC(C)(C)O)C[C@H]2c2ccccc2)cc(=O)n1CC(=O)NCc1cnc2[nH]cc(F)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 4-(1-(2-hydroxy-2-methylpropyl)-cis-3-phenylpyrrolidin-4-yl)-6-methyl-1-carboxymethyl-2-pyridinone from step 8 above (0.23 mmol), 5-aminomethyl-3-fluoro-7-azaindole bis hydrochloride (55 mg, 0.23 mmol), HOBT (35 mg, 0.23 mmol) and DIEA (0.12 mL, 0.69 mmol) in DMF (2 mL) was added EDC (134 mg, 0.46 mmol). The resulting solution was stirred at ambient temperature for 18 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography using a gradient elution of 96:4 to 92:8 CH2Cl2:MeOH as eluant to give the title compound as an amorphous solid (0.1 g, TLC Rf=0.4, 92:8 CH2Cl2:MeOH; HPLC RT=4.71 min, method A).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH:7]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:8][NH:9][C:10]([C:12]1[N:13]=[CH:14][C:15]2[C:20]([C:21]=1[OH:22])=[CH:19][CH:18]=[C:17]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:16]=2)=[O:11])(C)(C)C.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[OH:22][C:21]1[C:20]2[C:15](=[CH:16][C:17]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:18][CH:19]=2)[CH:14]=[N:13][C:12]=1[C:10]([NH:9][CH2:8][CH:7]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:6]([OH:36])=[O:5])=[O:11]
Reactant: CC(C)(C)OC(=O)C(CNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O)c1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCC(C(=O)O)c1ccccc1)c1ncc2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.2 %

Procedure:
A mixture of 3-[(4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-2-phenyl-propionic acid tert-butyl ester (50 mg) and TFA (2 mL) in DCM (2 mL) was stirred at rt for 3 h; then the mixture was concentrated and resulting residue was treated with water; the solids were collected via filtration and air dried to give desired product as white solids (35 mg). LC-MS ESI+: 429 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([CH:15]1[NH:20][CH2:19][C:18]2[S:21][C:22]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([S:32]([C:35]4[CH:44]=[CH:43][C:42]5[C:37](=[CH:38][CH:39]=[C:40]([Cl:45])[CH:41]=5)[CH:36]=4)(=[O:34])=[O:33])[CH2:28][CH:27]3[C:46](=[O:48])[NH2:47])=[O:25])=[N:23][C:17]=2[CH2:16]1)=O)(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:46]([CH:27]1[CH2:28][N:29]([S:32]([C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[C:40]([Cl:45])[CH:41]=3)[CH:36]=2)(=[O:34])=[O:33])[CH2:30][CH2:31][N:26]1[C:24]([C:22]1[S:21][C:18]2[CH2:19][NH:20][CH2:15][CH2:16][C:17]=2[N:23]=1)=[O:25])(=[O:48])[NH2:47]
Reactant: CC(C)(C)OC(=O)C1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3C(N)=O)sc2CN1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1nc2c(s1)CNCC2

Procedure:
To trifluoroacetic acid (1 ml), a solution of 1-[(6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-carbamoyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine (303 mg) dissolved in dichloromethane (1 ml) was added, followed by concentration under reduced pressure. The resulting precipitate was collected by filtration and washed with diethyl ether, whereby the title compound (263 mg, 83%) was obtained.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[C:25]([C@@H:26]([OH:28])[CH3:27])[C:20]=4[O:19][C:18]=3[CH3:29])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[H-].[Na+].[CH3:32]I>C1COCC1>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[C:25]([C@@H:26]([O:28][CH3:32])[CH3:27])[C:20]=4[O:19][C:18]=3[CH3:29])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nn2c(-c3c(C)oc4c([C@H](C)O)cccc34)c(C)nc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)oc4c([C@H](C)OC)cccc34)c(C)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A solution of (S)-1-{3-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-2-methyl-benzofuran-7-yl}-ethanol (0.19 g, 0.50 mmol) in THF (5 mL) is cooled to 0° C., treated with 60% NaH (23 mg, 0.56 mmol). The mixture is stirred at 0° C. for 30 min. CH3I (47 uL, 0.76 mmol) is added and the resulting mixture is stirred at 0° C. for 1 h and gradually warmed to rt. and stirred at rt overnight. The excess reagent is removed in vacuo. The residue is taked up with H2O (20 mL) and EtOAc (50 mL). It is washed with sat. NH4Cl (2×30 mL). The organic lay is dried with Na2SO4, filtered and concentrated. Purification of the crude material by chromatography gives the title compound (0.17 g, 0.41 mmol, 82%). 1H NMR (CDCl3): δ. 0.90 (t, J=7.5 Hz, 3H), 0.90 (t, J=7.5 Hz, 3H), 1.63 (d, J=4.0 Hz, 1.5H), 1.64 (d, J=4.0 Hz, 1.5H), 1.78-1.92 (m, 4H), 2.44 (s, 3H), 2.46 (s, 3H), 2.48 (s, 3H), 3.34-3.42 (m, 1H), 4.90-4.98 (m, 1H), 6.68 (s, 1H), 7.17-7.19 (m, 1H), 7.26-7.29 (m, 2H) ppm. ES-MS (m/z): calcd for C25H31N3O2 (M+H)+: 406.5. found: 406.2.
Reaction SMILES: [CH3:1][C:2]([OH:6])([CH3:5])[C:3]#[CH:4].[CH2:7]([O:9][CH2:10][CH2:11]Br)[CH3:8]>>[CH2:7]([O:9][CH2:10][CH2:11][O:6][C:2]([CH3:5])([CH3:1])[C:3]#[CH:4])[CH3:8]
Reactant: C#CC(C)(C)O
Reactant: CCOCCBr
Product: C#CC(C)(C)OCCOCC
Yield: 63.8 %

Procedure:
In accordance with the procedure of the step 1 of Example 10, and using 34.5 g of 3-methyl-1-butyn-3-ol and 69.0 g of 2-bromoethyl ethyl ether, 40.9 g of 3-(2-ethoxyethoxy)-3-methyl-1-butyne was obtained.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:9]=[C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]3=[CH:6][C:5]=2[C:4](=[O:15])[N:3]1[CH2:16][CH:17]([C:22]1([CH3:27])OCC[O:23]1)[C:18]([O:20][CH3:21])=[O:19].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>>[O:1]=[C:2]1[C:10]2[CH:9]=[C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]3=[CH:6][C:5]=2[C:4](=[O:15])[N:3]1[CH2:16][CH:17]([C:22](=[O:23])[CH3:27])[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)C(CN1C(=O)c2cc3ccccc3cc2C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: COC(=O)C(CN1C(=O)c2cc3ccccc3cc2C1=O)C(C)=O

Procedure:
Methyl 2-(1,3-dioxo-1,3-dihydro-benzo[f]isoindol-2-ylmethyl)-3-oxo-butyrate was prepared (18 mg, 51%) in the same manner as described in the above example 6 (1) from methyl 3-(1,3-dioxo-1,3-dihydro-benzo[f]isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (40 mg, 0.11 mmol) and pyridinium p-toluenesulfonate (5 mg), and the obtained product was identified with the following NMR data.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[OH:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25](O)=O>>[OH:21][C:22]1[CH:23]=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: Cc1ccc(C(=O)O)cc1O
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Product: Cc1ccc(-c2nc(Cn3ccc4c(C(F)(F)F)c(C#N)ccc43)no2)cc1O

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-hydroxy-4-methylbenzoic acid: MS (APCI): m/z 399 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4](=[C:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)[CH3:5].[ClH:20].O1CCOC[CH2:22]1>CCO>[ClH:20].[NH:9]1[CH2:10][CH2:11][C:6](=[C:4]([CH3:5])[C:3]([O:2][CH2:1][CH3:22])=[O:19])[CH2:7][CH2:8]1
Reactant: C1COCCO1
Reactant: COC(=O)C(C)=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(C)=C1CCNCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 145.6 %

Procedure:
tert-Butyl 4-(2-methoxy-1-methyl-2-oxoethylidene)piperidine-1-carboxylate (2.83 g; 10 mmol) was dissolved in EtOH (50 mL) and treated with 4M HCl/1,4-dioxane solution (20 mL, 80 mmol). The resulting solution was stirred at ambient temperature for 6 hrs. The solvents were removed under vacuum to leave a syrup. This was dried under vacuum to give the title product (3.199 g, ˜quantitative yield). This was used in the next stage without further purification. 1H NMR δ 1.22 (t, 3H), 1.78 (s, 3H), 2.44-2.57 (m, 2H), 2.65-2.77 (m, 2H), 2.98-3.15 (m, 4H), 4.14 (q, 2H), 9.52 (s, 2H). MS m/e MH+=184.32.
Reaction SMILES: [Mg].BrC(Br)C.Br[C:7]1[CH:16]=[CH:15][C:14]2[C:13]([CH3:18])([CH3:17])[CH2:12][CH2:11][C:10]([CH3:20])([CH3:19])[C:9]=2[CH:8]=1.CO[CH:23]=[C:24]=[CH2:25].[Cl-].[NH4+]>C1COCC1>[CH3:17][C:13]1([CH3:18])[CH2:12][CH2:11][C:10]([CH3:20])([CH3:19])[C:9]2[CH:8]=[C:7]([CH2:25][C:24]#[CH:23])[CH:16]=[CH:15][C:14]1=2
Reactant: C=C=COC
Reactant: CC1(C)CCC(C)(C)c2cc(Br)ccc21
Agent: CC(Br)Br
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: C#CCc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
20 g (0.82 mol) of magnesium activated with 0.1 ml of dibromoethane are introduced into a four litre reactor under a stream of nitrogen. A solution of 200 g (0.75 mol) of 2-bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene is added dropwise so as to maintain the reflux of the THF and the mixture is stirred at 50° C. for two hours. The reaction medium is then cooled to −5° C. and 1.2 g (8.2 mmol) of CuBr are added and a solution of 58 g (0.82 mol) of methoxyallene in 100 ml of THF is introduced dropwise. The mixture is stirred for one hour at −5° C. and is then allowed to return to room temperature and is stirred for two hours. The reaction medium is poured into saturated ammonium chloride solution and extracted with ethyl acetate, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The oil obtained is distilled at 0.02 mm Hg and the fraction passing at 95-100° C. is collected. 79 g (47%) of the expected product are obtained in the form of a colourless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1.[Br:10]N1C(=O)CCC1=O>C(#N)C>[Br:10][C:8]1[S:7][C:6]([NH2:9])=[N:5][C:4]=1[CH2:3][O:2][CH3:1]
Reactant: COCc1csc(N)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COCc1nc(N)sc1Br
Reaction time: 2 h

Procedure:
4-Methoxymethyl-thiazol-2-ylamine (170 mg, 1.1 mmol) is dissolved in acetonitrile and N-bromosuccinimide. (231 mg, 1.3 mmol, 1.1 equiv.) was added in one portion. The mixture was stirred at room temp. for 2 hours, then filtered and the filtrate was evaporated. After purification on silica-gel with ethyl acetate/n-heptane as eluent, 260 mg of a light red solid were obtained: MS: m/e 222.8 (M+H).
Reaction SMILES: C([Si](C)(C)[O:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH2:9][CH2:8]1)(C)(C)C>Cl.CCO>[OH:6][C@@H:7]1[CH2:8][CH2:9][C@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH2:11][CH2:12]1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCCC2=O)CC1
Agent: Cl
Solvent: CCO
Product: O=C1CCCN1[C@H]1CC[C@@H](O)CC1
Temperature: 25 °C

Procedure:
Heat a solution of cis-1-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-pyrrolidin-2-one (500 mg) in 5 mL of 1N HCl in EtOH to 45° C. for 1 h. Cool the mixture to room temp and concentrate. Dissolve the residue in NaHCO3 (10 mL) and CH2Cl2 (10 mL). Extract the aqueous layer two times with 10 mL of CH2Cl2. Dry the organic layer over Na2SO4, filter and concentrate. Purify the crude material by chromatography to yield the title compound: mass spectrum (m/z): 184 (M+1).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[N:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1.[CH2:22]([C:26]1[CH:37]=[CH:36][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:28][CH:27]=1)[CH2:23][C:24]#[CH:25].O>CN(C=O)C.[Cu]I>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:11]=[N:10][C:9]([C:25]#[C:24][CH2:23][CH2:22][C:26]3[CH:37]=[CH:36][C:29]([CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:28][CH:27]=3)=[CH:14][CH:13]=2)=[CH:16][CH:17]=1
Reactant: C#CCCc1ccc(CN2CCCC2)cc1
Reactant: Clc1ccc(-c2ccc(Cl)nn2)cc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(-c2ccc(C#CCCc3ccc(CN4CCCC4)cc3)nn2)cc1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
Under an argon atmosphere 0.1 mL (0.72 mmol) triethylamine, 3 mg (0.02 mmol) CuI and 8 mg (0.01 mmol) bis-triphenylphosphane-palladium(II)-chloride are added to a solution of 77 mg (0.34 mmol) 3-chloro-6-(4-chloro-phenyl)-pyridazine and 73 mg (0.34 mmol) 1-(4-but-3-ynyl-benzyl)-pyrrolidine (Example 2e) in 4 mL DMF and the reaction mixture is stirred for 20 min at 100° C. and at 300 W in the microwave. The reaction mixture is combined with 10 mL water, extracted with 10 mL EtOAc and the organic phase is washed with water and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, EtOAc/MeOH/NH3 90:10:1).