Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][N:14]3[C:26]4[C:25]5[N:24]=[CH:23][CH:22]=[CH:21][C:20]=5[N:19]=[CH:18][C:17]=4[N:16]=[C:15]3[CH2:27][CH2:28][CH3:29])[O:10][N:9]=2)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:38])C=1>C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][N:14]3[C:26]4[C:25]5[N:24]=[CH:23][CH:22]=[CH:21][C:20]=5[N+:19]([O-:38])=[CH:18][C:17]=4[N:16]=[C:15]3[CH2:27][CH2:28][CH3:29])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCc1nc2cnc3cccnc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Solvent: CCOCC
Product: CCCc1nc2c[n+]([O-])c3cccnc3c2n1Cc1cc(-c2ccc(F)cc2)no1

Procedure:
The method described in Part E of Example 12 was used to treat 1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridine (1.08 g, 2.79 mmol) with mCPBA (1.1 g of 75% pure material followed by 0.35 g) with the modification that the trituration of the crude product was carried out with diethyl ether. 1-{[3-(4-Fluorophenyl)isoxazol-5-yl]methyl}-5-oxido-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridine was obtained as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:8]2[S:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][C:11]=3[NH:12][C:7]=2[N:6]=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[CH3:23][O:24][CH2:25]Cl.[CH3:27]N(C)C=O>O>[C:1]([C:3]1[C:8]2[S:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][C:11]=3[N:12]([CH2:27][CH2:25][O:24][CH3:23])[C:7]=2[N:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: COCCl
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc2c(c1)Nc1nccc(C#N)c1S2
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COCCN1c2cc(C(=O)OC)ccc2Sc2c(C#N)ccnc21

Procedure:
To a solution of methyl 3-amino-4-(1-oxo-4-cyano-3-pyridylthio)benzoate in pyridine (20 ml) was added 5 ml of acetic anhydride and the resulting mixture was stirred for 16 hours. Then the reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluted with dichloromethane/ethyl acetate) to thereby give 0.45 g of methyl 3-acetamido-4-(1-oxo-4-cyano-3-pyridylthio)benzoate as a colorless solid. 0.079 g of sodium hydride was added in a nitrogen atmosphere to a solution of 0.45 g of methyl 3-acetamido-4-(1-oxo-4-cyano-3-pyridylthio)benzoate in N,N-dimethylformamide (15 ml) and the resulting mixture was stirred for 10 minutes. After adding 0.503 g of sulfur, the resulting mixture was stirred at 130° C. for 15 minutes. The reaction mixture was diluted with water and the crystals thus precipitated were taken up by filtration and washed with water. Thus 0.267 g of methyl 4-cyano-10H-pyrido[3,2-b][1,4]-benzothiazine-8-carboxylate was obtained as yellow crystals. To a solution of 0. 267 g of methyl 4-cyano-10H-pyrido[3,2-b][1,4]-benzothiazine-8-carboxylate in N,N-dimethylformamide (20 ml) were successively added in a nitrogen atmosphere 0.045 g of sodium hydride and a solution of 0.12 ml of chloromethyl methyl ether in N,N-dimethylformamide (9 ml) and the resulting mixture was stirred for 1 hour. Then the reaction mixture was diluted with water and eluted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with n-hexane/dichloromethane) to thereby give 0.152 g of the title compound as pale yellow crystals.
Reaction SMILES: [SH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11](=[O:14])([O-])[O-].[K+].[K+].CO[C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[O:27][CH:26]2[C:28]([NH2:30])=[O:29])=[CH:21][CH:20]=1>C(#N)C>[OH:27][CH:26]([CH:25]([S:1][CH2:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:22]1[CH:23]=[CH:24][CH:19]=[CH:20][C:21]=1[C:5]1[CH:10]=[CH:9][C:8]([O:14][CH3:11])=[CH:7][CH:6]=1)[C:28]([NH2:30])=[O:29]
Reactant: O=C(CS)c1ccccc1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C2OC2C(N)=O)cc1
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccccc2C(SCC(=O)c2ccccc2)C(O)C(N)=O)cc1

Procedure:
To a solution of 8.0 g (0.052 mol) of 2-mercapto-1-phenylethanone in 120 mL of acetonitrile was added 0.3 g (0.052 mol) of powdered potassium carbonate and 10.1 g (0.052 mol) of 3-(4-methoxyphenyl)oxiranecarboxamide. After the mixture was stirred and heated at reflux under nitrogen for 3.5 hours the solvent was removed under reduced pressure. The crude product was chromatographed on silica gel (150 g). The column was eluted with ethyl acetate, fractions 7-13 containing the product were combined and the solvent was removed under reduced pressure. The residue was crystallized from ethyl acetate to give 4.0 g (22%) of rac.-(R,*R*)-α-hydroxy-4-methoxyphenyl- β-[(2-oxo-2 -phenylethyl)thio]benzenepropanamide, mp 132°-134°.
Reaction SMILES: C(Cl)(C)(C)C.[Li].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1.FC1C=CC=C(F)C=1[Li].[C:24](OC(=O)C)(=[O:26])[CH3:25]>C1COCC1>[CH3:25][C:24]([C:9]1[C:8]([F:7])=[CH:13][CH:12]=[CH:11][C:10]=1[F:14])=[O:26]
Reactant: Fc1cccc(F)c1
Reactant: CC(=O)OC(C)=O
Agent: [Li]
Agent: [Li]c1c(F)cccc1F
Solvent: C1CCOC1
Solvent: CC(C)(C)Cl
Product: CC(=O)c1c(F)cccc1F
Temperature: -65 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A solution of tert-butyllithium in THF is firstly produced by reacting 9.25 g of tert-butyl chloride with 1.4 g of lithium granules in 100 g of THF at −78° C. After a conversion of >97% (GC a/a) has been reached, 1,3-difluorobenzene (11.4 g) is added and the mixture is stirred for another 30 minutes at −78° C. and subsequently for 2 hours at −65° C. The resulting solution of 2,6-difluoro-1-lithiobenzene is added dropwise to a solution of 22 g of acetic anhydride in 35 g of THF which has been cooled to −5° C. After the usual aqueous work-up, 2,6-difluoroacetophenone is obtained in a yield of 92%.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[N:10]([O-])=O.[Na+].[Cl:14][Sn]Cl>Cl>[Cl-:14].[Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][NH3+:10]
Reactant: Nc1ccc(F)cc1Br
Reactant: O=N[O-]
Reactant: Cl[Sn]Cl
Agent: Cl
Agent: [Na+]
Product: [Cl-]
Product: [NH3+]Nc1ccc(F)cc1Br
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 2-bromo-4-fluoroaniline in concentrated HCl (1.5M) at −10° C. was slowly added a 10.0M aqueous solution of NaNO2 (1.1 eq). The mixture was stirred at 0° C. for 2.5 hrs. A cold (−30° C.) solution of SnCl2 (3.8M) in concentrated HCl was then slowly added while maintaining the internal temperature below 10° C. The resulting mixture was stirred mechanically for 20 min at 0, then at room temperature for 1 hr. The thick slurry was filtered and the solid was air dried overnight. The solid was resuspended in cold HCl and filtered again. The dried material was suspended in Et2O, stirred for 10 min, filtered and air dried overnight to give the title compound as a beige solid.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]([N:5]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)=[CH:11][CH:10]=1)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[F:35][C:2]([F:1])([F:36])[C:3]([N:5]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)=[CH:11][CH:10]=1)[CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:4]
Reactant: Cn1cc(-c2ccc([C@@H]3C[C@H]3N(CC3CCN(C(=O)OC(C)(C)C)CC3)C(=O)C(F)(F)F)cc2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(-c2ccc([C@@H]3C[C@H]3N(CC3CCNCC3)C(=O)C(F)(F)F)cc2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
To a solution of tert-butyl 4-((2,2,2-trifluoro-N-(trans-2-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)cyclopropyl)acetamido)methyl)piperidine-1-carboxylate (110 mg, 0.217 mmol) in dichloromethane (DCM) (2 mL) was added TFA (0.5 mL, 6.49 mmol), and the mixture was stirred at room temperature for 3 h. The mixture was concentrated and the residue was treated with saturated NaHCO3 aqueous solution and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated to give 85 mg of product as pale yellow solid. MS: (M+H)+=407.2. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.41-1.54 (m, 2H), 1.58-1.81 (m, 3H), 2.40-2.52 (m, 1H), 2.56-2.69 (m, 2H), 3.06-3.20 (m, 3H), 3.44-3.62 (m, 2H), 3.92-3.97 (m, 3H), 7.13 (d, J=8.34 Hz, 2H), 7.47-7.52 (m, 2H), 7.77-7.82 (m, 1H), 7.92-7.96 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:11])=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[NH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[NH2:22])[C:16]([OH:18])=[O:17].[ClH:23].Cl.[C:25](=N)(OCC)[CH2:26][C:27](=N)OCC.C(O)(=O)C>Cl>[ClH:23].[ClH:23].[NH2:10][C:6]1[C:5]2[N:11]=[C:25]([CH2:26][C:27]3[NH:22][C:21]4[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=4[N:12]=3)[NH:1][C:4]=2[CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: Nc1cccc([N+](=O)[O-])c1N
Reactant: CCOC(=N)CC(=N)OCC
Agent: Cl
Solvent: CC(=O)O
Product: Nc1cccc2[nH]c(Cc3nc4cc(C(=O)O)ccc4[nH]3)nc12
Yield: 31.1 %

Procedure:
The following components were reacted according to General Procedure 1, above: 3-nitro-1,2-phenylenediamine (0.50 g; 3.26 mmoles) 3,4-diaminobenzoic acid (0.40 g; 3.26 mmoles), diethyl malonimidate dihydrochloride (1.1 eq.; 0.83 g; 3.60 mmoles) and acetic acid (25 mL). The crude mixture of three compounds was then reduced according to General Procedure 2, above. The crude solid product was taken up in 10 mL of dilute HCl, purified by preparative HPLC (2 to 40% acetonitrile (with 0.1% TFA) over 60 minutes) and converted to the HCl salt by three freeze drying cycles with dilute HCl. This procedure gave 0.213 g of pure 2-[(4-amino-1H-benzimidazol-2-yl)methyl]-1H-benzimidazole-5-carboxylic acid dihydrochloride in 17% yield. It had MS: m/z=308.2 [M+1] amu and gave one peak on HPLC at both 210 and 280 nm (10.20 minutes using the JWTFACN gradient).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][O:8][C:9]2[C:18]([CH3:19])=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][C:10]=2[CH3:20])[CH2:4][O:3]1.[CH2:22](C1C=C(C=C(C)C=1O)C#N)C>>[CH3:1][C:2]1([CH3:21])[O:6][C@@H:5]([CH2:7][O:8][C:9]2[C:10]([CH3:20])=[CH:11][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:17][C:18]=2[CH2:19][CH3:22])[CH2:4][O:3]1
Reactant: CCc1cc(C#N)cc(C)c1O
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Product: CCc1cc(C(=N)NO)cc(C)c1OC[C@H]1COC(C)(C)O1

Procedure:
The title compound is obtained as a yellow oil (0.77 g) in analogy to rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3,5-dimethyl-benzamidine starting from 3-ethyl-4-hydroxy-5-methyl-benzonitrile and D-alpha-beta-isopropyliden glycerol; LC-MS: tR=0.68 min, [M+H]+=308.99.
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.[C:25]([C:29]1[CH:30]=[C:31](C(O)=O)[N:32]([C:34]2[CH:35]=[N:36][C:37]([CH3:40])=[N:38][CH:39]=2)[N:33]=1)([CH3:28])([CH3:27])[CH3:26].C(C1C=C([NH:54][C:55]([NH:57][C:58]2[C:67]3[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=3)[C:61]([O:68][C:69]3[CH:74]=[CH:73][N:72]=[C:71]([NH:75][CH2:76][CH:77]4[CH2:79][CH2:78]4)[N:70]=3)=[CH:60][CH:59]=2)=[O:56])N(C)N=1)(C)(C)C>C(COC)OC.C1COCC1>[C:25]([C:29]1[CH:30]=[C:31]([NH:54][C:55]([NH:57][C:58]2[C:67]3[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=3)[C:61]([O:68][C:69]3[CH:74]=[CH:73][N:72]=[C:71]([NH:75][CH2:76][CH:77]4[CH2:79][CH2:78]4)[N:70]=3)=[CH:60][CH:59]=2)=[O:56])[N:32]([C:34]2[CH:39]=[N:38][C:37]([CH3:40])=[N:36][CH:35]=2)[N:33]=1)([CH3:26])([CH3:27])[CH3:28]
Reactant: Cc1ncc(-n2nc(C(C)(C)C)cc2C(=O)O)cn1
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(Oc2ccnc(NCC3CC3)n2)c2ccccc12
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: Cc1ncc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(NCC4CC4)n3)c3ccccc23)cn1
Temperature: 85 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
Diphenylphosphoryl azide (DPPA) (0.09 mL, 0.423 mmol, 1.1 equiv.) and triethylamine (0.075 mL, 0.54 mmol, 1.4 equiv.) were added to 5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazole-3-carboxylic acid (100 mg, 0.384 mmol, 1.0 equiv.) in 2.0 mL anhydrous dimethoxyethane in a sealed tube. The mixture was heated at 85° C. for 2.5 h, then a solution of the cyclopropylmethylaminopyrimidine-ether intermediate (see Example 4)(118 mg, 0.38 mmol, 1.0 equiv.) in 3.0 mL anhydrous THF was added and the resulting mixture stirred at room temperature overnight. The solvent was removed in vacuo and the crude urea was purified by column chromatography on silica gel using 0–65% EtOAc in hexanes eluent mixtures. The product was purified further by prep-HPLC affording 15 mg of the title compound (7% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:18]=[CH:17][C:8]2[N:9]([CH:13]3[CH2:16][CH2:15][CH2:14]3)[C:10](=[O:12])[NH:11][C:7]=2[CH:6]=1)=[O:4].[H-].[Na+].I[CH3:22]>CS(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[CH:18]=[CH:17][C:8]2[N:9]([CH:13]3[CH2:16][CH2:15][CH2:14]3)[C:10](=[O:12])[N:11]([CH3:22])[C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)n2C1CCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)n(C)c(=O)n2C1CCC1
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
To a solution of 1-cyclobutyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methyl ester (17.01 g, 69.1 mmol) in methyl sulfoxide (60 ml) was added sodium hydride (2.76 g as a 60% dispersion in oil, 69 mmol). The reaction mixture was stirred for 30 minutes prior to the dropwise addition of iodomethane (4.3 ml, 69.1 mmol). The reaction was stirred for 1 hour, was diluted with water and extracted with ethyl acetate. The organic layer was dried with sodium sulfate and concentrated in vacuo to give 17.76 g of 1-Cyclobutyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[O:6][C:7]2[C:13]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)=[O:4].CC1C=CC(S(O[CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[N:35]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:41][O:40][C:36]1[N:35]=[C:34]([CH2:33][CH2:32][N:17]2[CH2:18][CH2:19][N:14]([C:13]3[C:7]4[O:6][C:5]([C:3]([N:2]([CH3:20])[CH3:1])=[O:4])=[CH:9][C:8]=4[CH:10]=[CH:11][CH:12]=3)[CH2:15][CH2:16]2)[CH:39]=[CH:38][CH:37]=1
Reactant: COc1cccc(CCOS(=O)(=O)c2ccc(C)cc2)n1
Reactant: CN(C)C(=O)c1cc2cccc(N3CCNCC3)c2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(CCN2CCN(c3cccc4cc(C(=O)N(C)C)oc34)CC2)n1
Temperature: 80 °C

Procedure:
A reaction mixture of N,N-dimethyl-7-(piperazin-1-yl)benzofuran-2-carboxamide (0.090 g, 0.33 mmol) (Example 39d), 2-(6-methoxypyridin-2-yl)ethyl 4-methylbenzenesulfonate (0.10 g, 0.33 mmol) and potassium carbonate (0.046 g, 0.33 mmol) in dry acetonitrile (10 mL) was heated at 80° C. for over night. After cooling, the mixture was filtered and the solvent removed in vacuo. The product was purified by preparative HPLC to give the title compound. Yield: 0.048 g (36%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:19])[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)([OH:11])[CH2:9][CH2:8][NH:7][CH2:6]1)=[O:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:27][CH2:28][CH:29]=[C:30]1[C:36]2[CH:37]=[CH:38][CH:39]=[N:40][C:35]=2[CH2:34][O:33][C:32]2[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]1=2>C(#N)C.O>[CH3:1][O:2][C:3]([C:5]1([CH3:19])[C:10]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)([OH:11])[CH2:9][CH2:8][N:7]([CH2:27][CH2:28][CH:29]=[C:30]2[C:36]3[CH:37]=[CH:38][CH:39]=[N:40][C:35]=3[CH2:34][O:33][C:32]3[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]2=3)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1(C)CNCCC1(O)c1ccc(Cl)cc1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C1(C)CN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 57.9 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-4-hydroxy-3-methyl-piperidine-3-carboxylic acid methyl ester (0.71 g, 2.5 mmol) in acetonitrile/water (8:2) (25 mL) was added K2CO3 (1.40g, 10.0 mmol) and 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.937 g, 2.5 mmol). The solution was allowed to stir at room temperature for 48 h. The reaction was concentrated and partitioned between EtOAc/H2O, extracted with EtOAc (3×). The organics were collected together dried over Mg2SO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (50% ethyl acetate/50% hexane to 75% ethyl acetate/25% hexane to 100% ethyl acetate) to yield the title compound (0.835 g, 58%). 1H-NMR (CDCl3): 1.30 (s, 3H), 1.57 (s, 6H), 1.76 (d, 1H), 2.24-2.53 (m, 7H), 2.65 (d, 1H), 2.86 (d, 2H), 3.44 (s, 3H), 5.30 (bs, 2H), 6.16 (d, 1H), 6.82 (d, 1H), 7.26 (m, 4H), 7.45 (s, 1H), 7.53 (d, 1H), 7.58 (d, 1H), 8.49 (d, 1H). ESI-MS m/z: 577 (M+1), retention time 1.50.
Reaction SMILES: [CH3:1][Si:2]([CH:5]=[N+:6]=[N-:7])([CH3:4])[CH3:3].C([Li])CCC.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=2)([CH3:26])[CH:22]([CH3:35])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([CH3:26])([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]3[N:34]=[N:7][NH:6][C:5]=3[Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:28]=2)[CH:22]([CH3:35])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC1CN(Cc2ccccc2)CCC1(C)c1cccc(C#N)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1CN(Cc2ccccc2)CCC1(C)c1cccc(-c2nn[nH]c2[Si](C)(C)C)c1
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
To a solution of (trimethylsilyl)diazomethane (2.0 M in hexane, 9.86 mL, 19.7 mmol) in tetrahydrofuran (40 mL) at 0° C. under an atmosphere of nitrogen was added n-butyllithium (2.5 M in hexane, 7.9 mL, 19.7 mmol) dropwise. After 30 min, a solution of 1-benzyl-4-(3-cyanophenyl)-3,4-dimethylpiperidine (Preparation 3, 5.0 g, 16.4 mmol) in tetrahydrofuran (40 mL) was added such that the internal temperature remained at 0° C. After stirring overnight, the reaction was quenched with saturated aqueous sodium hydrogencarbonate (100 mL) and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a pale brown foam (6.53 g, 79%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.[CH2:15]1[O:25][C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16]1.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:21]1([OH:24])[CH2:22][CH2:23][C:18]2([O:25][CH2:15][CH2:16][O:17]2)[CH2:19][CH2:20]1
Reactant: COc1ccccc1Br
Reactant: O=C1CCC2(CC1)OCCO2
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1C1(O)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-Bromoanisole (1.87 g, 10.0 mmol) in 10 mL THF under Argon was added n-butyllithium (4.0 mL 2.5M in hexane, 10.0 mmol) cooled to −78° C. The solution was stirred 10 min. at −78° C., and a solution of 1,4-Cyclohexanedione mono-ethylene ketal (1.56 g, 10.0 mmol) in 10 mL THF was added slowly. The solution was warmed to r.t. and stirred for 60 min., then poured onto saturated sodium bicarbonate and extracted with ethylacetate. The combined organic layers were washed with saturated sodium chloride, dried with magnesium sulfate, and concentrated in vacuo. The crude solid was crystallized with hexane/diethylether 2:1 to give 8-(2-Methoxy-phenyl)-1,4-dioxaspiro[4.5]decan-8-ol as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19]O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:19][CH2:18][CH2:17][N:16]([CH3:21])[CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Reactant: CN(C)CCCO
Product: COc1cc2c(Cl)ncnc2cc1OCCCN(C)C

Procedure:
The compound was synthesised according to GP 4 from 4-chloro-7-hydroxy-6-methoxy-quinazoline and 3-Dimethylamino-propan-1-ol. LC/ESI-MS: m/z=296 [M+H].
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].C[N+](C)(C)C.[OH-].[C:12](#[N:15])[CH:13]=[CH2:14].Cl>O>[C:12]([CH2:13][CH2:14][NH:1][CH2:2][C:3]([OH:5])=[O:4])#[N:15]
Reactant: NCC(=O)O
Reactant: C=CC#N
Agent: C[N+](C)(C)C
Agent: Cl
Agent: [OH-]
Solvent: O
Product: N#CCCNCC(=O)O
Temperature: 10 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
Glycine (5 g, 67 mmol) was suspended in water (10 cm3) and TMAH (25% in water, 24.3 g, 67 mmol) was added slowly, keeping the temperature at <30° C. with an ice-bath. The mixture was then cooled to 10° C. and acrylonitrile (3.89 g, 73 mmol) was added. The mixture was stirred overnight, and allowed to warm to room temperature slowly. The mixture was then neutralized with HCl (6M, 11.1 cm3), concentrated to 15 cm3 and diluted to 100 cm3 with EtOH. The solid precipitated was collected by filtration, dissolved in hot water (6 cm3) and reprecipitated with EtOH (13 cm3) to give 2-(2-cyanoethylamino)acetic acid (5.94 g, 69.6%) as a white solid, mp 192° C. (lit mp 190-191° C.).
Reaction SMILES: [CH3:1][C:2]([OH:9])([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]#[CH:4].I[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>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.CN(C=O)C.CCN(CC)CC>[CH3:1][C:2]([OH:9])([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]#[C:4][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: C#CC(C)(O)CC(C)C
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(C)(O)CC(C)C)c21

Procedure:
Using Method C above, 3,5-dimethyl-1-hexyn-3-ol (61 mg, 0.48 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 2 supra) (146 mg, 0.4 mmol) using (Ph3P)2PdCl2 (20 mg) and Cul (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 15 h to yield rac-(Z)-1,3-dihydro-4-(3,5-dimethyl-3-hydroxy-1-hexynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 87 mg, 60%).
Reaction SMILES: [C:1](=[O:4])([OH:3])N.[N:5]1[N:9]2[CH:10]=CC=C[C:8]2=[C:7](C(OC)=O)[CH:6]=1.S(=O)(=O)(O)O.[CH3:23]O>>[CH3:10][N:9]1[CH:8]=[CH:7][C:6]([C:1]([O:3][CH3:23])=[O:4])=[N:5]1
Reactant: CO
Reactant: NC(=O)O
Reactant: COC(=O)c1cnn2ccccc12
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccn(C)n1

Procedure:
To a solution of compound 1 (1.26 g, 10 mmol) in methanol (30 mL) was added sulfuric acid (0.5 mL). The resulting mixture was refluxed for 2 h and the solvent was evaporated. The residue was dissolved in EA (60 mL) and washed with brine, dried over Na2SO4. Then filtered and concentrated to give the product.