Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][C:3]=1[CH:12]=O.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:25])[CH2:22][C:23]#[N:24])=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][C:3]=1/[CH:12]=[C:22](/[C:21]([C:18]1[CH:17]=[CH:16][C:15]([F:14])=[CH:20][CH:19]=1)=[O:25])\[C:23]#[N:24]
Reactant: Cc1n[nH]c2cc(F)c(C=O)cc12
Reactant: N#CCC(=O)c1ccc(F)cc1
Product: Cc1n[nH]c2cc(F)c(/C=C(\C#N)C(=O)c3ccc(F)cc3)cc12

Procedure:
Following the procedure described for Example 2A, the title compound was prepared using 500 mg (2.81 mmol) 6-fluoro-3-methyl-1H-indazole-5-carbaldehyde (Example 3A) and 504 mg (3.09 mmol) 3-(4-fluorophenyl)-3-oxopropanenitrile to yield 768 mg (69% of th.) of the crude product (81% purity) which was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1(O)[C:12]2[C:7](=[C:8]([O:15][CH3:16])[C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:4]1.[ClH:24]>C(O)(C)C>[ClH:24].[NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[C:8]([O:15][CH3:16])[C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH:5]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:4]=1
Reactant: COc1ccc2c(c1OC)CC(c1ccccc1)CC2(O)CN
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc2c(c1OC)CC(c1ccccc1)C=C2CN
Yield: 98 %

Procedure:
1-Aminomethyl-5,6-dimethoxy-1-hydroxy-3-phenyl-1,2,3,4-tetrahydronaphthalene (11.5 g, 37 mmol), from Step 1, was heated at reflux temperature in 300 mL of isopropyl alcohol saturated with hydrochloric acid for 2 h. The resultant solution was concentrated and the solid residue was triturated with hot toluene to give 10.6 g (98% yield) of 1-aminomethyl-5,6-dimethoxy-3-phenyl-3,4-dihydronaphthalene hydrochloride, m.p. 189.5-190° C.; 1H NMR (d6 -DMSO) δ: 2.78 (dd, 1H), 3.11 (dd, 1H), 3.2-3.4 (m, 2H+H2O), 3.6 (s, 3H), 3.81 (s, 3H), 3.93 (d, 1H), 6.1 (d, 1H), 6.93 (d, 1H), 7.12 (d, 1H), 7.2-7.4 (m, 5H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1)[CH3:4].C(O[CH2:17][CH2:18][CH2:19]C)=C.N1C=CC=CC=1.S(=O)(=O)(O)O>O1CCOCC1>[CH2:1]([O:2][CH:3]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH:10]=[CH2:11])=[CH:12][CH:13]=1)[CH3:4])[CH2:17][CH2:18][CH3:19].[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1
Reactant: C=Cc1ccc(OC(C)OC)cc1
Reactant: C=COCCCC
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: C=Cc1ccc(O)cc1
Product: C=Cc1ccc(OC(C)OCCCC)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of poly(p-hydroxystyrene) (4.8 g) obtained in the same manner as described in Synthesis Example 3, (2) and n-butyl vinyl ether (3.0 g) in a mixed solvent (50 ml) of pyridine and 1,4-dioxane, a catalytic amount of conc. sulfuric acid was added, then continued to stir at room temperature for 16 hours. The reaction mixture was treated in the same manner as described in Synthesis Example 2, (3) to give 4.2 g of poly[p-(1-n-butoxyethoxy)styrene/p-hydroxystyrene] as a white powder having Mw 10000 (GPC with polystyrene calibration). The composition of the polymer was found to be p-(1-n-butoxyethoxy)styrene unit and p-hydroxystyrene unit in a molar ratio of 4:6 based on 1HNMR.
Reaction SMILES: CN1C(C(NC2C=CC=C(OC3C=CC4N(C=C(NC(=O)C(F)(F)F)N=4)C=3)C=2)=O)=CC(C)=N1.[CH3:34][N:35]1[N:39]=[N:38][C:37]([C:40]([OH:42])=O)=[N:36]1.C(Cl)(=O)C(Cl)=O.[NH2:49][C:50]1[CH:51]=[C:52]([CH:69]=[CH:70][CH:71]=1)[O:53][C:54]1[CH:55]=[CH:56][C:57]2[N:58]([CH:60]=[C:61]([NH:63][C:64]([CH:66]3[CH2:68][CH2:67]3)=[O:65])[N:62]=2)[CH:59]=1>CN(C)C=O.CN(C)C(=O)C.O1CCCC1>[CH:66]1([C:64]([NH:63][C:61]2[N:62]=[C:57]3[CH:56]=[CH:55][C:54]([O:53][C:52]4[CH:51]=[C:50]([NH:49][C:40]([C:37]5[N:38]=[N:39][N:35]([CH3:34])[N:36]=5)=[O:42])[CH:71]=[CH:70][CH:69]=4)=[CH:59][N:58]3[CH:60]=2)=[O:65])[CH2:67][CH2:68]1
Reactant: Cn1nnc(C(=O)O)n1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Agent: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C(F)(F)F)cn4c3)c2)n(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1nnc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c2)n1
Yield: 54.2 %

Procedure:
In the same manner as in Example 7-4 and using a mixture of 1-methyl-1H-tetrazole-5-carboxylic acid (1) and 2-methyl-2H-tetrazole-5-carboxylic acid (2) ((1):(2)≈1:1, 200 mg, 1.56 mmol), oxalyl chloride (141 μL, 1.72 mmol), N-[6-(3-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (70.0 mg, 0.227 mmol), tetrahydrofuran (10 mL), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (51.5 mg, 54%) was obtained as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].C(C1C=CC(OC)=C(O)C=1C(O)=O)C(CO)O.[CH3:25][O:26][C:27]1[CH:38]=[CH:37][CH:36]=[CH:35][C:28]=1[O:29][CH2:30][CH:31]([OH:34])[CH2:32][OH:33].N1C=CC=CC=1.O>C(Cl)Cl>[OH:34][CH:31]([CH2:30][O:29][C:28]1[CH:35]=[CH:36][CH:37]=[CH:38][C:27]=1[O:26][CH3:25])[CH2:32][O:33][S:3](=[O:5])(=[O:4])[N:2]([CH3:7])[CH3:1]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COc1ccccc1OCC(O)CO
Agent: COc1ccc(CC(O)CO)c(C(=O)O)c1O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COc1ccccc1OCC(O)COS(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 100 %

Procedure:
To a stirred solution of 21.9 g (152.5 mole) of the dimethylsulfamoyl chloride prepared in (a) above in 60 ml of methylene chloride was added a solution of 7.6 g (0.038 mole) of 3-(2-methoxyphenoxy)-1,2-propanediol (glyceryl guaiacolate) and 12.1 g (0.152 mole) of pyridine in 40 ml of methylene chloride at such a rate that the reaction temperature was maintained at ≤12° C. The reaction mixture was stirred at ambient temperature for 4 days. Water, 200 ml, was added to the mixture and the layers were separated. The organic layer was washed successively with two 200 ml portions of 2N hydrochloric acid and 200 ml of water, dried over magnesium sulfate and the solvent was evaporated under reduced pressure to give 11.6 g of yellow liquid. The liquid was purified by high pressure chromatography using a Waters Associates Prep LC/System 500 A with PrepPak® silica. Eluting solvent used was 10:1 mixture of methylene chloride to ethyl acetate at a flow rate of 200 ml/min. Fractions containing the title compound were combined and the solvents were evaporated under reduced pressure to give 3.9 g (33%) of title compound as a yellow, viscous oil.
Reaction SMILES: I[C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:5]=[C:4]([I:16])[N:3]=1.C([Li])CCC.O.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[I:16][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[C:7]([O:8][CH3:9])=[CH:2][N:3]=1
Reactant: COCCCCc1cc(I)nc(I)c1OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCCCCc1cc(I)ncc1OC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
2 mmol of 2,6-diiodo-3-methoxy-4-(4-methoxy-butyl)-pyridine are added to a solution of 4 mmol n-butyllithium in 1.6 ml hexane and 10 ml tetrahydrofuran at −78° C. under an argon atmosphere. The reaction mixture is stirred at −78° C. for 15 minutes. 2 mmol of water are introduced and the reaction mixture is warmed to room temperature. 10% Aqueous ammonium chloride solution is added to the mixture followed by extraction with tert-butyl methyl ether (3×). The combined organic layers are dried over sodium sulphate, filtered and concentrated. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) and identified based on its Rf value.
Reaction SMILES: O.O.O.C([O-])(=O)C.[Na+].Br[CH:10](Br)[C:11]([C:13]([F:16])([F:15])[F:14])=O.CC1C=C(C=[CH:25][N:26]=1)C=O.[NH3:27]>O.CO>[F:14][C:13]([F:16])([F:15])[C:11]1[N:27]=[CH:25][NH:26][CH:10]=1
Reactant: O=C(C(Br)Br)C(F)(F)F
Reactant: Cc1cc(C=O)ccn1
Reactant: N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: FC(F)(F)c1c[nH]cn1
Reaction time: 4.5 h

Procedure:
To a solution of sodium acetate trihydrate (5.8 g.) in water (20 ml.) is added 1,1-dibromo-3,3,3-trifluoroacetone (5.9 g., 0.022 mole). The solution is heated 45 minutes at steam bath temperature and then cooled. The solution is added to a solution of 2-methylisonicotinaldehyde (2.4 g., 0.02 mole) in methanol (100 ml.) and concentrated aqueous ammonia (25 ml.). The reaction mixture is allowed to stand 4.5 hours at room temperature. The reaction mixture is concentrated under reduced pressure; an oil separates and solidifies and this is filtered (0.6 g.) after recrystallization from a mixture of water and ethanol to afford 2-methyl-4-pyridyl)-4-trifluoromethylimidazole, m.p., 195°-197° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=O)[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:26][O:27][CH2:28][CH2:29][NH2:30]>CN(C)C(=O)C>[OH:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:8])[N:30]([CH2:29][CH2:28][O:27][CH3:26])[C:11]2=[O:13]
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Reactant: COCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Product: COCCN1C(=O)c2ccc(O)cc2C1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.5 %

Procedure:
A mixture of 4-hydroxyphthalic acid (0.91 mg, 5.0 mmol) and carbonyldiimidazole (0.85 g, 5 mmol) in N,N-dimethylacetamide (3 mL) was stirred at room temperature for 45 min. To this mixture was added 2-methoxyethylamine (0.47 g, 6.0 mmol) and the resulting mixture heated under reflux for 15 min. After cooling to room temperature, the mixture was evaporated and the residue was purified by chromatography (SiO2, CH2Cl2: 2N NH3/MeOH 19:1 to 9:1) to afford the title compound (1.1 g, 95%) as a light yellow solid. MS: m/e=220.1 (M−H−).
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C1COCC1.[C:14]1(=[O:20])[CH2:19][CH2:18][CH2:17][CH:16]=[CH:15]1.Cl>C(OCC)(=O)C>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][C:14]1([OH:20])[CH2:19][CH2:18][CH2:17][CH:16]=[CH:15]1)[CH3:8]
Reactant: O=C1C=CCCC1
Reactant: CCOC(=O)C[Zn]Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)C=CCCC1
Yield: 87 %

Procedure:
Under nitrogen atmosphere, 20 mL of ethyl acetate was added to 3.05 g (5 mmol, 1.0 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.48 g (5 mmol) of 2-cyclohexen-1-one in 5 mL of ethyl acetate was added dropwise while stirring at 0˜5° C. The mixture was stirred at 0˜5° C. for 3 hours. 10 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL (×2) of an aqueous saturated sodium chloride solution, 10 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 10 mL of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 0.80 g of the desired product (yield 87%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([CH2:17][C:18]1[NH:19][CH:20]=[CH:21][N:22]=1)=[C:11]2[CH3:23])=[O:7])[CH3:4].S(OC)(O[CH3:28])(=O)=O>CN(C)C=O>[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:28])[C:12]([CH2:17][C:18]1[NH:22][CH:21]=[CH:20][N:19]=1)=[C:11]2[CH3:23])=[O:7])[CH3:4]
Reactant: CCOC(=O)c1ccc2[nH]c(Cc3ncc[nH]3)c(C)c2c1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)c(C)c(Cc1ncc[nH]1)n2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
Sodium hydride (0.11 g of 50% dispersion in mineral oil) was added portionwise to a stirred solution of 2-[1-imidazolylmethyl]-3-methylindole-5-carboxylic acid ethyl ester (0.57 g) in dry N,N-dimethylformamide (20 ml) and the mixture was stirred at room temperature for 30 minutes. A solution of dimethyl sulphate (0.26 g) in dry N,N-dimethyl-formamide (2.5 ml) was added dropwise and the mixture was stirred at room temperature for 18 hours and then evaporated. The residue was chromatographed on silica gel. Elution with chloroform first gave mineral oil and impurity followed by pure product. Evaporation of the product-containing fractions gave a solid which was crystallised froml ethyl acetate/petrol (b.p. 60°-80°) to give 1,3-dimethyl-2-[1-imidazolylmethyl]indole-5-carboxylic acid ethyl ester (0.40 g), m.p. 109°-110°.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=[C:3]1[C:12]#[N:13].[N-:14]=[N+:15]=[N-:16].[Na+].[Cl-].[NH4+]>CN(C)C=O>[NH:14]1[C:12]([C:3]2[C:2](=[O:1])[N:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]3=[N:5][CH:4]=2)=[N:13][N:16]=[N:15]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cnc2ccccn2c1=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c(-c2nnn[nH]2)cnc2ccccn12
Yield: 19.1 %

Procedure:
A stirred mixture of 4-oxo-4H-pyrido[1,2-a]-pyrimidine-3-carbonitrile (2.17 g., 0.0127 mole), sodium azide (0.911 g., 0.014 mole), and ammonium chloride (0.75 g., 0.014 mole) in N,N-dimethylformamide (20 ml.) was heated by means of an oil bath maintained at 120° for 19 hours. The solvent was removed and the residue treated with hot aqueous sodium bicarbonate. The mixture was filtered. The filtrate was acidified with acetic acid. The precipitate was collected and recrystallized from acetic acid to give the title compound (0.52 g., 19%) m.p. 308°-309° (decomp). Recrystallization from acetic acid with charcoal treatment gave analytical material, m.p. 311°-312° (decomp).
Reaction SMILES: C([N:3]([CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:4](=[O:10])[O:5][C:6]([CH3:9])(C)C)C.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1.C(=O)([O-])O.[Na+]>C(#N)C>[CH2:6]([O:5][C:4](=[O:10])[NH:3][CH:11]1[CH2:12][CH2:13][N:14]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([OH:34])([C:26]([F:27])([F:28])[F:29])[C:30]([F:31])([F:32])[F:33])=[CH:23][CH:24]=2)[CH2:15][CH2:16]1)[CH3:9]
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: CCN(C(=O)OC(C)(C)C)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)NC1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Yield: 70.4 %

Procedure:
A mixture of tert-butyl ethyl(piperidin-4-yl)carbamate (10.95 mmol, 2.5 g), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (10.95 mmol, 3.69 g) and sodium hydrogencarbonate (16.42 mmol, 1.380 g) in acetonitrile (40 ml) was refluxed for 2 hours. The reaction was concentrated under reduced pressure and dichloromethane was added. The suspension was filtered and the filtrate was chromatographed on silica (eluting with a gradient of dichloromethane to ethyl acetate) to give the title compound (3.3 g). MS (ESI) m/z 485.1 [M+H]+
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:10]2=[N:11][C:12]([NH:15][C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)=[N:13][CH:14]=[C:9]2[CH:8]=[N:7]1.[O:25]1[CH2:30][CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH2:27][CH2:26]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.CO>[O:25]1[CH2:26][CH:27]=[C:28]([C:2]2[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=2)[CH2:5][N:6]2[C:10]3=[N:11][C:12]([NH:15][C:16]4[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=4)=[N:13][CH:14]=[C:9]3[CH:8]=[N:7]2)[CH2:29][CH2:30]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Cn1cc(Nc2ncc3cnn(Cc4cccc(I)c4)c3n2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC#N
Product: Cn1cc(Nc2ncc3cnn(Cc4cccc(C5=CCOCC5)c4)c3n2)cn1

Procedure:
1-(3-iodobenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (50 mg, 0.12 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (29 mg, 1.2 eq), sodium carbonate (31 mg, 2.5 eq) and bis(diphenylphosphino)-ferrocenedichloropalladium(II)-DCM-complex (5 mg, 0.05 eq) in ACN/water (1:1, 2 mL) were heated in the microwave for 30 min at 130° C. The reaction mixture was diluted with methanol, passed through a thiol column, washed with methanol and evaporated. The residue was dissolved in DCM, the organic phase washed with water, dried over sodium sulfate and concentrated in vacuo to afford 1-(3-(3,6-dihydro-2H-pyran-4-yl)benzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4](=O)[CH2:3]1.[CH:9]([NH2:12])([CH3:11])[CH3:10]>>[CH3:10][CH:9]([N:12]=[C:4]1[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3]1)[CH3:11]
Reactant: CC(C)N
Reactant: CC1CCCC(=O)C1
Product: CC1CCCC(=NC(C)C)C1
Reaction time: 8 h

Procedure:
To a mixture of 112 g. 3-methyl cyclohexanone and 120 g. isopropylamine are added 100 g. Linde Type 3A molecular sieves. The mixture is allowed to stand overnight at room temperature, after which the sieves are removed by filtration and the excess of isopropylamine is removed in vacuo at room temperature. The oil residue is 1-methyl-N-(3-methyl cyclohexylidene)-ethylamine, b.p. 36 to 0.5 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][NH:15][CH:16]=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[CH:12].C(N(CC)CC)C.C(=O)(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[C:37]1([CH2:43][CH2:44][CH:45]=[O:46])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[OH:46][CH:45]([CH2:44][CH2:43][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:16]([NH:15][CH2:14][CH2:13][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]#[CH:12])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:17]
Reactant: C#CCOc1ccc(CCNC=O)cc1OC
Reactant: O=CCCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCOc1ccc(CCNC(=O)C(O)CCc2ccccc2)cc1OC
Temperature: -78 °C
Reaction time: 4 h

Procedure:
N-[2-(3-Methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-formamide (8.0 g, 34 mmol) and triethylamine (8.3 g, 82 mmol) are dissolved in dichloromethane (80 ml). Bis(trichloromethyl) carbonate (triphosgene, 4.0 g, 14 mmol) in dichloromethane (40 ml) is added at +5° C. The mixture is stirred for 4 hours at +5° C. and then cooled to −78° C. A solution of titanium tetrachloride (7.0 g, 38 mmol) in dichloromethane (70 ml) is added and the mixture is stirred for 2 hours at −40° C. 3-Phenylpropionaldehyde (4.8 g, 36 mmol) in dichloromethane (50 ml) is added dropwise and the mixture is stirred for 17 hours at room temperature. The mixture is hydrolysed with 5N HCl (25 ml), stirred 30 minutes at room temperature and washed with water. After evaporation of the organic layer the residue is submitted to flash-chromatography (ethyl acetate/hexane 6:3) to give 2-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxyphenyl)-ethyl]-4-phenyl-butyramide (Compound E1.01).
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:23][CH:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:24])[C:14](=[O:25])[CH:13]1[CH:9]([CH2:10][CH:11]([O:26][C:27]3[CH:32]=[C:31]([C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)[N:30]=[C:29]([O:41][CH3:42])[N:28]=3)[CH2:12]1)[C:8](=[O:43])[NH:7]2)=[O:5])C.[Li+].[OH-]>C1COCC1.CO>[CH3:42][O:41][C:29]1[N:28]=[C:27]([O:26][CH:11]2[CH2:10][CH:9]3[CH:13]([C:14](=[O:25])[N:15]([CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][CH:22]4[C:6]([C:4]([OH:5])=[O:3])([NH:7][C:8]3=[O:43])[CH2:23]4)[CH2:12]2)[CH:32]=[C:31]([C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)[N:30]=1
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(-c4ccc(OC)cc4)nc(OC)n3)CC1C(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2cc(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)nc(OC)n2)cc1
Yield: 35.4 %

Procedure:
A solution of the ethyl ester 16e (1.2 g, 2 mmol) in THF/MeOH 1:1 (30 ml) was treated with a 1M solution of LiOH as described in Example 13 step d. Purification by column chromatography on silica gel gave the crude title compound, (400 mg, 77%), (M+H)+565.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[N:13]3[C:14]([C:24]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[CH:30][CH:29]=4)=[C:25]([CH2:26][CH3:27])[C:12]3=[CH:11][CH:10]=1)=C(C(O)=O)C=2C(O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:42]([O:45][C:46](=[O:48])[CH3:47])(=[O:44])[CH3:43]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:17]2[N:13]3[C:14]([C:24]([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[CH:32][CH:33]=4)=[C:25]([CH2:26][CH3:27])[C:12]3=[CH:11][CH:10]=1)=[C:47]1[C:46](=[O:48])[O:45][C:42](=[O:44])[C:43]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c(C(=O)O)c(C(=O)O)c3c(OCc4ccccc4)ccc1n32
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c3c(c4c(OCc5ccccc5)ccc1n42)C(=O)OC3=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7Benzyloxy-3-(4-benzyloxyphenyl)-4-ethylpyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylic acid (34.00 g, 60 mmol) was dissolved in 200 ml of pyridine under a nitrogen atmosphere. Acetic acid anhydride (8.8 ml, 90 mmol) was added and the mixture was stirred at room temperature for 21/2 hours. The reaction mixture was allowed to cool to room temperature and the product was filtered off, and washed with petroleum ether. This gave 25.63 g (81%) of the title compound as yellow crystals. M.p. 229-231° C. MS(SP): m/z 527 (M+). 1H-NMR (CDCl3, and DMSO-d6, 300 MHz) δ: 1.47 (t, 3H); 3.20 (q, 2H); 5.18 (s, 2H); 5.59 (s, 2H); 7.19 (d, 2H); 7.30-7.55 (m, 9H); 7.62 (d, 2H); 7.79 (d, 2H); 7.98 (d, 1H).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH3:6])[CH2:3][CH3:4].Cl[C:8]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:11]([CH2:12][O:13][CH2:14][CH2:15][OH:16])=[C:10]([CH3:22])[C:9]=1[N+:23]([O-:25])=[O:24].Cl>C1(C)C=CC=CC=1>[CH2:3]([CH:2]([NH:1][C:8]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:11]([CH2:12][O:13][CH2:14][CH2:15][OH:16])=[C:10]([CH3:22])[C:9]=1[N+:23]([O-:25])=[O:24])[CH2:5][CH3:6])[CH3:4]
Reactant: Cc1c(COCCO)cc([N+](=O)[O-])c(Cl)c1[N+](=O)[O-]
Reactant: CCC(N)CC
Agent: Cl
Solvent: Cc1ccccc1
Product: CCC(CC)Nc1c([N+](=O)[O-])cc(COCCO)c(C)c1[N+](=O)[O-]
Yield: 93.1 %

Procedure:
3-Aminopentane (1.74 g; 0.02 mol) is added to a solution of 2-(4-chloro-2-methyl-3,5-dinitrobenzyloxy)ethanol (0.5 g; 1.7×10-3 mol) in toluene. The reaction mixture is heated at reflux for 3 hours. Analysis by tlc (silica gel plate; eluent: methanol-benzene in a 1:9 ratio) shows the reaction to be complete. The reaction mixture is poured into 10% hydrochloric acid and extracted with methylene chloride. The organic phase is dried over calcium sulfate; and evaporated in vacuo to afford 0.54 g (91.8%) of an orange-colored oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH3:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:12].O.O.[C:15](O)(=[O:19])[C:16](O)=[O:17]>Cl>[OH:17][C:16]1[C:15]([OH:19])=[N:1][C:2]2[C:3](=[CH:4][CH:5]=[C:6]3[N:7]([CH3:11])[N:8]=[N:9][C:10]3=2)[N:12]=1
Reactant: O=C(O)C(=O)O
Reactant: Cn1nnc2c(N)c(N)ccc21
Agent: Cl
Solvent: O
Product: Cn1nnc2c3nc(O)c(O)nc3ccc21
Yield: 90.8 %

Procedure:
A solution of 4,5-diamino-1-methylbenzotriazole (1.2 g, 7.4 mmol) and oxalic acid dihydrate (1.2 g, 9.6 mmol) in 40 ml of 4M hydrochloric acid was refluxed on an oil bath for 2 h and allowed to cool. The resulting precipitate was collected by filtration and washed with water and ethanol to give 1.46 g (91%) of the title compound; m.p.>300° C.; IR (KBr): 1700 cm-1 ; 1H-NMR (DMSO-d6) 4.32 (s, 3H, CH3)), 7.33 (d, J=9 Hz), 1H, ArH), 7.55 (d, J=g Hz, 1H, ArH), 12.03 (broad s, 1H, OH), 12.67 (broad s, 1H, OH).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[Cl:13][CH2:14][CH2:15][CH2:16][S:17](Cl)(=[O:19])=[O:18].O.C(OCC)(=O)C>N1C=CC=CC=1>[Cl:13][CH2:14][CH2:15][CH2:16][S:17]([NH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12])(=[O:19])=[O:18]
Reactant: COC(=O)c1ccc(N)c(C)c1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NS(=O)(=O)CCCCl)c(C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
100 mg (0.61 mmol) methyl 4-amino-3-methyl-benzoate dissolved in 3 ml of pyridine are combined with 82 μl (0.67 mmol) 3-chloropropanesulphonic acid chloride and stirred for 16 hours at ambient temperature. The reaction solution is combined with water and ethyl acetate and then the aqueous phase is again extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down i. vac. The residue is further reacted without any more purification.