Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[Cl:10].[C:11]1([Si:17]([C:30]#[CH:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCOCC1.[Cu]I>[C:24]1([Si:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:30]#[C:31][C:2]2[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=2[Cl:10])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C#C[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Clc1cc(Cl)c(Br)c(Cl)c1
Agent: [Cu]I
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Clc1cc(Cl)c(C#C[Si](c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1
Reaction time: 20 h

Procedure:
In an argon atmosphere, 9 g (34.6 mmol) of 1-bromo-2,4,6-trichlorobenzene, 9.8 g (34.45 mmol) of triphenylsilylacetylene, and 15 mL of triethylamine are dissolved in 100 mL of absolute dioxane and at 90° C. combined with 0.2 g (1.04 mmol) of copper (I) iodide and 1.2 g (1.04 mmol) of tetrakistriphenylphosphine palladium and stirred for 20 hours. The reaction mixture is filtered through CELITE® filter aid and the filtrate is evaporated down. The residue is taken up in ethyl acetate and extracted with water. The organic phase is dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluant: petroleum ether/toluene (5:1)). The product is recrystallized from petroleum ether and dried in the vacuum drying chamber at 70° C. Yield: 6.9 g (43% of theory); melting point: 115° C.-120° C.; C26H17Cl3Si (M=463.87); calc.: molecular ion peak (M+H)+: 463/465/467/469; found: molecular ion peak (M+H)+: 463/465/467/469; Rf value: 0.6 (silica gel, petroleum ether/toluene (4:1)).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]([C:8]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][N:9]=1)=[O:7])[CH3:2].C(OC(=O)C(C(C1C(F)=CC=CN=1)=O)=[CH:21][N:22]([CH3:24])[CH3:23])C>>[CH2:1]([O:3][C:4](=[O:15])[C:5]([C:6]([C:8]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][N:9]=1)=[O:7])=[CH:21][N:22]([CH3:24])[CH3:23])[CH3:2]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ncccc1F
Reactant: CCOC(=O)CC(=O)c1nccnc1Cl
Product: CCOC(=O)C(=CN(C)C)C(=O)c1nccnc1Cl

Procedure:
2-(3-Chloro-pyrazine-2-carbonyl)-3-dimethylamino-acrylic acid ethyl ester (13) (1.2 g, crude) was synthesized as a sticky liquid from 1 g of 3-(3-chloro-pyrazin-2-yl)-3-oxo-propionic acid ethyl ester (12) following the procedure described for 3-dimethylamino-2-(3-fluoro-pyridine-2-carbonyl)-acrylic acid ethyl ester (4).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]([OH:8])=O)(=[O:4])=[O:3].[NH2:9][CH2:10][C@H:11]([CH3:39])[O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[C:15]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[C:26]([Cl:38])[CH:25]=1)=[N:16][CH:17]=[N:18]2>>[Cl:38][C:26]1[CH:25]=[C:24]([NH:23][C:15]2[C:14]3[C:19](=[CH:20][CH:21]=[CH:22][C:13]=3[O:12][C@@H:11]([CH3:39])[CH2:10][NH:9][C:6](=[O:8])[CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[N:18]=[CH:17][N:16]=2)[CH:29]=[CH:28][C:27]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1
Reactant: CS(=O)(=O)CC(=O)O
Reactant: C[C@@H](CN)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: C[C@@H](CNC(=O)CS(C)(=O)=O)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 72 %

Procedure:
The procedure described in Example 1 was repeated using methanesulfonylacetic acid and 5-[(1S)-2-amino-1-methylethoxy]-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 36, preparation of starting materials) to give the title compound in 72% yield; NMR spectrum (DMSO-d6) 1.42 (d, 3H), 3.02 (s, 3H), 3.49 (m, 1H), 3.76 (m, 1H), 4.06 (s, 2H), 4.89 (m, 1H), 5.28 (s, 2H), 7.22 (m, 2H), 7.34 (m, 2H), 7.56 (d, 2H), 7.72 (t, 1H), 7.86 (dt, 1H), 8.15 (d, 1H), 8.48 (s, 1H), 8.58 (d, 1H), 8.71 (t, 1H), 9.93 (s, 1H); Mass Spectrum MH+ 556.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:22]([O:24]C)=O)[C:15](=[CH:20][CH:21]=1)[C:16]([O:18]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](#[N:28])[CH3:27].[H-].[Na+]>CCOCC>[C:26]([CH:27]1[C:22](=[O:24])[C:14]2[C:15](=[CH:20][CH:21]=[C:12]([O:11][CH2:10][CH2:9][CH2:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:13]=2)[C:16]1=[O:18])#[N:28]
Reactant: COC(=O)c1ccc(OCCCOc2ccccc2)cc1C(=O)OC
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: N#CC1C(=O)c2ccc(OCCCOc3ccccc3)cc2C1=O
Reaction time: 6 h
Yield: 86 %

Procedure:
A mixture of dimethyl 4-(3-phenoxypropoxy)phthalate (6.5g; 0.019 mole), acetonitrile (10ml) and sodium hydride (0.69g of 100%) was stirred at 100° for 6 hours and dry ether added to the cooled yellow product. The solid which separated was filtered off, dissolved in water and the solution strongly acidified with concentrated hydrochloric acid. Filtration of the precipitated solid gave the title compound which recrystallised from ethanol dilute hydrochloric acid with mp 148°-150° (dec) and in 86% yield. (Found; C, 69.00; H, 4.90; N, 4.41; C19H15NO4 0.5H2O requires; C, 69.08; H, 4.88; N, 4.24%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=1)(=[O:9])=[O:8].[NH3:17]>CO>[NH2:17][C:13]1[N:12]=[CH:11][C:10]([S:7]([NH:6][C:2]2[S:1][CH:5]=[CH:4][N:3]=2)(=[O:9])=[O:8])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Nc1nccs1)c1ccc(Cl)nc1
Reactant: N
Solvent: CO
Product: Nc1ccc(S(=O)(=O)Nc2nccs2)cn1

Procedure:
6-Chloro-pyridine-3-sulfonic thiazol-2-ylamide (200 mg, 0.0007 mol) in 7 M of Ammonia in methanol (5.00 mL) was heated at 160° C. in a pressure bottle for ˜6 h. The reaction had to be stopped because the pressure was too high and some of the reaction solution was leaking. By LC/MS, reaction show ˜30% conversion. The reaction solution was concentrated and then purified on Gilson (Prep LC, reverse phase, Phenomenex 250×30 mm, 15 micron C18 column, 40 mL/min. Gradient, 85% A to 100% B over 25 min. Solvent A: 7800 water/200 acetonitrile/8 TFA. Solvent B: 7200 acetonitrile/800 water/8). Fractions were checked by LC/MS and dried on a lyophilizer to give the product as a brown oil.
Reaction SMILES: [O:1]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][NH:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O1CCOCC1>[O:1]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][N:4]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCCO2
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(C(=O)OCc1ccccc1)CCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (5.80 g) and dioxane (100 mL), 1 M aqueous sodium hydroxide (24.9 mL) and benzyl chloroformate (3.55 mL) were added sequentially under ice cooling and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and then extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=9:1-1:1) to give 4-benzyl 9-tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4,9-dicarboxylate (8.06 g) as a colorless syrup.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]3[C:11]([CH2:12][NH:13][CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:17][CH2:16]1.C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35]>ClCCl>[Cl:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]3[C:11](=[N:10][N:9]=[C:8]3[C@H:15]3[CH2:16][CH2:17][C@H:18]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:19][CH2:20]3)[CH2:12][N:13]([C:34](=[O:36])[CH3:35])[CH2:14][C:5]=2[CH:4]=1
Reactant: CC(=O)Cl
Reactant: CC(C)O[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CNC3)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](OC(C)C)CC2)C1
Reaction time: 19 h

Procedure:
To a solution of trans-8-chloro-1-(4-isopropoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride (0.080 g, 0.20 mmol) and triethylamine (0.059 ml, 0.42 mmol) in dichloromethane (5 ml) was added acetyl chloride (0.016 ml, 0.22 mmol) at room temperature. After stirring for 19 h the reaction mixture was concentrated in vacuo. Flash-chromatography with n-heptane/2-propanol as eluent gave the title compound (0.062 g, 77%) as white solid. MS m/e: 403 (M+H+).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].C([O:8][C:9](=O)[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20](=[O:35])[C:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:14][CH:13]=1)C>CO.O>[OH:3][NH:2][C:9](=[O:8])/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20](=[O:35])[C:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)C=Cc1ccc(CNC(=O)C(=Cc2ccccc2)c2ccccc2)cc1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(/C=C/c1ccc(CNC(=O)C(=Cc2ccccc2)c2ccccc2)cc1)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.2 %

Procedure:
Hydroxylamine hydrochloride (1.2 g, 17.5 mmol) in methanol (7.5 mL) was mixed with KOH (1.2 g, 17.5 mmol) in methanol (4 mL) at 0° C. and the reaction mixture was sonicated for 5 minutes. A white precipitate was formed which was filtered. The filtrate was immediately added to the ethyl-3-(4-((2,3-diphenylacrylamido)methyl)phenyl)acrylate (0.4 g, 0.9 mmol) followed by the addition of KOH. (0.14 g, 2.4 mmol) and the mixture was stirred at room temperature for 1 hour. Reaction mixture was diluted with water 20 mL and extracted with ethyl acetate, (100 mL). The organic layer was washed successively with water (3×50 mL) and brine solution (3×50 mL). The organic layer was dried over Na2SO4 and concentrated to give the crude compound, triturated with dichloromethane (20 mL), to afford the title compound as a pure colorless solid (0.040 g, 10% yield). 1H NMR (DMSO-d6) δ (ppm): 4.02-4.04 (2H, d, —CH2), 6.41-6.45 (1H, d, ═CH), 7.01-7.03 (2H, d, Ar—H), 7.17-7.22 (5H, m, Ar—H), 7.28-7.30 (2H, d, Ar—H), 7.41-7.46 (4H, m, Ar—H & ═CH), 7.46 (1H, s, ═CH), 7.50-7.52 (2H, d, Ar—H), 7.99-8.01 (1H, t, —NH), 9.03 (1H, s, —OH), 10.74 (1H, s, —NH). MS m/z: 399.1 (M++1). The following compounds were prepared according to the above procedure
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([O:17][C:18]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=O)C(=O)C1.CO.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>O>[OH:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][C:18]([NH:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:17])=[CH:27][CH:26]=1
Reactant: NCCc1ccccc1
Reactant: O=C(CCc1ccc(O)cc1)ON1C(=O)CCC1=O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(CCc1ccc(O)cc1)NCCc1ccccc1
Reaction time: 0.5 h
Yield: 75 %

Procedure:
β-Phenylethylamine is derivatized with Bolton-Hunter reagent as follows. β-Phenylethylamine and Bolton-Hunter reagent were mixed in equimolar quantities in a 1:1 solution of methanol and sodium phosphate buffer (1M, pH 8). After 30 minutes, an excess of water was added. A crystalline solid was collected, washed with water and dried in vacuo giving 1-[3-(4-hydroxyphenyl)-propionylamino]-2-(phenyl) ethane in 75% yield.
Reaction SMILES: [CH2:1]1[CH2:27][O:26][C:3]2([CH2:8][CH2:7][N:6]([C:9]3[N:14]=[C:13](Cl)[CH:12]=[C:11]([N:16]4[CH2:21][CH2:20][C:19]5([O:25][CH2:24][CH2:23][O:22]5)[CH2:18][CH2:17]4)[N:10]=3)[CH2:5][CH2:4]2)[O:2]1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:1]1[CH2:27][O:26][C:3]2([CH2:8][CH2:7][N:6]([C:9]3[N:10]=[C:11]([N:16]4[CH2:21][CH2:20][C:19]5([O:25][CH2:24][CH2:23][O:22]5)[CH2:18][CH2:17]4)[CH:12]=[C:13]([N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[N:14]=3)[CH2:5][CH2:4]2)[O:2]1
Reactant: Clc1cc(N2CCC3(CC2)OCCO3)nc(N2CCC3(CC2)OCCO3)n1
Reactant: C1CNCCN1
Product: c1c(N2CCNCC2)nc(N2CCC3(CC2)OCCO3)nc1N1CCC2(CC1)OCCO2
Yield: 55.7 %

Procedure:
2,6-bis(4,4-Ethylenedioxy-1-piperidinyl)-4-chloropyrimidine is reacted with piperazine in the way described in Example 5 to obtain the title compound in a yield of 55.7%, m.p.:130°-140° C.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:15][O:16][C:17](=[O:25])/[C:18](/[N+:23]#[C-:24])=[CH:19]/N(C)C.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:15][O:16][C:17]([C:18]1[N:23]=[CH:24][N:12]([CH2:11][C:10]2[CH:13]=[CH:14][C:7]([CH2:6][N:1]3[CH:5]=[CH:4][CH:3]=[N:2]3)=[CH:8][CH:9]=2)[CH:19]=1)=[O:25]
Reactant: [C-]#[N+]/C(=C\N(C)C)C(=O)OC
Reactant: NCc1ccc(Cn2cccn2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COC(=O)c1cn(Cc2ccc(Cn3cccn3)cc2)cn1
Temperature: 120 °C

Procedure:
A mixture of 4-Pyrazol-1-ylmethyl-benzylamine (550 mg, 2.5 mmol), (Z)-methyl-3-(dimethylamino)-2-isocyanoacrylate (380 mg, 2.5 mmol) and DIPEA (1.3 mL, 7.4 mmol) in 20 mL nBuOH was heated to 120° C. for 16 h. The mixture was concentrated in vacuo and the crude product was used in the next step without further purification. LCMS (method A) RtA=1.210 min; [M+H]+=297.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11](Cl)=[CH:10][C:9]=2[CH3:15])=[CH:4][CH:3]=1.[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[NH:17][NH2:18]>C(O)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:18][NH:17][C:16]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][C:9]=2[CH3:15])=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)nnc1-c1ccc(Br)cc1
Reactant: CCOC(=O)NN
Solvent: CCCCO
Product: CCOC(=O)NNc1cc(C)c(-c2ccc(Br)cc2)nn1
Temperature: 25 °C

Procedure:
A mixture of 8.49 g. of 6-(p-bromophenyl)-5-methyl-3-chloropyridazine and 6.25 g. of ethyl carbazate in 100 ml. of n-butyl alcohol is prepared. This solution is stirred and heated at reflux temperature for 4 hours. The reaction mixture is cooled to room temperature and the solvent removed on a rotating evaporator. Water is added to the residue and the resulting solid filtered, washed with water, ether and dried. The product is recrystallized from ethanol to yield the product, m.p. 178°-179° C.
Reaction SMILES: [C:1](=O)([CH3:20])[CH2:2][N:3]1[CH2:8][C@H:7]2[CH2:9][C@@H:4]1[CH2:5][N:6]2S(C1C=CC(C)=CC=1)(=O)=O.[H][H]>CC1OCCC1.[Pd]>[CH:4]([N:6]1[CH2:5][C@H:4]2[CH2:9][C@@H:7]1[CH2:8][N:3]2[C:2]1[CH:1]=[CH:20][C:2]([NH2:3])=[CH:1][CH:20]=1)([CH3:9])[CH3:5]
Reactant: [H][H]
Reactant: CC(=O)CN1C[C@H]2C[C@@H]1CN2S(=O)(=O)c1ccc(C)cc1
Agent: [Pd]
Solvent: CC1CCCO1
Product: CC(C)N1C[C@H]2C[C@@H]1CN2c1ccc(N)cc1

Procedure:
A solution of 3 (1.6 g; 6 1 mmol) in 2-MeTHF (25 mL) is stirred under a 1 bar hydrogen atmosphere in the presence of Pd/C catalyst (10% Degussa type E101 NE/W; 0.1 g) at 30° C. for a period of 3 h. The catalyst is filtered off over a bed of Dicalite 478 and the filter cake washed with 2-MeTHF (2×10 mL). The filtrate is concentrated in vacuo to a volume of 25 mL and the resulting solution is used as such in the next step.
Reaction SMILES: [C:1]([NH:5][C:6]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[C:8](=[C:9](I)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:27]2[NH:31][C:30]3[C:32]4([CH2:37][CH2:36]4)[NH:33][C:34](=[O:35])[C:29]=3[CH:28]=2)O1>>[C:1]([NH:5][C:6]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[C:8](=[C:9]([C:27]3[NH:31][C:30]4[C:32]5([CH2:37][CH2:36]5)[NH:33][C:34](=[O:35])[C:29]=4[CH:28]=3)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(NC(C)(C)C)nc2c(I)cccc2c1=O
Reactant: CC1(C)OB(c2cc3c([nH]2)C2(CC2)NC3=O)OC1(C)C
Product: Cn1c(NC(C)(C)C)nc2c(-c3cc4c([nH]3)C3(CC3)NC4=O)cccc2c1=O
Yield: 21.1 %

Procedure:
This compound (35 mg, 21% yield) as a brown solid was prepared according to the procedure described for Example 448, using 2-(tert-butylamino)-8-iodo-3-methylquinazolin-4(3H)-one (701) (157 mg, 0.44 mmol) and 2′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1′H-spiro[cyclopropane-1,6′-pyrrolo[3,4-b]pyrrol]-4′(5′H)-one (707) (157 mg, 0.57 mmol) as the starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.57 (1H, br.), 7.89 (2H, t, J=7.4 Hz), 7.67 (1H, s), 7.19 (1H, t, J=7.6 Hz), 6.81 (1H, s), 5.96 (1H, s), 3.49 (3H, s), 1.50 (9H, s), 1.41 (2H, m), 1.34 (2H, m). m/z (ESI, +ve) 378.0 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:15]=[CH:14][NH:13][C:9]=3[N:10]=[CH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([I:23])C(=O)C1>CN(C=O)C>[I:23][C:15]1[C:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:12][CH:11]=[N:10][C:9]=2[NH:13][CH:14]=1
Reactant: O=C1CCC(=O)N1I
Reactant: c1ccc(-c2ncnc3[nH]ccc23)cc1
Solvent: CN(C)C=O
Product: Ic1c[nH]c2ncnc(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-phenyl-7H-pyrrolo[2,3-d]pyrimidine (5.28 g, 27.0 mmol) in DMF (100 mL) was added NIS (6.57 g, 29.2 mmol). The reaction was stirred at room temperature for 1.5 hours. The reaction mixture was quenched with water (150 mL) and the resulting precipitated product was filtered and washed with water. The filtrate cake was dried under vacuum to afford 5-iodo-4-phenyl-7H-pyrrolo[2,3-d]pyrimidine as a yellow solid. LRMS (ESI) calcd for C12H8IN3 [M]+: 321, found 321. 1H NMR (600 MHz, DMSO-D6) δ 12.71 (s, 1H), 8.83 (s, 1H), 7.87 (d, J=2.45 Hz, 1H), 7.68 (t, J 1.45 Hz, 1H), 7.67 (d, J=3.42 Hz, 1H), 7.54 (d, J=1.96 Hz, 2H), 7.53 (t, J=1.46 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14]C(=O)OCC)=S)[N:4]=1.Cl.NO.C([N:26](C(C)C)CC)(C)C>C(O)C>[NH2:26][C:12]1[N:11]=[C:5]2[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]2[N:14]=1
Reactant: CCOC(=O)NC(=S)Nc1nc(OC)cc(OC)n1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: NO
Solvent: CCO
Product: COc1cc(OC)n2nc(N)nc2n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.4 %

Procedure:
Ethyl N-[N′-(4,6-dimethoxypyrimidin-2-yl)-thiocarbamoyl]carbamate (0.50 g, 1.7 mmol) was mixed with ethanol (5 mL). To this mixture was added hydroxylamine hydrochloride (0.12 g, 1.7 mmol) and diisopropylethylamine (0.30 mL, 1.7 mmol). The resulting mixture was allowed to stir at room temperature. After 2.5 hours, additional diisopropylethylamine (0.30 mL, 1.7 mmol) was added to the mixture. After 48 hours the ethanol was removed in vacuo and the residue was partitioned between H2O and Et2O to give a powder. The powder was filtered and dried to afford the product as a tan powder (0.27 g, 82%). mp 215-220° C. 1H NMR (DMSO-d6): δ6.04 (s, 1H); 5.97 (bs, 2H); 4.04 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:5].C(N(CC)CC)C.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:14])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:23]=[O:25])=[CH:9][CH:8]=1)[CH3:5]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)C(C)Oc1ccc(N)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)C(C)Oc1ccc(N=C=O)cc1
Temperature: 75 °C
Reaction time: 26 h
Yield: 143.8 %

Procedure:
To a mixture of 2-(4-Aminophenoxy)propionic acid methyl ester 18 (15 grams, 76.9 mmol) and triethylamine (15.6 g, 154.16 mmol) in toluene (210 ml) under nitrogen atm. was added triphosgene (8.4 g, 28.3 mmol) in one lot. Later the reaction mixture was heated to 75° C. over a period of one hour and maintained at this temp. for 26 hours. The reaction mixture was cooled to room temperature, the solids were filtered off, and the toluene was distilled off under vacuum to get crude 32, which was vacuum distilled to get pure 32 (9 g, 52.9%) as a light yellow syrup.
Reaction SMILES: [C:1]([NH:9][C@H](C(O)=O)CCC(O)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1[CH:24]=CC=C[CH:20]=1>>[C@H:1]1([NH2:9])[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:24][CH2:19][CH2:20]1
Reactant: c1ccccc1
Reactant: O=C(O)CC[C@H](NC(=O)c1ccccc1)C(=O)O
Product: N[C@@H]1CCCc2ccccc21

Procedure:
The (R) amine is made in the same way as described in Example 8, but from the salt from N-benzoyl-(S)-glutamic acid. It has [α]D25 -54.0° (c 5.1, benzene).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:28]=[C:27]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:25][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[C:14]([CH2:16][C:17]([OH:19])=[O:18])[CH:15]=1)=O)[CH:2]([CH3:4])[CH3:3].[H][H]>C(O)C.[C].[Pd]>[CH2:1]([O:5][C:6]1[CH:28]=[C:27]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:25][C:7]=1[CH2:8][C:10]1[CH:11]=[CH:12][C:13]([O:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[C:14]([CH2:16][C:17]([OH:19])=[O:18])[CH:15]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COc1ccc(C(=O)c2ccc(OCC(C)C)c(CC(=O)O)c2)c(OCC(C)C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)COc1ccc(Cc2ccc(OCC(C)C)c(CC(=O)O)c2)c(OCC(C)C)c1
Yield: 72.2 %

Procedure:
In 2 ml of ethanol is dissolved 200 mg of 2-[5-(2,4-diisobutoxybenzoyl)-2-isobutoxyphenyl]acetic acid. After adding 40 mg of 5% palladium-carbon, the mixture thus obtained is stirred at ambient temperature for one hour in a stream of hydrogen gas. The reaction mixture is filtered with Celite, and the solvent is distilled off under reduced pressure from the filtrate. The residue thus obtained is purified by silica gel column chromatography [eluent; n-hexane:ethyl acetate=4:1] to obtain 140 mg of 2-[5-(2,4-diisobutoxybenzyl)-2-isobutoxyphenyl]acetic acid as a colorless oily product.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9](Br)=[CH:10][CH:11]=3)[CH:6]=[CH:5][C:4]=2[CH:3]=1.B(OC(C)C)(OC(C)C)[O:18]C(C)C.C([Li])CCC.Cl>C1COCC1.CCCCCC>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([OH:18])=[CH:10][CH:11]=3)[CH:6]=[CH:5][C:4]=2[CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc2c(ccc3cc(Br)ccc32)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Oc1ccc2c(ccc3cc(Br)ccc32)c1
Reaction time: 1 h

Procedure:
25.0 g (74.4 mmol) of 2,7-dibromophenanthrene (CAS No. 62325-30-8) and 24.0 ml (104 mmol) of triisopropyl borate are initially introduced in 750 ml of THF, and 61 ml (97 mmol) of a 15 percent solution of n-butyllithium in hexane are added dropwise at −70° C. When the addition is complete, the batch is left to stir for a further 1 h, hydrolysed using 2 N hydrochloric acid, and the cooling is removed. After addition of MTB ether, the aqueous phase is removed and extracted with MTB ether. The combined org. phases are dried over sodium sulfate, evaporated, and the residue is recrystallised from heptane. 30 ml of 30 percent hydrogen peroxide are added to the resultant boronic acid in 350 ml of toluene and 150 ml of 2 N sodium hydroxide solution with vigorous stirring at such a rate that the temp. does not exceed 45° C. When the addition is complete, the batch is left to stir for a further 30 min, added to 200 ml of water and acidified using 2 N hydrochloric acid. The aqueous phase is separated off and extracted three times with ethyl acetate. The combined org. phases are washed with dil. ammonium iron(II) sulfate solution and water and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is filtered through silica gel with dichloromethane and recrystallised from toluene, giving 2-bromo-7-hydroxyphenanthrene as colourless crystals.