Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]([C:10]2[N:15]3[N:16]=[C:17]([NH2:19])[N:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3].Cl[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:3][CH:2]([C:4]1[CH:5]=[C:6]([C:10]2[N:15]3[N:16]=[C:17]([NH:19][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=4)[N:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:1]
Reactant: Cc1cc(Cl)ccn1
Reactant: CC(C)c1cccc(-c2cccc3nc(N)nn23)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc3cccc(-c4cccc(C(C)C)c4)n3n2)ccn1
Temperature: 210 °C
Yield: 54.2 %

Procedure:
A suspension of 5-[3-(propan-2-yl)phenyl][1,2,4]triazolo[1,5-a]pyridin-2-amine (88.9 mg, 0.352 mmol, 1.00 equiv), 4-chloro-2-methylpyridine (53.9 mg, 0.423 mmol, 1.20 equiv), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (17.6 mg, 0.0369 mmol, 0.105 equiv), cesium carbonate (237 mg, 0.727 mmol, 2.06 equiv), and tris(dibenzylideneacetone)dipalladium(0) (10.0 mg, 0.0109 mmol, 0.0310 equiv) in N,N-dimethylformamide (2 mL) was heated in the microwave to 210° C. for 20 min. The reaction mixture was concentrated in vacuo (˜1 mm Hg). The resulting residue was partitioned between saturated aqueous sodium chloride solution (5 mL) and ethyl acetate (5 mL). The organic was separated, and the aqueous phase was extracted with ethyl acetate (2×5 mL). The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by preparative HPLC yielded a white solid (65.5 mg, 54%). 1H NMR (400 MHz, DMSO-d6), δ: 10.13 (s, 1H), 8.16 (m, 1H), 7.95 (s, 1H), 7.83 (m, 1H), 7.63-7.72 (m, 2H), 7.44-7.55 (m, 4H), 7.25 (dd, J=7.1, 1.3 Hz, 1H), 3.03 (m, 1H), 2.37 (s, 3H), 1.30 (d, J=6.9 Hz, 6H).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[C:4]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[CH:22]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:34]([O:38][C:39]([N:41]1[CH2:46][C@H:45]2[CH2:47][C@@H:42]1[CH2:43][NH:44]2)=[O:40])([CH3:37])([CH3:36])[CH3:35].O>CN(C=O)C>[Cl:27][C:23]1[CH:22]=[C:21]([C:4]2[N:3]=[C:2]([N:44]3[CH2:43][C@H:42]4[CH2:47][CH:45]3[CH2:46][N:41]4[C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])[N:7]3[CH:8]=[N:9][N:10]=[C:6]3[C:5]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:20])[F:19])[CH:12]=2)[CH:26]=[CH:25][N:24]=1
Reactant: FC(F)(F)c1cccc(-c2c(-c3ccnc(Cl)c3)nc(Cl)n3cnnc23)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C[C@@H]1CN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2C[C@@H]1CN2c1nc(-c2ccnc(Cl)c2)c(-c2cccc(C(F)(F)F)c2)c2nncn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5-chloro-7-(2-chloro-4-pyridyl)-8-(3-(trifluoromethyl)-phenyl)-1,2,4-triazolo[4,3-c]pyrimidine (820 mg, 2.0 mmole), potassium carbonate (ca. 1.0 g) and (−)-2-(tert-butoxycarbonyl)-(1R, 4R)-2,5-diaza-bicyclo[2.2.1]heptane (436 mg, 2.2 mmole) in 10 ml of DMF was stirred at room temperature for 16 hours. The reaction solution was poured into water (50 mL), and precipitate was filtered and washed with water and dried under vacuum to give product as off white solid; MS m/z (M)+ 572.3; C27H25ClF3N7O2 requir. 572.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:32])[CH3:31])[CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])=[O:21])[C:15]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:53]([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:55])[CH3:54])(=O)=O.Cl>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:32])[CH3:31])[CH:24]([O:29][Si:53]([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:55])[CH3:54])[C:25]([F:27])([F:28])[F:26])=[O:21])[C:15]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)OCc2ccccc2)c1=O)C(O)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)OCc2ccccc2)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Reaction time: 1.5 h

Procedure:
To a suspension of 2-(5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide (1.13 g) and 2,6-lutidine (0.5 mL) in dichloromethane (5 mL) at 0° C. was added tert-butyldimethylsilyl trifluoromethanesulfonate (0.73 mL). The mixture was allowed to stir for 1.5 h. over which time the suspension became a solution. The mixture was poured into 1N hydrochloric acid and extracted into ether. The organic layer was washed (water), dried and evaporated to give an oil, which crystallized upon addition of ether:hexane to give a white solid. The solid was collected and washed with hexane to yield 2-(5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide as a white solid (1.1 g); MS: m/z=647(M+1).
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:20]([OH:22])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(C(C)C)C(C)C.Cl.[NH2:57][C@H:58]([C:74]([O:76][CH3:77])=[O:75])[CH2:59][C:60]1[CH:65]=[CH:64][C:63]([O:66][CH2:67][C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)=[CH:62][CH:61]=1>CN(C=O)C>[NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[C@H:2]([C:20]([NH:57][C@H:58]([C:74]([O:76][CH3:77])=[O:75])[CH2:59][C:60]1[CH:61]=[CH:62][C:63]([O:66][CH2:67][C:68]2[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=2)=[CH:64][CH:65]=1)=[O:22])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:10])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 169.3 %

Procedure:
Dipeptide Boc-Arg(Tos)-Tyr(Bzl)-OCH3 : A solution of Boc-Arg(Tos)-OH (2.14 g, 5 mmol) and DPPA (1.37 g, 5 mmol) in DMF (100 mL) was cooled to -5° C. DIEA (2.6 mL, 15 mmol) and HCl.H-Tyr(Bzl)-OCH3 (1.44 g, 4.5 mmol) were added, each in one portion, to the cooled solution. The solution was stirred at -10° C. for 2h, allowed to stand at 4° C. for 18h, and then evaporated to dryness. The residue was dissolved in EtOAc (75 mL). The solution was washed sequentially with H2O, 1N HCl, 5% aqueous NaHCO3 and H2O, dried, and evaporated to dryness. The residue was dissolved in EtOAc. Addition of Et2O caused an oil to separate from the solution. The mixture was cooled (0° C.) and triturated. The solvent phase of the mixture was removed by decantation. Et2O was added to the residue. After warming the mixture, the preceding trituration and decantation treatment was repeated. Finally, the product was dried under reduced pressure to yield Boc-Arg(Tos)-Tyr(Bzl)-OCH3 (5.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C1C(=O)N([Br:31])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N>FC(F)(F)C1C=CC=CC=1>[C:13]([O:12][C:10]([N:9]([C:3]1[CH:4]=[CH:5][C:6]([CH2:8][Br:31])=[CH:7][C:2]=1[Br:1])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: Cc1ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: FC(F)(F)c1ccccc1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ccc(CBr)cc1Br

Procedure:
A solution of di-tert-butyl (2-bromo-4-methylphenyl)imidodicarbonate (Compound 108C, 5.0 g, 13 mmol), NBS (2.56 g, 14.2 mmol) and 2,2′-Azo-bis-isobutyronitrile (0.217 g, 1.29 mmol) in α,α,α-trifluorotoluene (16 mL) was heated at 80° C. under an atmosphere of nitrogen for 3 h. Solvent was removed in vacuo and the residue was partitioned between EtOAc and water and separated. The aqueous was extracted with EtOAc (3×) and the combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the title compound. 1H NMR (400 MHz, chloroform-d) δ 7.64 (d, J=1.77 Hz, 1H), 7.34 (dd, J=2.02, 8.08 Hz, 1H), 7.19 (d, J=8.08 Hz, 1H), 4.44 (s, 2H), 1.41 (s, 18H); MS (ES+): m/z: N/A [MH+]. HPLC: tR=1.83 min (UPLC TOF MS: polar—3 min).
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([C:9](=[O:28])[CH2:10][C:11]([CH3:27])([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)[O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([O:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([CH:9]([OH:28])[CH2:10][C:11]([CH3:27])([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)[O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2c(c1C)OC(C)(COc1ccc([N+](=O)[O-])cc1)CC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)Oc1ccc2c(c1C)OC(C)(COc1ccc([N+](=O)[O-])cc1)CC2O
Yield: 55.1 %

Procedure:
A procedure similar to that described in Preparation 2 was repeated, except that 5 g of 7-acetoxy-2,8-dimethyl-2-(4-nitrophenoxymethyl)-4-oxochroman (prepared as described in Preparation 17), 980 mg of sodium borohydride and 20 ml of methanol were reacted, to afford 2.77 g of the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH2:7][CH2:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:5]2=[CH:4][N:3]=1.[S]>C1C2C(CCCC2)CCC1>[CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:5]2=[CH:4][N:3]=1
Reactant: Cc1ncc2n1CCC=C2c1ccccc1
Agent: [S]
Solvent: C1CCC2CCCCC2C1
Product: Cc1ncc2c(-c3ccccc3)cccn12
Temperature: 25 °C

Procedure:
Add 250 g (1.2 mol) of the product from Example XVIII to a solution of 75 g (2.3 mol) of sulfur in 1.5 liters of decalin and heat to 180°-190° C. under nitrogen for 6 hr. Cool to room temperature and extract with 2×1.5 liters of 2N sulfuric acid. Combine the acid extracts and make basic with potassium hydroxide, then wash with 2×1 liter of methylene chloride. Combine the methylene chloride extracts, dry over sodium sulfate, treat with charcoal, and remove the solvent in vacuo. Crystallize the residue from ether to provide the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[CH:7][C:4]=1[CH:5]=[O:6].[I-].[Na+].[Al+3].[Cl-].[Cl-].[Cl-]>C(#N)C>[OH:2][C:3]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: COc1cc(C=O)c(OC)cc1C
Agent: [Al+3]
Agent: [Cl-]
Agent: [I-]
Solvent: CC#N
Product: COc1cc(C=O)c(O)cc1C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
The above prepared 2,5-Dimethoxy-4-methyl-benzaldehyde (4.153 g, 23 mmol) was dissolved in 115 mL of acetonitrile and treated successively with sodium iodide (5.18 g, 1.5 eq.) and AlCl3 (3.07 g, 1.0 eq.), and the mixture kept at 80° C. for 1 h. Cooling, pouring onto crashed ice, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=9/1), gave 3.80 g of the title compound as off-white solid.
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[F:15][C:16]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([O:25][CH3:26])[C:17]=1[CH:18]=[O:19]>O1CCCC1>[Cl:8][C:5]1[N:4]=[C:3]([Cl:9])[C:2]([CH:18]([C:17]2[C:20]([O:25][CH3:26])=[CH:21][CH:22]=[C:23]([F:24])[C:16]=2[F:15])[OH:19])=[CH:7][N:6]=1
Reactant: COc1ccc(F)c(F)c1C=O
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1ccc(F)c(F)c1C(O)c1cnc(Cl)nc1Cl
Temperature: -30 °C
Reaction time: 0.33 h
Yield: 85.1 %

Procedure:
A solution of 5-bromo-2,4-dichloropyrimidine (18.8 g, 82.5 mmol, Aldrich) in tetrahydrofuran (50 mL) was chilled to −30° C. and isopropylmagnesium chloride (41.25 mL, 82.5 mmol, 2M in tetrahydrofuran, Aldrich) was added. The mixture was stirred at −30° C. for 20 minutes and a solution of 2,3-difluoro-6-methoxybenzaldehyde (12.91 g, 75 mmol, Apollo) in tetrahydrofuran (40 mL) was added slowly at this temperature. The mixture was then stirred at 0° C. for one hour and quenched with aqueous ammonium chloride. Extraction with ethyl acetate and crystallization from ethyl ether/hexanes gave 20.5 g of rac-(2,4-dichloro-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanol as a light yellow solid, MP 99–101° C. MS(ES) MH+ 322
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([Sn](C)(C)C)=[CH:18][CH:17]=1.[Cl-]>CN(C)C=O>[C:12]([NH:11][S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:10])=[O:9])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1Br
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Temperature: 90 °C
Reaction time: 5 h
Yield: 74 %

Procedure:
2-Bromo-N-(tert-butyl)benzenesulfonamide (from Step B) (1.00 g, 3.92 mmol), p-tolyltrimethyltin (from Step C) (1.95 g, 6.67 mmol), bis(triphenylphosphinepalladium(II) chloride (Aldrich) (165 mg, 0.235 mmol) and dimethylformamide (25 ml) were heated with stirring under nitrogen at 90° C. for 5 hours. The black suspension was cooled to room temperature, then filtered through a pad of Celite which was washed with tetrahydrofuran. The colorless filtrate was evaporated to dryness, then chromatographed (silica gel, 10% ethyl acetate-hexane) to give the title compound (0.88 g, 74%) as a white solid; 1H NMR (300 MHz, CDCl3) δ8.16 (d, J=7.9 Hz, 1H), 7.60-7.37 (m, 4H), 7.36-7.24 (m, 3H), 3.57 (s, 1H), 2.42 (s, 3H), 0.99 (s, 9H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][CH:24]2[CH2:26][CH2:25]2)=[C:8]([C:10]2[C:11]3[NH:18][CH:17]=[C:16]([C:19]([OH:21])=O)[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:9]=1)(=[O:3])[CH3:2].[NH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34](=[O:36])[CH3:35])[CH2:30][CH2:29]1>>[C:34]([N:31]1[CH2:32][CH2:33][CH:28]([NH:27][C:19]([C:16]2[C:12]3[N:13]=[CH:14][N:15]=[C:10]([C:8]4[CH:9]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=[CH:6][C:7]=4[O:22][CH2:23][CH:24]4[CH2:26][CH2:25]4)[C:11]=3[NH:18][CH:17]=2)=[O:21])[CH2:29][CH2:30]1)(=[O:36])[CH3:35]
Reactant: CC(=O)N1CCC(N)CC1
Reactant: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c[nH]c23)c1
Product: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(C)=O)CC4)c[nH]c23)c1

Procedure:
Starting from 4-(5-acetyl-2-cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A81) and 1-(4-Amino-piperidin-1-yl)-ethanone (A191) the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:37]4[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccc(OC)cc4)cc3)oc2C)cc1

Procedure:
To a 25 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (0.410 mmoles, 200 mg) (see Ex. 2, Part B), 4-methoxyphenyl boronic acid (0.451 mmoles), toluene (5 mL), ethanol (5 mL), and sodium carbonate (0.819 mmoles, 0.410 mL of a 2M solution). This mixture was vacuum degassed and nitrogen was added in at a positive pressure. Pd(PPh3)4 (catalytic, spatula tip) was added and the reaction was heated to reflux for 3 h. Distilled water was added to the mixture. Subsequently, this was extracted with ethyl acetate and washed with brine. The organic layer was collected, filtered over a thin pad of silica gel, and concentrated in-vacuo. The crude mixture was then purified by chromatography on silica gel affording 2-(4-{2-[2-(4′-methoxybiphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C@H:21]([CH3:29])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:28])[CH:26]=[CH2:27])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([OH:20])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([O:41][CH3:42])=[CH:33][N:32]=1.CC([O-])(C)C.[K+]>CS(C)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:21]([CH3:29])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:28])[CH:26]=[CH2:27])[C:10]([N:12]1[CH2:16][C@H:15]([O:17][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]([O:41][CH3:42])=[CH:33][N:32]=2)[CH2:14][C@H:13]1[C:18]([OH:20])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(C)CCC[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: COc1cnc(Cl)c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=CC(C)CCC[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc2ncc(OC)c3ccccc23)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
To a solution of (2S,4R)-1-((3R)-2-((tert-butoxycarbonyl)amino)-3,7-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (1.5 g, 3.6 mmol) in DMSO was added 1-chloro-4-methoxyisoquinoline (840 mg, 4.4 mmol) followed by t-BuOK (1M sol. in THF, 18 mL) at room temperature under nitrogen atmosphere. The reaction mass was stirred at room temperature for 4 h. The reaction mass was quenched with aqueous citric acid solution and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get crude compound. The crude compound was purified by combiflash to get desired product (800 mg, 40%) as off-white solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.11-8.09 (m, 2H), 7.70-7.66 (t, J=7.4 Hz, 1H), 7.56-7.51 (t, J=8.0 Hz, 1H), 7.47 (s, 1H), 5.78 (bs, 1H), 5.69-5.65 (m, 1H), 5.14-5.11 (m, 1H), 4.96-4.88 (m, 3H), 4.43-4.41 (m, 1H), 4.27-4.24 (m, 1H), 3.99 (s, 4H), 2.75-2.73 (m, 1H), 2.67-2.65 (m, 1H), 2.10 (bs, 1H), 1.88-1.85 (m, 2H), 1.31 (s, 9H), 1.24 (s, 2H), 0.98-0.96 (m, 4H), 0.91-0.86 (m, 4H) MS: MS m/z 568.2 (M++1).
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[CH2:87]([N:89]1[CH2:94][CH2:93][N:92]([CH2:95][C:96](O)=[O:97])[CH2:91][CH2:90]1)[CH3:88]>>[CH2:87]([N:89]1[CH2:94][CH2:93][N:92]([CH2:95][C:96]([NH:1][C@:2]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)=[O:97])[CH2:91][CH2:90]1)[CH3:88]
Reactant: CCN1CCN(CC(=O)O)CC1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN3CCN(CC)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 34 %

Procedure:
The title compound was prepared in 34% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 2-(4-ethylpiperazin-1-yl)acetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 684.6 (M+H)+, 2.35 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=7.92 (d, J=8.2 Hz, 2H), 7.20 (d, J=8.2 Hz, 2H), 6.90 (s, 1H), 5.29 (d, J=6.1 Hz, 1H), 4.75 (d, J=1.2 Hz, 1H), 3.27-3.14 (m, 5H), 2.96 (br. s., 3H), 2.64 (d, J=13.4 Hz, 1H), 2.55-2.38 (m, 2H), 2.13 (dd, J=6.4, 17.1 Hz, 1H), 1.92-1.76 (m, 2H), 1.74 (br. s., 1H), 1.72 (s, 3H), 1.70-1.67 (m, 1H), 1.61-1.41 (m, 9H), 1.37 (t, J=7.3 Hz, 4H), 1.35-1.31 (m, 1H), 1.29-1.23 (m, 1H), 1.18-1.12 (m, 2H), 1.06 (s, 3H), 1.03 (s, 3H), 1.01 (s, 2H), 0.94 (s, 3H), 0.94 (s, 3H).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([N+:21]([O-])=O)[CH:15]=2)=[CH:7][CH:6]=1)#[N:4].CCOC(C)=O>CCO.S([O-])([O-])(=O)=O.[Cu+2]>[NH2:21][C:16]1[CH:15]=[C:14]([O:13][CH2:12][CH2:11][C:8]2[CH:7]=[CH:6][C:5]([C:3]#[N:4])=[CH:10][CH:9]=2)[CH:19]=[CH:18][C:17]=1[CH3:20]
Reactant: Cc1ccc(OCCc2ccc(C#N)cc2)cc1[N+](=O)[O-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(OCCc2ccc(C#N)cc2)cc1N
Reaction time: 0.5 h
Yield: 26 %

Procedure:
Sodium borohydride (0.127 g; 3.35 mmol) was added in portions to a cold suspension (ice:water temperature) of [2-(4-cyanophenyl)ethoxy]-4-methyl-3-nitrobenzene (0.19 g; 0.67 mmol; from step (i) above) and aqueous copper sulfate (1.34 mL; 1M; 1.34 mmol) in EtOH (5 mL) over five minutes. The temperature was allowed to rise to ambient and the stirring continued for 30 minutes. Addition of EtOAc (50 mL) and filtration through Celite afforded a clear solution that was washed with water, dried (K3CO3) and concentrated in vacuo. Flash chromatography (SiO2; toluene:EtOAc (10:1)) afforded 0.044 g (26%) of the sub-title compound as a white solid.
Reaction SMILES: CC1C(Cl)=CC(S([O-])(=O)=O)=C(NN=[C:15]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:16]2=O)C=1.CC1C(Cl)=CC(S([O-])(=O)=O)=C(NN=C2C3C(=CC=CC=3)C=C[C:41]2=[O:42])C=1.[Ba+2]>C1C=C2C3[N-]C(C2=CC=1)=NC1=NC(C2C1=CC=CC=2)=NC1[N-]C(=C2C=1C=CC=C2)N=C1C2C(C(=N1)N=3)=CC=CC=2.[Cu]>[OH:42][CH2:41][CH:24]1[CH2:23][CH:22]2[CH2:15][CH:25]1[CH:20]1[CH:21]2[CH2:16][CH2:18][CH2:19]1
Reactant: Cc1cc(NN=C2C(=O)C=Cc3ccccc32)c(S(=O)(=O)[O-])cc1Cl
Agent: [Cu]
Agent: [Ba+2]
Agent: c1ccc2c(c1)-c1nc-2nc2[n-]c(nc3nc(nc4[n-]c(n1)c1ccccc41)-c1ccccc1-3)c1ccccc21
Product: OCC1CC2CC1C1CCCC21

Procedure:
The procedure of Example 6 is repeated, replacing the β-copper phthalocyanine pigment by 14.2 g of the azo pigment, C.I. Pigment Red 166, obtained direct from the synthesis and 0.8 g of 8-hydroxymethyltricyclo[5.2.1.02,6 ]decane [TCD alcohol M®, ex Hoechst] and grinding for 15 instead of 4 hours, to give a high yield azo pigment of the same structure which can be very readily incorporated in plastics and varnishes.