Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[NH:16][N:15]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Cu]I>[F:24][C:13]([F:12])([F:23])[C:14]1[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[N:16]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=2)[N:15]=1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Reactant: COC(=O)c1ccc(I)cc1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Temperature: 180 °C
Reaction time: 0.75 h
Yield: 36.4 %

Procedure:
A mixture of methyl 4-iodobenzoate (1.40 g, 5.34 mmol), 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (1.22 g, 6.42 mmol), copper (I) iodide (1 mol %, 10 mg, 0.05 mmol), trans-1,2-diaminocyclohexane (10 mol %, 62 mg, 0.54 mmol) and potassium carbonate (1.56 g, 11.3 mmol) in 1,4-dioxane (8 ml) was stirred at 180° C. in a microwave reactor for 45 minutes, then fresh copper (I) iodide (1 mol %, 10 mg, 0.05 mmol) and trans-1,2-diaminocyclohexane (10 mol %, 62 mg, 0.54 mmol) were added and the reaction stirred at 180° C. in a microwave reactor for 1 h 45 minutes. The reaction mix was cooled and added to a 50 g pre-packed silica column which was then eluted from 0-50% ethyl acetate in petroleum ether to give a crop of the title compound as a brown oil (630 mg, 36%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:21])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][OH:20])[CH2:15][CH2:14]2)[CH3:11])=[CH:4][CH:3]=1.[Br:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>ClCCl.[OH-].[Na+].S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9](=[O:21])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][O:20][CH2:26][CH2:25][CH2:24][CH2:23][Br:22])[CH2:15][CH2:14]2)[CH3:11])=[CH:6][CH:7]=1
Reactant: BrCCCCBr
Reactant: CN(C[C@H]1CC[C@H](CO)CC1)C(=O)Oc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C[C@H]1CC[C@H](COCCCCBr)CC1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to the method described in example 19.1, trans-(4-hydroxymethyl-cyclohexylmethyl)-methyl-carbamic acid 4-chloro-phenyl ester (example 5.3) was reacted with 1,4-dibromo-butane in dichloromethane and aqueous sodium hydroxide solution in the presence of tetrabutylammonium hydrogensulfate to yield trans-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester as colorless solid, MS: 446 (MH+, 1Cl, 1Br).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:10]([N:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH2:14][CH:13]1[C:21]([O:23]C)=[O:22])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Li+]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:10]([N:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH2:14][CH:13]1[C:21]([OH:23])=[O:22])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1Cc2cccnc2N1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1c2ncccc2CC1C(=O)O)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
In a 50 mL round-bottomed flask, methyl 1-((S)-2-(tert-butoxycarbonylamino)-2-cyclohexylacetyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (660 mg, 1.58 mmol, Eq: 1.00) was combined with THF (14.8 mL) and methanol (4.95 mL) to give a colorless solution. The solution was cooled in an ice-bath and 1 M aqueous lithium hydroxide (4.74 mL, 4.74 mmol, Eq: 3) was added. The cooling bath was removed and the reaction was stirred at rt for 1 h. 0.1 M Aqueous KHSO4 (4 mL) was added and the resulting mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 1-((S)-2-(tert-butoxycarbonylamino)-2-cyclohexylacetyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid as a white solid (600 mg), m/z=404 (M+H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](CC3C=CC(OC)=CC=3)[N:9]=[C:10]([CH:11]([CH3:13])[CH3:12])[C:3]=12.IC1C=CN=C2NN=C(C(C)C)C=12.COC1C=CC(CCl)=CC=1.Cl.[CH3:47][N:48]1[CH:52]=[C:51]([C:53]2[N:54]=[CH:55][NH:56][CH:57]=2)[CH:50]=[N:49]1>>[CH:11]([C:10]1[C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[N:56]2[CH:57]=[C:53]([C:51]3[CH:50]=[N:49][N:48]([CH3:47])[CH:52]=3)[N:54]=[CH:55]2)[NH:8][N:9]=1)([CH3:12])[CH3:13]
Reactant: Cn1cc(-c2c[nH]cn2)cn1
Reactant: COc1ccc(Cn2nc(C(C)C)c3c(I)ccnc32)cc1
Agent: CC(C)c1n[nH]c2nccc(I)c12
Agent: COc1ccc(CCl)cc1
Agent: Cl
Product: CC(C)c1n[nH]c2nccc(-n3cnc(-c4cnn(C)c4)c3)c12
Yield: 63 %

Procedure:
According to Example 97(1), 4-iodo-3-isopropyl-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine was prepared using compound (100a) (15.5 g) instead of compound (40d) and using 4-methoxybenzyl chloride instead of {2-(chloromethoxy)ethyl}silane and was used in the subsequent reaction without being purified. According to Example 97(2), 3-isopropyl-1-(4-methoxybenzyl)-4-{4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl}-1H-pyrazolo[3,4-b]pyridine was prepared using 4-iodo-3-isopropyl-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine instead of compound (97a) and using 4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazole hydrochloride instead of 4-phenyl-1H-imidazole and was used in the subsequent reaction without being purified. This 3-isopropyl-1-(4-methoxybenzyl)-4-{4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl}-1H-pyrazolo[3,4-b]pyridine was dissolved in trifluoroacetic acid (60 mL) and anisole (19 mL), followed by reflux for 5 hr. The reaction solution was concentrated and then diluted with acetonitrile, and saturated sodium bicarbonate water was added thereto. The precipitate was collected by filtration and was dried under reduced pressure to obtain compound (100b) (12.3 g, the third stage yield: 63%) as a white solid.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:18]2[NH:31][C:21]3=[N:22][CH:23]=[C:24]([C:26]#[C:27][CH2:28][O:29][CH3:30])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:31][C:21]3=[N:22][CH:23]=[C:24]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCC#Cc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Agent: [Pd]
Solvent: CO
Product: COCCCc1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Temperature: 50 °C
Yield: 32.4 %

Procedure:
A mixture of 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine (302 mg, 0.7 mmol) and 10% palladium on activated carbon (80 mg) in methanol (250 mL) was heated at 50° C. under hydrogen (50 psi) for 8 h. The mixture was cooled to room temperature. The catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-5-(3-methoxy-propyl)-1H-pyrrolo[2,3-b]pyridine (100 mg, 32.5%) as a colorless oil: LC/MS m/e calcd for C25H32N2O3S [M+H]+ 441.61, observed 441.1; 1H NMR (400 MHz, CD3OD) δ ppm 8.25 (s, 1H), 8.10 (br. s., 1H), 7.90-7.95 (m, J=8.1 Hz, 2H), 7.60-7.65 (m, J=8.3 Hz, 2H), 6.65 (s, 1H), 4.39 (t, J=7.8 Hz, 1H), 3.43 (t, J=6.2 Hz, 2H), 3.35 (s, 3H), 3.11 (s, 3H), 2.88 (t, J=7.6 Hz, 2H), 2.26-2.34 (m, 1H), 2.13-2.22 (m, 1H), 1.92-1.99 (m, 2H), 1.63-1.89 (m, 5H), 1.46-1.58 (m, 2H), 1.19-1.34 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29](C)([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=1.C(O)(C(F)(F)F)=O.C(N(C(C)C)CC)(C)C.ClC(OC(C)C)=O>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3F)nc2)CC1
Agent: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3F)nc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 71 %

Procedure:
1,1-Dimethylethyl 4-[({6-[2-fluoro-4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (prepared as in Example 76, 47 mg, 0.10 mmol) was dissolved in CH2Cl2 (3 mL) and treated with TFA (0.20 mL). The mixture was stirred at ambient temperature for 6 h. The mixture was then cooled to 0° C. in an ice bath, and diisopropylethylamine (1.0 mL) was added, followed by addition of isopropyl chloroformate (1.0M in toluene, 0.12 mL, 0.12 mmol). The reaction mixture was allowed to warm to ambient temperature, and stirred overnight, then diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a light brown solid. The crude product was purified by chromatography on a silica gel column eluted with 25% EtOAc/CH2Cl2 to give 32 mg (70%) of the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ 8.40 (d, 1H, J=2.9 Hz), 8.20-8.10 (m, 1H), 7.90-7.75 (m, 3H), 7.50 (dd, 1H, Ja=8.8 Hz, Jb=3.0 Hz), 4.90-4.80 (m, 1H), 4.25-4.15 (m, 2H), 4.00 (d, 2H, J=6.1 Hz), 3.18 (s, 3H), 2.95-2.80 (m, 2H), 2.15-2.00 (m, 1H), 1.95-1.85 (m, 2H), 1.40-1.20 (m, 8H); LRMS (ESI), m/z 451 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([C@H:22]2[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]2)=[C:15]2[C:19]=1[C:18](=[O:20])[N:17]([CH3:21])[CH2:16]2.CCN(C(C)C)C(C)C.O>CC(N(C)C)=O.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C@H:22]3[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]3)=[C:15]3[C:19]=2[C:18](=[O:20])[N:17]([CH3:21])[CH2:16]3)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CN1Cc2c(c(N)ccc2[C@H]2CC[C@H](O)CC2)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CN1Cc2c(c(Nc3nc(Cl)ncc3Cl)ccc2[C@H]2CC[C@H](O)CC2)C1=O
Temperature: 100 °C

Procedure:
A solution of 2,4,5-trichloropyrimidine (550.5 mg, 3.001 mmol) and 7-amino-4-(trans-4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (166.6 mg, 0.6400 mmol) in DMA (8 mL) was charged with DIPEA (1 mL, 6 mmol) and then heated to 100° C. overnight. The reaction mixture was cooled to ambient temperature, diluted with EtOAc, and poured into water. The material was extracted thrice with EtOAc and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude material was adsorbed onto a pre-filled solid loading cartridge [RediSepRf 25 gram] and purified using the Teledyne/ISCO system [RediSepRf 12 gram silica], eluting first with 0-100% EtOAc:CH2Cl2 and then 0-5% MeOH:CH2Cl2. The desired fractions were pooled together and concentrated in vacuo, giving the title material as a brown solid, 173.0 mg. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.07 (s, 1H), 8.52 (s, 1H), 8.43 (d, J=8.6 Hz, 1H), 7.52 (d, J=8.6 Hz, 1H), 4.60 (d, J=4.5 Hz, 1H), 4.57 (s, 2H), 3.48 (ddd, J=15.0, 6.4, 4.4 Hz, 1H), 3.10 (s, 3H), 1.93 (br s, 2H), 1.77 (br d, J=12.4 Hz, 2H), 1.55 (dtd, J=13.0, 12.7, 2.5 Hz, 2H), 1.22-1.37 (m, 3H). MS (ES+): m/z 407.10/409.10 (100/72) [MH+]. HPLC: tR=1.40 min (TOF, polar—3 min).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][C:13]#[N:14])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([CH2:12][C:13]#[N:14])[CH2:7][CH2:8][N:9]([S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[Cl:15])(=[O:24])=[O:23])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CCOC(=O)C1(CC#N)CCNCC1
Solvent: c1ccncc1
Product: CCOC(=O)C1(CC#N)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
4-Cyanomethyl-piperidine-4-carboxylic acid ethyl ester (14.2 g) was dissolved in pyridine (150 ml), 2-chlorobenzenesulfonyl chloride (16.83 g) was added and the reaction mixture was stirred overnight at RT. Then, most of pyridine was evaporated off in vacuo, the residue was dissolved in AcOEt, washed with 0.5M aqueous HCl and brine. The organic layer was dried over magnesium sulphate and concentrated in vacuo. The residue (crude oil) was chromatographed over silica (AcOEt/Heptanes, gradient from 0 to 25%) to give the desired material (8.5 g) as viscous brown oil. MS (ESI): 388.1 (M+NH4)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4]([C:12]([O:14]CC)=[O:13])([C:7]([O:9]CC)=[O:8])[CH2:3][CH2:2]1.Cl>[OH-].[Na+]>[O:1]1[CH2:2][CH2:3][C:4]([C:7]([OH:9])=[O:8])([C:12]([OH:14])=[O:13])[CH2:5][CH2:6]1
Reactant: CCOC(=O)C1(C(=O)OCC)CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1(C(=O)O)CCOCC1
Temperature: 25 °C
Reaction time: 28 h
Yield: 91.5 %

Procedure:
Diethyl tetrahydro-2H-pyran-4,4-dicarboxylate (4.04 g, 20 mmol) is suspended in a 30% aqueous sodium hydroxide solution (10 mL), and the mixture is stirred at room temperature for 28 hours. The pH value of the reaction solution is adjusted to pH 1 with conc. hydrochloric acid, and the mixture is separated into water and ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, and the solvent is evaporated. Ethyl acetate (30 mL) is added to the obtained crude product, and the mixture is washed by repulping, and the resulting solid is collected by filtration, and dried to give tetrahydro-4H-pyran-4,4-dicarboxylic acid (3.19 g, 18.3 mmol, 92%).
Reaction SMILES: C[Al](C)C.COC(=O)C(O[Si](C(C)(C)C)(C)C)C1C=CC=CC=1.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[C:31]1([CH:37]2[CH:41]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[NH:40][C:39]([CH:48]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[OH:49])=[N:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[C:31]1([C@H:37]2[C@@H:41]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[NH:40][C:39]([CH:48]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[OH:49])=[N:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OC(C1=NC(c2ccccc2)C(c2ccccc2)N1)c1ccccc1
Agent: COC(=O)C(O[Si](C)(C)C(C)(C)C)c1ccccc1
Agent: C[Al](C)C
Solvent: O=C(O)C(F)(F)F
Product: OC(C1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1)c1ccccc1

Procedure:
Employing the general trimethylaluminum coupling procedure and using (tert-butyl-dimethyl-silanyloxy)-phenyl-acetic acid methyl ester prepared in accordance with the procedures set out in Step 1 above and meso-1,2-diphenylethylene-diamine there is made: (4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-phenyl-methanol trifluoroacetate. 1H NMR (DMSO) δ 10.95 (bs, 2H), 7.70-7.67 (m, 2H), 7.57-7.46 (m, 3H), 7.2-7.0 (m, 7H), 6.9-6.8 (m, 4H), 5.88 (s, 1H), 5.77 (s, 2H); LC/MS: 2.39 min/m/z 329 (M++1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:18]3[CH:26]=[C:25]([NH:27]CC4C=CC(OC)=CC=4)[N:24]=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:18]3[CH:26]=[C:25]([NH2:27])[N:24]=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: COc1ccc(CNc2cc3c(Nc4ccc(OCc5ccccn5)c(Cl)c4)ncnc3cn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Nc1cc2c(Nc3ccc(OCc4ccccn4)c(Cl)c3)ncnc2cn1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
To a stirred heterogeneous mixture of compound 212 (2.88 g, 5.77 mmol) and DCVI (60 ml) was added trifluoroacetic acid (4.38 ml, 57.7 mmol), followed by anisole (1.27 ml, 11.5 mmol), and the mixture was stirred further at room temperature. After 72 h another batch of trifluoroacetic acid (4.38 ml, 57.7 mmol) was added and stirred further for 49 h. It was poured into petroleum ether (250 ml) and stirred at room temperature for ca. 20 min. Petroleum ether layer was decanted and discarded. The process was repeated with more petroleum ether (250 ml). The solid left behind was dissolved in acetone (150 mL) and 5M NH3 (125 ml) added at 0° C. The mixture was stirred at room temperature for 30 min. The solid was collected and washed successively with acetone/water (1:4) (5×30 ml), petroleum ether/ethyl acetate=3:1 (5×30 ml), and dried to give N4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)pyrido[3,4-d]-pyrimidine-4,6-diamine (221) (1.94 g, 89%), mp 247-250° C.; 1H NMR. δ [(CD3)2SO] 9.64 (s, 1H), 8.68 (s, 1H), 8.62-8.56 (m, 1H), 8.33 (s, 1H), 8.06 (d, J=2.6 Hz, 1H), 7.88 (td, J=7.7, 1.8 Hz, 1H), 7.73 (dd, J=9.0, 2.6 Hz, 1H), 7.58 (br d, J=7.8 Hz, 1H), 7.40-7.34 (m, 1H), 7.26 (d, J=9.0 Hz, 1H), 7.12 (s, 1H), 6.23 (s, 2H), 5.29 (s, 2H). Anal. Calcd for C19H13ClN6O.1.5H2O: C, 56.23; H, 4.47; N, 20.71%. Found C, 56.55; H, 4.45; N, 20.42%.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16]([NH:18][C:19]2[S:20][C:21]([CH:24]=O)=[CH:22][N:23]=2)=[O:17])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:27][O:28][C:29](=[O:32])[CH2:30][NH2:31]>>[CH3:27][O:28][C:29](=[O:32])[CH2:30][NH:31][CH2:24][C:21]1[S:20][C:19]([NH:18][C:16]([NH:15][C:9]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:7])=[O:17])=[N:23][CH:22]=1
Reactant: COC(=O)CN
Reactant: Cc1ccc(NC(=O)Nc2ncc(C=O)s2)c(C(=O)C2CCCC2)c1
Agent: Cl
Product: COC(=O)CNCc1cnc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)s1
Yield: 45 %

Procedure:
({2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-5-ylmethyl}-amino)-acetic acid methyl ester (38 mg, 45%) was prepared from 1-(2-cyclopentanecarbonyl-4-methyl-phenyl)-3-(5-formyl-thiazol-2-yl)-urea (0.072 g, 0.2 mmol) and glycine methyl ester hydrochloride following the general procedure O.
Reaction SMILES: C([O:3][CH2:4][CH3:5])=O.O.Cl.[CH2:8]([Mg]Br)[CH2:9][CH2:10][CH2:11][CH3:12]>>[CH3:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:4]([OH:3])[CH2:5][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCOC=O
Reactant: CCCCC[Mg]Br
Agent: Cl
Solvent: O
Product: CCCCCC(O)CCCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of n-pentylmagnesium bromide in tetrahydrofuran synthesized in Example 2, 162 mL (2.0 mol) of ethyl formate was added dropwise in a nitrogen atmosphere and the mixture was stirred overnight at room temperature. After careful addition of water, the reaction mixture was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and thereafter concentrated to give 340.8 g of 6-undecanol.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:40][N:14]4[CH2:15][CH2:16][N:17]([C:19](=[O:39])[CH:20]([NH:31][C:32](=[O:38])[O:33][C:34](C)(C)C)[C:21]5[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=5)[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C1(C2N=CC(O[C@H]3CN4CCN(C(=O)C(NC(=O)OC(C)(C)C)C5C=CC=C(C(F)(F)F)C=5)C[C@@H]4C3)=NC=2)CC1>>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:40][N:14]4[CH2:15][CH2:16][N:17]([C:19](=[O:39])[CH:20]([NH:31][C:32](=[O:38])[O:33][CH3:34])[C:21]5[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=5)[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1)c1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)OC(=O)NC(C(=O)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1)c1cccc(C(F)(F)F)c1
Product: COC(=O)NC(C(=O)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared according to the procedure described for Example 182, substituting the product from Example 181 for the product from Example 180. 1H NMR (300 MHz, CDCl3) δ ppm 0.81-1.03 (m, 4 H) 1.18-3.29 (m, 9 H) 3.53-3.88 (m, 5 H) 4.52-4.81 (m, 1 H) 5.18-5.40 (m, 1 H) 5.54-5.71 (m, 1 H) 6.35 (d, J=7.12 Hz, 1 H) 7.45-7.58 (m, 2 H) 7.58-7.67 (m, 2 H) 7.86-8.07 (m, 2 H); MS (ESI) m/z 520 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:5]=[N:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl>N1C=CC=CC=1>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:2]2[N:1]=[N:5][NH:4][C:3]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1nnn(-c2ccc(Cl)cc2)c1N
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1[nH]nnc1Nc1ccc(Cl)cc1
Yield: 100 %

Procedure:
A solution of ethyl 5-amino-1-(p-chlorophenyl)-1,2,3-triazole-4-carboxylate (10 g) in dry pyridine (50 ml) was refluxed for 6 hrs. and the cooled solution poured into dilute hydrochloric acid. The precipitated solid was filtered off and recrystallised from 90% ethanol to give 10 g (100%) of the rearrangement product of mp 161° C. (lit mp 162° C. Ger Offen No. 2,009,134 [1970]). (Found; C, 49.46; H, 4.31; N, 20.85; C11H11CIN4O2 requires; C, 49.54; H, 4.16; N, 21.01%).
Reaction SMILES: CN1CCN(C)[C:4]2[CH:9]=NC=[CH:12][C:3]1=2.[C:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[C:18]2[CH:25]=[CH:26][N:27]=[CH:28][C:17]1=2)(=[O:15])[CH3:14]>CO>[C:13]([N:16]1[CH:21]2[CH:20]([CH2:12][CH2:3][CH2:4][CH2:9]2)[N:19]([C:22](=[O:24])[CH3:23])[C:18]2[CH:25]=[CH:26][N:27]=[CH:28][C:17]1=2)(=[O:15])[CH3:14]
Reactant: CC(=O)N1CCN(C(C)=O)c2cnccc21
Reactant: CN1CCN(C)c2cnccc21
Solvent: CO
Product: CC(=O)N1c2ccncc2N(C(C)=O)C2CCCCC21

Procedure:
27 (1.20 g, 6.34 mmol), 40 ml of pyridine, 30 ml (32.36 g, 317 mmol, ρ=1.082 g/ml) of acetic anhydride and 0.234 g (25 mol %) of PPY were introduced into a 250 ml round-bottomed flask while cooling in ice. The reaction mixture was heated to an oil bath temperature of 100° C. and maintained at this temperature for 48 hours. The reaction was followed by TLC on basic aluminum oxide (EtOAC/MeOH, 10:1). After cooling to room temperature, the solvent was distilled off under reduced pressure and the crude product obtained was purified by flash chromatography on basic aluminum oxide (EtOAc/MeOH, 10:1). This gave a dark yellow solid (1.17 g, 4.31 mmol, 68%). Rf=0.45 (EtOAC/MeOH, 10:1). 1H NMR: (400 MHz, CDCl3): δ=1.34 (m, 4H), 1.60 (d, 4H), 2.23 (s, 3H, H3C—CO—N), 2.27 (s, 3H, H3C—CO—N), 4.74 (m, 1H), 4.85 (m, 1H), 7.25 (d, 3J=5.6 Hz, 1H, H-4), 8.41 (d, 3J=5.6 Hz, H-3), 8.49 (s, 1H, H-1) ppm. 13C NMR (75 Hz, CDCl3): δ=21.7, 21.9 (C-7,8), 23.1, 23.6 (H3C—CO—N), 28.4, 28.5 (C-6,9), 55.2, 56.0 (CH, C-5a,9a), 119.6 (C-4), 130.8 (Cq, C-10a), 141.6 (Cq, C-4a), 147.1, 147.2 (C-1, C-3) 169.1, 169.2 (C═O) ppm. GC-MS (EI): RT 10.45 min, m/e (%) 274 (13), 273 (M+, 58), 232 (15), 231 (100), 230 (42), 216 (5), 214 (5), 213 (5), 203 (3), 202 (4), 190 (13), 189 (84), 188 (45), 173 (5), 172 (6), 160 (7), 159 (5), 158 (5), 147 (8), 146 (40) 134 (6), 133 (13), 132 (15), 120 (7), 43 (9); IR (neat): ν=2940 (m), 1660 (vs), 1587 (m), 1559 (w), 1498 (s), 1448 (w), 1427 (w), 1388 (m), 1353 (w), 1337 (m), 1289 (s); 1270 (s), 1248 (s), 1248 (m), 1220 (w), 1183 (w), 1102 (w), 1036 (m), 978 (m), 857 (w), 839 (w) 777 (w) cm−1. HRMS (EI): calculated for C11H15N3 273.1477 [M+], found: 273.1482.