Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[NH2:13][C@H:14]([C:23](O)=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>>[NH2:13][C@H:14]([C:23]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O

Procedure:
Amino acid analysis (acidolysis): Arg, 1.06(1); Tyr, 0.94(1); Average recovery, 90.6%.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:4]2[C:13]3[CH:12]=[CH:11][C:10]([O:14][CH2:15][CH2:16][CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)=[CH:9][C:8]=3[N:7]=[C:6]([NH2:23])[C:5]=2[N:24]=1.[CH:29]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:29]1([C:34]([N:20]2[CH2:19][CH2:18][CH:17]([CH2:16][CH2:15][O:14][C:10]3[CH:11]=[CH:12][C:13]4[C:4]5[N:3]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:2]([CH3:1])=[N:24][C:5]=5[C:6]([NH2:23])=[N:7][C:8]=4[CH:9]=3)[CH2:22][CH2:21]2)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C(Cl)C1CCCC1
Reactant: Cc1nc2c(N)nc3cc(OCCC4CCNCC4)ccc3c2n1CC(C)C
Product: Cc1nc2c(N)nc3cc(OCCC4CCN(C(=O)C5CCCC5)CC4)ccc3c2n1CC(C)C

Procedure:
The general method described in Example 15 was used to treat 2-methyl-1-(2-methylpropyl)-7-(2-piperidin-4-ylethoxy)-1H-imidazo[4,5-c]quinolin-4-amine with cyclopentanecarbonyl chloride to provide 0.158 g of 7-{2-[1-(cyclopentylcarbonyl)piperidin-4-yl]ethoxy}-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine, which was isolated as an off-white solid, mp 235.7-238.1° C.
Reaction SMILES: [BH4-].[Na+].C(O)(C(F)(F)F)=O.[CH2:10]([O:13][C:14](=[O:47])[C@@H:15]([NH:34][C:35](=[O:46])[C:36]1[C:41]([F:42])=[CH:40][C:39]([C:43]#[N:44])=[CH:38][C:37]=1[F:45])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:33])[N:25]([CH3:32])[C:26](=[O:31])[N:27]([CH3:30])[C:28]=2[CH3:29])=[CH:19][CH:18]=1)[CH2:11][CH3:12].C(O)(C)C>C1COCC1.C(OC(C)C)(=O)C>[CH2:10]([O:13][C:14](=[O:47])[C@@H:15]([NH:34][C:35](=[O:46])[C:36]1[C:37]([F:45])=[CH:38][C:39]([CH2:43][NH2:44])=[CH:40][C:41]=1[F:42])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:33])[N:25]([CH3:32])[C:26](=[O:31])[N:27]([CH3:30])[C:28]=2[CH3:29])=[CH:19][CH:18]=1)[CH2:11][CH3:12]
Reactant: CCCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(F)cc(C#N)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)OC(C)C
Solvent: C1CCOC1
Product: CCCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(F)cc(CN)cc1F
Reaction time: 0.17 h
Yield: 74.5 %

Procedure:
To solution of sodium borohydride (0.29 g, 7.62 mmol, 2 eq.) in THF (5 ml) was added TFA (566 μL, 7.62 mmol, 2 eq.), the reaction was stirred for 10 min., and then a solution of (S)-2-(4-cyano-2,6-difluoro-benzoylamino)-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-phenyl]-propionic acid propyl ester (2.0 g, 3.81 mmol) in THF (6 ml) was added drop wise (flask was rinsed w/THF (2×1 ml) and added to reaction). The reaction was stirred at room temperature under nitrogen for 1.3 h. The reaction mixture was cooled in an ice bath and quenched with water (20 ml) and a sodium chloride solution (20 ml water, 100 ml saturated solution). The aqueous mixture was extracted with DCM (2×200 ml), and then the organic layers were washed with brine, combined, and dried over magnesium sulfate, and then concentrated to yield an off white solid, 1.77 g. The crude product was suspended in isopropyl acetate (75 ml) and isopropyl alcohol (0.75 ml and TMSC1 (1 ml) was added dropwise. The reaction was stirred at room temperature for 2 h and the white precipitate was filtered and washed with isopropyl acetate and hexanes to obtain 1.5 g (63% yield) of (S)-2-(4-aminomethyl-2,6-difluorobenzoylamino)-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid propyl ester as an amorphous white solid. ES-HRMS m/e calcd for C27H30F2N4O5 (M+H)+ 529.2257, found 529.2258.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[N:8]=[C:7](O)[N:6]=[CH:5]2.O=P(Cl)(Cl)[Cl:17]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[N:8]=[C:7]([Cl:17])[N:6]=[CH:5]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(Br)cc2cnc(O)nc12
Product: COc1cc(Br)cc2cnc(Cl)nc12
Temperature: 110 °C
Yield: 30 %

Procedure:
A suspension of 6-bromo-8-methoxyquinazolin-2-ol (43.96 mmol) in POCl3 (120 mL) was heated to 110° C. for 30 minutes The mixture was cooled to room temperature, evaporated POCl3 and partitioned between water and dichloromethane. The organic portion was concentrated to give a crude material which was purified by column chromatography (silica gel, eluted with 2% MeOH in dichloromethane) to yield pure material as a yellow solid in 30% yield (3 steps, 3.62 g). ES/MS m/z 272/274 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[CH:18][C:17]([N:20]3[CH2:24][CH2:23][C@@H:22]([OH:25])[CH2:21]3)=[CH:16][N:15]=2)=[N:6]1.[H-].[Na+].I[CH3:33].O>CN(C=O)C>[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[CH:18][C:17]([N:20]3[CH2:24][CH2:23][C@H:22]([O:25][CH3:33])[CH2:21]3)=[CH:16][N:15]=2)=[N:6]1
Reactant: CI
Reactant: O[C@@H]1CCN(c2cnc(-c3nn(Cc4ccccc4F)c4ncccc34)nc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CO[C@H]1CCN(c2cnc(-c3nn(Cc4ccccc4F)c4ncccc34)nc2)C1
Reaction time: 2 h

Procedure:
100 mg (0.21 mmol, purity 80%) of (3S)-1-{2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl}-3-pyrrolidinol (example XIX, step 3) are dissolved in 2 ml of DMF under argon and, while cooling in an ice bath 8 mg (0.33 mmol) of sodium hydride are added. 32 mg (0.23 mmol) of iodomethane are added dropwise to the suspension, likewise while cooling in an ice bath, and the mixture is stirred at this temperature for 2 hours. 0.5 ml of distilled water is added, and the reaction mixture is chromatographed directly on a preparative HPLC. 35 mg (42% of theory) of the product are obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].II.FC(F)(F)C(O[I:17](C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[I:17][C:5]1[S:1][C:2]([C:6]([O:8][CH3:9])=[O:7])=[CH:3][CH:4]=1
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Reactant: COC(=O)c1cccs1
Agent: II
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(I)s1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90.5 %

Procedure:
To a stirred solution of methyl thiophene-2-carboxylate (0.46 mL, 4 mmol) in anhydrous methylene chloride (5 mL) was added iodine (510 mg, 2 mmol) followed by [bis(trifluoroacetoxy)iodo]benzene (900 mg, 2.1 mmol). The reaction mixture was stirred at RT for 1.5 hr before saturated aqueous sodium bicarbonate solution (10 mL) and saturated aqueous sodium thiosulfate solution (2 mL) were added. The mixture was then stirred at RT for 20 min. The aqueous layer was separated and extracted with methylene chloride (2×1 mL). The combined organic solutions were dried (Na2SO4). Silica gel flash chromatography (0-100% ethyl acetate in hexanes) gave methyl 5-iodothiophene-2-carboxylate (500 mg, 1.9 mmol, 47% yield) as a solid.
Reaction SMILES: C1C=C(OC(OC2N=CC=CC=2)=S)N=CC=1.NC1C=CN=CN=1.[NH:24]([C:26](=[O:47])[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([C@H:36]2[CH2:41][CH2:40][C@H:39]([CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH2:38][CH2:37]2)=[CH:32][CH:31]=1)=[O:28])[NH2:25].CC[N:50]=[C:51]=[N:52][CH2:53][CH2:54][CH2:55][N:56]([CH3:58])C>C(Cl)Cl.CO.CN(C=O)C>[N:52]1[CH:53]=[CH:54][C:55]([NH:56][C:58]2[O:47][C:26]([C:27]([NH:29][C:30]3[CH:31]=[CH:32][C:33]([C@H:36]4[CH2:37][CH2:38][C@H:39]([CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH2:40][CH2:41]4)=[CH:34][CH:35]=3)=[O:28])=[N:24][N:25]=2)=[N:50][CH:51]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Reactant: CCN=C=NCCCN(C)C
Agent: Nc1ccncn1
Agent: S=C(Oc1ccccn1)Oc1ccccn1
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4ccncn4)o3)cc2)CC1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
Di-2-pyridyl thionocarbonate (367 mg, 1.58 mmol) was added in one portion to a stirred solution of 4-aminopyrimidine (150 mg, 1.58 mmol) in DCM (3 mL) and the reaction mixture was heated at 100° C. for 20 minutes in the microwave and then cooled to room temperature. This solution was added to a suspension of methyl [trans-4-(4-{[hydrazino(oxo)acetyl]amino}-phenyl)cyclohexyl]acetate (Intermediate 43, 421 mg, 1.26 mmol) in DCM (5 mL) and the mixture stirred at room temperature for 5 minutes. DMF (8 mL) was added and the DCM was removed under reduced pressure. The solution was heated at 85° C. for 40 minutes in the microwave and then cooled to room temperature. EDCI (303 mg, 1.58 mmol) was added in one portion and the reaction mixture was heated at 85° C. for 60 minutes in the microwave. The reaction was quenched by the addition of H2O (200 mL) and EtOAc (250 mL) was added. The layers were separated and the aqueous layer was extracted with EtOAc (2×150 mL). The combined organic layer was washed with brine (100 mL), dried (MgSO4) and concentrated in vacuo to leave a dark brown gummy solid. MeOH (40 mL) was added and the mixture was heated to reflux for 2 minutes and then cooled to room temperature to leave a white suspension. The solid was filtered to give the title compound (110 mg, 20%) as a solid; 1H NMR δ 1.10-1.17 (2H, m), 1.43-1.47 (2H, m), 1.75-1.81 (5H, m), 2.24-2.26 (2H, d), 2.44 (1H, t), 3.61 (3H, s), 7.24 (2H, d), 7.69-7.73 (2H, m), 7.92 (1H, d), 8.69 (1H, d), 8.87 (1H, s), 11.02 (1H, s); MS m/e MH+ 437.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]#[N:14])[C:9]([C:15]#[N:16])=[CH:8][CH:7]=2)[CH2:2][CH3:3].Cl[CH2:18][C:19]1[N:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[O:21][N:20]=1>>[CH2:1]([C:4]1[N:5]([CH2:18][C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=3)[O:21][N:20]=2)[C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]#[N:14])[C:9]([C:15]#[N:16])=[CH:8][CH:7]=2)[CH2:2][CH3:3]
Reactant: CCCc1cc2c(C#N)c(C#N)ccc2[nH]1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Product: CCCc1cc2c(C#N)c(C#N)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 4 from 2-propyl-1H-indole-4,5-dicarbonitrile and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole: 1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J=7.6 Hz, 1 H), 8.25 (s, 1 H), 8.14 (s, 1 H), 8.07 (d, J=7.6 Hz, 1 H), 7.90-7.80 (m, 2 H), 7.70 (d, J=8.4 Hz, 1 H), 5.95 (s, 2 H), 3.06 (t, 2 H), 1.79-1.67 (m, 2 H), 0.95 (t, J=7.2 Hz, 3 H); MS (ES) m/z 436 (M+1).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][CH:5]1[CH:7]([C:8]([OH:10])=[O:9])[C:6]1([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][C:23]=1[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C>[F:1][C:2]([F:13])([F:14])[CH2:3][O:4][CH:5]1[CH:7]([C:8]([O:10][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([F:21])=[C:23]([O:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:24]=2)=[O:9])[C:6]1([CH3:11])[CH3:12]
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Reactant: CC1(C)C(OCC(F)(F)F)C1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)C(OCC(F)(F)F)C1C(=O)OCc1ccc(F)c(Oc2ccccc2)c1
Reaction time: 15 h

Procedure:
To 10 ml DMF is added 0.88 g 3-(2,2,2-trifluoroethoxy)-2,2-dimethylcyclopropanecarboxylic acid (4.14 mmol) and 1.146 g potassium carbonate (8.29 mmol), after which is added 1.2 g 4-fluoro-3-phenoxybenzyl bromide. This mixture is stirred under nitrogen for 15 hours. The reaction mixture is extracted with ether and the ether phase is washed with water (3×) and brine, and dried over sodium sulfate. The solvent is then removed to yield 4-fluoro-3-phenoxybenzyl 3-(2,2,2-trifluoroethoxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([O-:11])=[O:10].[H-].[Na+]>CN(C)C=O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([O:18][C:15]2[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 55.3 %

Procedure:
After adding 4,6-dichloropyrimidine (750 mg) to a suspension of 4-nitrophenol (700 mg) and sodium hydride (60%) (200 mg) in dimethylformamide (13 ml) at 0° C., the mixture was heated and stirred at 80° C. for 1.5 hours. The reaction solution was poured into saturated saline and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated. The obtained residue was passed through an NH silica gel column (Fuji Silicia Chemical), eluted with a solvent (ethyl acetate-hexane=1-4) and concentrated to obtain 700 mg of the title compound.
Reaction SMILES: [OH-].[K+].C([O:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH:8]1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)(=O)C>O.C(O)C>[O:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][CH:8]2[CH2:9][CH2:10][CH2:11][CH:7]2[OH:6])=[CH:14][CH:15]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(=O)OC1CCCC1Oc1ccc(Oc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OC1CCCC1Oc1ccc(Oc2ccccc2)cc1

Procedure:
A solution of 1.68 g of potassium hydroxide in 20 ml of water is added at room temperature to a solution of 6.24 g of 1-acetoxy-2-(4-phenoxyphenoxy)-cyclopentane in 50 ml of ethanol. The mixture is then refluxed for 3 hours and, after cooling, concentrated to 166 of its original volume by rotary evaporation. The residue is poured into ice-water. After extraction with ether, the organic phase is washed three times with saturated sodium chloride solution, dried over sodium sulphate and concentrated by rotary evaporation. Distillation of the residue yields 2-(4-phenoxyphenoxy)-cyclopentan-1-ol as a colourless oil with a boiling point of 181°-185° C./0.001 torr.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[S:28])[NH:6]2.C(=O)([O-])[O-].[K+].[K+].I[CH2:36][CH3:37]>CN(C)C=O>[CH2:36]([S:28][C:5]1[NH:4][C:3]2[C:7](=[N:8][C:9]([C:11]3[C:19]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[F:27])[N:12]=3)=[N:10][C:2]=2[NH2:1])[N:6]=1)[CH3:37]
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=S)[nH]c12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCSc1nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N)c2[nH]1
Temperature: 70 °C
Reaction time: 16 h
Yield: 56.7 %

Procedure:
150 mg (0.382 mmol) of the compound from example 28 were dissolved in 2 ml of dimethylformamide, and 58 mg (0.420 mmol) of potassium carbonate were added. The mixture was heated to 70° C. for 10 min and, after cooling, 31 μl (0.382 mmol) of iodoethane were added and the mixture was stirred at RT for 16 h. The mixture was concentrated, and the residue was adsorbed on silica gel and purified by means of chromatography on silica gel (eluent: dichloromethane/methanol=20:1). 91 mg of the title compound were obtained (51% of theory).
Reaction SMILES: [OH:1][CH:2]([CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([O:36]CC2C=CC=CC=2)=[CH:32][CH:31]=1)[CH2:3][NH:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([P@:13]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:19])[O:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][CH2:8]1>CO.[Pd]>[OH:1][CH:2]([CH2:28][O:29][C:30]1[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=1)[CH2:3][NH:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([P@:13]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)(=[O:19])[O:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][CH2:8]1
Reactant: CCCCO[P@](=O)(COc1ccccc1)C1CCC(CCNCC(O)COc2ccc(OCc3ccccc3)cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CCCCO[P@](=O)(COc1ccccc1)C1CCC(CCNCC(O)COc2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of (S)-4-{2-[2-hydroxy-3-(4-benzyloxyphenoxy)propylamino]ethyl}phenoxymethylcyclohexylphosphinic acid, n-butyl ester (1.00 g, 1.64 mMol) in methanol (100 ml) containing 10% palladium on charcoal (50 mg) was hydrogenated at 40° C. and 40 p.s.i. for 24 hours. After cooling to room temperature the suspension was filtered through a pad of filter aid and the filtrate was evaporated giving the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([OH:26])=[CH:10][C:11]([CH2:17][C:18]3[C:19]([NH2:25])=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)=[CH:12][C:13]=2[O:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1.CC([O-])(C)C.[K+].Br[CH2:34][CH:35]1[CH2:37][CH2:36]1>CN(C)C=O.O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([O:26][CH2:34][CH:35]3[CH2:37][CH2:36]3)=[CH:10][C:11]([CH2:17][C:18]3[C:19]([NH2:25])=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)=[CH:12][C:13]=2[O:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1
Reactant: BrCC1CC1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(O)c1-c1cccc(N)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC2CC2)c1-c1cccc(N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3′-Amino-4-(2,4-diamino-pyrimidin-5-ylmethyl)-6-ethoxy-biphenyl-2-ol (351 mg; 1 mmol) is dissolved in dimethylformamide (22.5 ml; dried over a molecular sieve), while gassing with argon, and potassium tert-butylate (172 mg; 1.5 mmol) is added at room temperature. After the mixture has been stirred for one hour, bromomethyl-cyclopropane (0.124 ml; 1.3 mmol) is added and stirring is continued for 1 hour at a bath temperature of 60° C. The reaction mixture is then cooled to room temperature and concentrateds The residue is taken up in water/ethyl acetate and the mixture is poured into a separating funnel and extracted by shaking. The aqueous phase is separated off and re-extracted once with ethyl acetate. The combined organic phases are washed with an aqueous saturated sodium chloride solution, dried over magnesium sulphate, filtered with suction and concentrated. The residue is chromatographed over silica gel (21 g) with methylene chloride/methanol/NH4OH conc. (19/1/0.05). The pure fractions are concentrated and the residue is stirred with diethyl ether (10 ml) for 1 hour, filtered off with suction, rinsed with diethyl ether and dried under a high vacuum.
Reaction SMILES: C(OC([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:13]=2[CH2:12]1)=O)C1C=CC=CC=1>[Pd].CO>[C:28]([O:27][C:25]([CH2:24][N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[CH2:22][CH2:23][NH:11][CH2:12][C:13]1=2)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)Cn1c2c(c3ccccc31)CCN(C(=O)OCc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Cn1c2c(c3ccccc31)CCNC2

Procedure:
2-Benzyloxycarbonyl-9-tert-butyloxycarbonylmethyl-1,2,3,4-tetrahydro-9H-pyrido-[3,4-b]indole (3.28 g, 7.81 mmol) was stirred under an atmosphere of hydrogen in the presence of 10% palladium on charcoal (500 mg) in methanol (30 ml) at room temperature for two hours. The reaction mixture was filtered through a pad of celite and evaporated to dryness affording the product. (2.14 g, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].S(=O)(=O)(O)O.[C:24](=O)(O)[O-].[Na+]>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([O:14][CH3:24])=[O:13]
Reactant: O=C([O-])O
Reactant: COc1ccccc1Sc1ccccc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccccc1Sc1ccccc1OC
Temperature: 25 °C

Procedure:
Dissolve 115 g of the acid of Step A in 3.5 l of methanol and add slowly 25 ml of sulfuric acid. Stir under reflux for 72 hours. Cool the reaction mixture to room temperature and add 100 g of sodium bicarbonate in portions. Stir for an additional hour and strip to dryness. Dissolve the residue in methylene chloride and wash the solution three times with water. Dry the solution and strip to an oil which solidifies. (m.p. 82°-84° C.).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].C(O)(=O)C(C(C(O)=O)O)O>CO.CC(C)=O>[CH3:1][CH2:2][O:3][C:4]([C@H:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: CCOC(=O)C(N)c1ccccc1
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: CO
Solvent: CC(C)=O
Product: CCOC(=O)[C@H](N)c1ccccc1

Procedure:
A solution of ethyl DL-phenylglycinate (5.051 g., contains 0.05 mole methylene chloride i.e. 27.5 mmole) and (+)-tartaric acid (4.264 g., 28.4 mmole, 1.03 equiv.) in methanol: acetone (1:1, 50 ml.) was stirred at 20° to 25°; crystallisation began immediately. After 231/2 hours the mixture was filtered and the product washed with solvent (2 × 12 ml.) and dried at 24°/2 mm. for 31/2 hours giving ethyl D-phenylglycinate (+)-hemitartrate solvated with 1.0 mole methanol (7.265g., 73%), [α]D24 - 47.4° (c 2.519, H2O).
Reaction SMILES: C(N(CC)CC)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[C:29]([N:32]1[CH2:39][CH2:38][CH2:37][C@H:33]1[C:34]([OH:36])=O)(=[O:31])[CH3:30].[CH:40]1[C:48]2[C:47]3[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][C:46]=3[O:45][C:44]=2[CH:43]=[CH:42][C:41]=1[NH2:54]>>[C:29]([N:32]1[CH2:39][CH2:38][CH2:37][C@H:33]1[C:34]([NH:54][C:41]1[CH:42]=[CH:43][C:44]2[O:45][C:46]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][C:47]=3[C:48]=2[CH:40]=1)=[O:36])(=[O:31])[CH3:30]
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Reactant: CC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC[C@H]1C(=O)Nc1ccc2oc3c(c2c1)CCCCC3

Procedure:
Following the procedure of Example 30, triethylamine (0.21 mL, 1.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.15 g, 0.78 mmol), N-hydroxybenzotriazole (0.11 g, 0.78 mmol), N-acetyl-L-proline (0.094 g, 0.60 mmol), and 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (0.12 g, 0.60 mmol) 1-acetyl-N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-yl-L-prolinamide (0.13 g). MS (ESI) m/z 341 ([M+H]+); MS (ESI) m/z 339.1 ([M−H]−); HRMS: calcd for C20H24N2O3+H+, 341.18597; found (ESI, [M+H]+), 341.1863.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]([CH3:12])[CH3:11])[N:4]=1.C([O:15][C:16](=[O:28])[C:17]([CH3:27])([CH3:26])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)C>>[CH:10]([S:9][C:5]1[N:4]=[C:3]([CH2:2][O:25][C:22]2[CH:21]=[CH:20][C:19]([CH2:18][C:17]([CH3:27])([CH3:26])[C:16]([OH:28])=[O:15])=[CH:24][CH:23]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:12])[CH3:11]
Reactant: CCOC(=O)C(C)(C)Cc1ccc(O)cc1
Reactant: CC(C)Sc1cccc(CCl)n1
Product: CC(C)Sc1cccc(COc2ccc(CC(C)(C)C(=O)O)cc2)n1
Yield: 81.5 %

Procedure:
2-Chloromethyl-6-isopropylsulfanyl-pyridine (0.02 g, 0.099 mmol) obtained in Step C of Preparation Example 16 and 3-(4-hydroxy-phenyl)-2,2-dimethyl-propionic acid ethyl ester (0.022 g, 0.099 mmol) obtained in Step D of Preparation Example 39 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.029 g, 81%).