Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[CH:16][C:17]4[C:22]([CH:23]=3)=[CH:21][C:20]([C:24]3[CH:25]=[N:26][N:27]([CH:29]5[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]5)[CH:28]=3)=[CH:19][CH:18]=4)=[C:9]([O:42][CH3:43])[CH:8]=2)=[CH:5][N:4]=[C:3]1[CH3:44].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[CH:16][C:17]4[C:22]([CH:23]=3)=[CH:21][C:20]([C:24]3[CH:25]=[N:26][N:27]([CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)[CH:28]=3)=[CH:19][CH:18]=4)=[C:9]([O:42][CH3:43])[CH:8]=2)=[CH:5][N:4]=[C:3]1[CH3:44]
Reactant: COc1cc(-c2cnc(C)n2C)ccc1Nc1cc2cc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)ccc2cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2cnc(C)n2C)ccc1Nc1cc2cc(-c3cnn(C4CCNCC4)c3)ccc2cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.5 %

Procedure:
To a solution of tert-butyl 4-(4-(3-((4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-amino)isoquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Example 4, 27 mg, 0.045 mmol) in DCM (6 mL) at 0° C. was added TFA (0.6 mL) and the reaction was stirred at room temperature for 4 hours. The solvents were removed in vacuo and the residue was purified by SCX-2 column eluting with 2M NH3/MeOH to afford the title compound as a yellow oil (19 mg, 85%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.C([Mg]Cl)(C)C.[CH3:14][C:15]1[CH:16]=[C:17]([P:22]([C:24]2[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[CH:25]=2)Cl)[CH:18]=[C:19]([CH3:21])[CH:20]=1>C1COCC1.CC(OC)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[P:22]([C:24]1[CH:25]=[C:26]([CH3:31])[CH:27]=[C:28]([CH3:30])[CH:29]=1)[C:17]1[CH:16]=[C:15]([CH3:14])[CH:20]=[C:19]([CH3:21])[CH:18]=1
Reactant: Brc1ccccc1I
Reactant: Cc1cc(C)cc(P(Cl)c2cc(C)cc(C)c2)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: Cc1cc(C)cc(P(c2cc(C)cc(C)c2)c2ccccc2Br)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of 9.67 g (34.2 mmol) of 1-bromo-2-iodobenzene in 30 ml of THF are added dropwise, at −78° C., 17.6 ml (37.6 mmol) of an isopropylmagnesium chloride solution (2 molar in THF). The mixture is stirred at a temperature between −30° C. and −40° C. for a further 1 hour, then cooled again to −78° C., and a suspension of 10.4 g (37.6 mmol) of bis(3,5-dimethylphenyl)chlorophosphine in 10 ml of THF and 10 ml of TBME are added. The cooling is removed and the reaction mixture is stirred at room temperature overnight. The resulting solution is admixed with 50 ml of water and extracted with water/TBME. The organic phases are collected and dried over sodium sulphate, and the solvent is distilled off under reduced pressure on a rotary evaporator. The solid white crude product is purified by chromatography (silica gel 60; eluent=methylene chloride). The desired product is obtained as a white solid in a yield of 56%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11]>>[CH3:9][C:4]1[N:3]=[C:2]2[NH:1][C:10](=[O:11])[O:8][C:7]2=[CH:6][CH:5]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc(O)c(N)n1
Product: Cc1ccc2oc(=O)[nH]c2n1

Procedure:
Reaction of 2-amino-6-methylpyridin-3-ol with CDI (carbonyldiimidazole) in a corresponding manner to Example 1.2 gives the desired product; ESI: 151 (M+H), Rt=1.58 min (method B).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:18])[CH2:10][CH2:11][CH:12]2[NH:16][C:15](=[O:17])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([OH:18])[CH2:10][CH2:11][CH:12]2[NH:16][C:15](=[O:17])[CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C(CCC1CCC(=O)N1)Cc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C1CCC(CCC(O)Cc2ccc(F)cc2)N1
Reaction time: 20 h
Yield: 75.5 %

Procedure:
Analogous to the procedure described for Compound 1A, Step B, 5-[4-(4-fluoro-phenyl)-3-oxo-butyl]-pyrrolidin-2-one (2.64 g, 10.6 mmol) was reduced with NaBH4 (400 mg, 10.5 mmol) at room temperature for 1 h. Additional NaBH4 (150 mg, 3.95 mmol) was added and the reaction mixture was stirred for 20 h. Purification by medium pressure chromatography using a solvent gradient (CH2Cl2 to 2% MeOH in CH2Cl2 to 4% MeOH in CH2Cl2) provided 5-[4-(4-fluoro-phenyl)-3-hydroxy-butyl]-pyrrolidin-2-one (2.01 g). 1H NMR (CDCl3) δ 7.14 (m, 2H), 6.98 (m, 2H), 6.78 (m, 1H), 3.76 (m, 1H), 3.65 (m, 1H), 2.76 (m, 1H), 2.64 (m, 1H), 2.32-2.18 (m, 4H), 1.72-1.47 (m, 5H).
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(F)(F)F.[CH3:13][CH2:14]OCC>C(O)(=O)C.C(Cl)Cl>[NH:7]1[C:1]2[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=[CH:13]1
Reactant: CCOCC
Reactant: NNc1ccccc1
Agent: FB(F)F
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc2[nH]ccc2c1
Temperature: 50 °C
Yield: 275.1 %

Procedure:
To a solution of 1 (90 mg, 0.27 mmol) in acetic acid (2 mL) was added a solution of phenylhydrazine (0.026 mL, 0.27 mmol) in acetic acid (1 mL) and the mixture heated at 50° C. for 1 hour. The reaction was cooled to room temperature then boron trifluoride etherate (0.060 mL, 0.46 mmol) added and the reaction heated at 80° C. for 16 hours. The mixture was diluted with CH2Cl2 (25 mL) and washed with satd NaHCO3 (3×15 mL, caution: vigorous gas evolution). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was chromatographed on silica gel, eluted with 40% EtOAc/hexanes, to give 2 (87 mg, 78% yield) as an off-white solid. Rt=1.96 min using Phenomenex 30×4.6 5u column with flow rate of 5 mL/min over 2 min gradient. 0 to 100% B. Solvent A=10/90/0.1% MeOH/H2O/TFA. Solvent B=90/10/0.1%. [M+H]=411.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:4]=2[S:5][C:6]=1[C:7]([N:9]1[CH2:12][CH:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:10]1)=[O:8].[S:27]1[CH:31]=[C:30]([C:32](O)=[O:33])[N:29]=[CH:28]1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(OCC)C>[Cl:1][C:2]1[C:3]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][C:4]=2[S:5][C:6]=1[C:7]([N:9]1[CH2:12][CH:11]([N:13]2[CH2:18][CH2:17][N:16]([C:32]([C:30]3[N:29]=[CH:28][S:27][CH:31]=3)=[O:33])[CH2:15][CH2:14]2)[CH2:10]1)=[O:8]
Reactant: O=C(O)c1cscn1
Reactant: O=C(c1sc2cc(C(F)(F)F)ccc2c1Cl)N1CC(N2CCNCC2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(c1cscn1)N1CCN(C2CN(C(=O)c3sc4cc(C(F)(F)F)ccc4c3Cl)C2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of compound 1d (0.15 mmol), thiazole-4-carboxylic acid 1e (23 mg, 0.18 mmol), and Et3N (0.09 mL, 0.65 mmol) in CH2Cl2 (3 mL) at room temperature was added HATU (68 mg, 0.18 mmol). The reaction mixture was stirred at room temperature for 18 h. It was diluted with diethyl ether, washed with aq. NaHCO3 and aq. NaCl, dried over Na2SO4, filtered, and concentrated. Purification by flash column chromatography (silica gel, 3% MeOH/CH2Cl2) gave compound 1. 1H NMR (400 MHz, CD3OD): δ 8.80 (d, J=2 Hz, 1H), 8.13 (t, J=0.8 Hz, 1H), 8.03 (d, J=2 Hz, 1H), 8.01 (d, J=8.6 Hz, 1H), 7.73 (dd, J=1.2 Hz, 8.6 Hz, 1H), 4.31 (m, 2H), 4.21 (m, 1H), 4.15 (m, 1H), 4.01 (m, 1H), 3.93 (m, 2H), 3.81 (m, 1H), 3.33 (m, 1H), 2.55-2.40 (m, 4H); MS m/z (M+H+) 515.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH3:20])[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=1)[C:13]([O:15]C)=[O:14])=[O:8])(=O)C.C(SCC(C)C(NC1N=CC=CC=1C(OC)=O)=O)(=O)C>>[SH:4][CH2:5][CH:6]([CH3:20])[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=1)[C:13]([OH:15])=[O:14])=[O:8]
Reactant: COC(=O)c1ccnc(NC(=O)C(C)CSC(C)=O)c1
Agent: COC(=O)c1cccnc1NC(=O)C(C)CSC(C)=O
Product: CC(CS)C(=O)Nc1cc(C(=O)O)ccn1

Procedure:
Following the procedure of Example 3, but substituting an equivalent amount of methyl 2-(2-acetylthiomethyl-propionamido)-isonicotinate, obtained as disclosed in Example 29, for methyl 2-(2-acetylthiomethyl-propionamido)-nicotinate; 2-(2-mercaptomethyl-propionamido)-isonicotinic acid is obtained; m.p. 247°-248° C., from ethanol/water.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[CH2:13]([NH:17][CH2:18][C@@H:19]([C@H:21]([C@@H:23]([C@@H:25]([CH2:27][OH:28])[OH:26])[OH:24])[OH:22])[OH:20])[CH2:14][CH2:15][CH3:16]>>[CH2:13]([NH:17][CH2:18][C@@H:19]1[O:20][C@:25]([OH:26])([CH2:27][OH:28])[C@@H:23]([OH:24])[C@@H:21]1[OH:22])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CCCCNC[C@@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O

Procedure:
The process of claim 1 in which D-glucose is aminated to N-n-butyl glucamine which in turn is oxidized to produce 6-n-butylamino-6-deoxy-α-L-sorbofuranose which is reduced to produce N-n-butyl-1-deoxynojirimycin.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=[O:15])[C:12](=[CH2:14])[CH3:13])=[CH:10][C:5]=2[O:4][C:3]1=[O:16].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CC(C)=O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=[O:15])[CH:12]([CH3:13])[CH2:14][N:28]3[CH2:27][CH2:26][N:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[O:18][CH3:17])[CH2:30][CH2:29]3)=[CH:10][C:5]=2[O:4][C:3]1=[O:16]
Reactant: COc1ccccc1N1CCNCC1
Reactant: C=C(C)C(=O)c1ccc2c(c1)oc(=O)n2C
Solvent: CC(C)=O
Product: COc1ccccc1N1CCN(CC(C)C(=O)c2ccc3c(c2)oc(=O)n3C)CC1

Procedure:
100 cm3 of anhydrous acetone, 0.01 mole of 3-methyl-6-(2-methylenepropionyl)benzoxazolinone and 0.01 mole of 1-(2-methoxyphenyl)piperazine are introduced successively into a 250-cm3 ground-necked flask equipped with a reflux condenser and a magnetic stirrer. The mixture is brought to reflux for 6 hours and allowed to cool. The product is drained: the product of the title is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C@@H:6]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:17])[CH2:7][N+:8]([O-])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)C.[ClH:32]>O1CCCC1.O1CCCC1.O>[ClH:32].[NH2:8][CH2:7][C@H:6]([C@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[OH:17])[C:5]1[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc([C@H](C[N+](=O)[O-])C2CCCCC2=O)cc1OC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COc1ccc([C@H](CN)[C@H]2CCCC[C@H]2O)cc1OC
Reaction time: 8 h

Procedure:
A solution of 50.5 g (163 mmol) of rac-(2S*)-2-[(R*)-3,4-dimethoxy-α-(nitromethyl)benzyl]cyclohexanone in 500 ml of dry tetrahydrofuran is added dropwise while stirring to a suspension of 15.4 g (407 mmol) of lithium aluminium hydride in 350 ml of dry tetrahydrofuran under argon so that the temperature does not exceed 50°. The reaction mixture is stirred at 50° overnight and treated, after cooling, firstly with ethanol and subsequently with tetrahydrofuran/water (1:1). The separated precipitate is filtered off under suction while washing with methylene chloride and the filtrate is evaporated. The oily crude product obtained is converted into the hydrochloride which is recrystallized from alcohol. There is obtained rac-(1S*)-cis-2-[(R*)-α-(aminomethyl)-3,4-dimethoxybenzyl]cyclohexanol hydrochloride of m.p. 216°-218°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([OH:11])[CH2:6][CH2:5]2.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][O:29]1)[CH2:6][CH2:5]2
Reactant: C1=COCCC1
Reactant: OC1CCc2cc(Br)ccc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Brc1ccc2c(c1)CCC2OC1CCCCO1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
9.6 g of 5-bromo-1-hydroxyindane was dissolved in 100 ml of dry methylene chloride. To the solution were added, at room temperature, 570 mg of pyridinium p-toluenesulfonate and 4.5 ml of 3,4-dihydro-2H-pyran. The resulting mixture was stirred at the same temperature for 3 hours. The reaction mixture was added to ice water. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: toluene/ethyl acetate=15/1) to obtain 13.1 g of oily 5-bromo-1-(tetrahydropyran-2-yloxy)indane.
Reaction SMILES: [CH2:1]1[C@H:5]([N:6]2[C:11](=[O:12])[N:10]=[C:9]([NH2:13])[CH:8]=[CH:7]2)[O:4][C@H:3]([CH2:14][O:15][P:16]([OH:19])([OH:18])=[O:17])[C@H:2]1[O:20][P:21]([O:24][CH2:25][C@H:26]1[O:30][C@@H:29]([N:31]2[C:35]3[N:36]=[CH:37][N:38]=[C:39]([NH2:40])[C:34]=3[N:33]=[CH:32]2)[C@H:28]([OH:41])[C@@H:27]1[OH:42])([OH:23])=[O:22].[CH3:43][O:44][C@@H:45]([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:46](OCC#N)=[O:47].N1C=CN=C1.C(O)(C(F)(F)F)=O>[Cl-].C[N+](C)(C)CCCCCCCCCCCCCCCC.O>[CH3:43][O:44][C@H:45]([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:46]([O:42][C@H:27]1[C@@H:28]([OH:41])[C@H:29]([N:31]2[CH:32]=[N:33][C:34]3[C:35]2=[N:36][CH:37]=[N:38][C:39]=3[NH2:40])[O:30][C@H:26]1[CH2:25][O:24][P:21]([O:20][C@H:2]1[CH2:1][C@H:5]([N:6]2[CH:7]=[CH:8][C:9]([NH2:13])=[N:10][C:11]2=[O:12])[O:4][C@@H:3]1[CH2:14][O:15][P:16]([OH:18])([OH:19])=[O:17])([OH:23])=[O:22])=[O:47]
Reactant: CO[C@@H](Cc1ccccc1)C(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Agent: c1c[nH]cn1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CO[C@H](Cc1ccccc1)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.5 %

Procedure:
((2R,3S,5R)-5-(4-Amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h, 0.32 g, 0.50 mmol) and (S)-cyanomethyl 2-methoxy-3-phenylpropanoate (Compound 7b, 0.44 g, 2.01 mmol) were added to a solution of imidazole (3.40 g, 50.00 mmol) and N,N,N-trimethylhexadecan-1-aminium chloride (3.20 g, 10.00 mmol) dissolved in water (30 ml), and the mixture was stirred at room temperature for 30 minutes. TFA (1.0 ml) was added to the reaction solution, followed by concentration. The resulting residue was purified by preparative HPLC (0.05% aqueous TFA solution:acetonitrile=84:16→60:40) to afford the title compound (66 mg, 16%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH3:14])[CH2:12][OH:13])=[N:8][C:7]([SH:15])=[N:6][C:5]=2[N:16]=1.[Cl:17][C:18]1[S:22][N:21]=[N:20][C:19]=1CCl>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH3:14])[CH2:12][OH:13])=[N:8][C:7]([S:15][C:19]3[N:20]=[N:21][S:22][C:18]=3[Cl:17])=[N:6][C:5]=2[N:16]=1
Reactant: C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Reactant: ClCc1nnsc1Cl
Product: C[C@H](CO)Nc1nc(Sc2nnsc2Cl)nc2nc(N)sc12

Procedure:
Prepared by the method of example 32 step c), using the product of example 32 step b) and 5-chloro-4-(chloromethyl)-1,2,3-thiadiazole.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].C([O-])(O)=O.[Na+].C(=O)([O-])OC1C(CCOCCC2C=CC=CC=2)=CC=CN=1.[CH2:35]([O:43][CH2:44][CH2:45][O:46][C:47](N1C=CC=CC1=O)=[O:48])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O.C1COCC1>[OH:4][C@@H:3]([CH3:5])[C@@H:2]([NH:1][C:47]([O:46][CH2:45][CH2:44][O:43][CH2:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:48])[C:6]([OH:8])=[O:7]
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Reactant: O=C(OCCOCCc1ccccc1)n1ccccc1=O
Agent: O=C([O-])O
Agent: O=C([O-])Oc1ncccc1CCOCCc1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](O)[C@@H](NC(=O)OCCOCCc1ccccc1)C(=O)O
Reaction time: 15 h
Yield: 97.6 %

Procedure:
To a stirred mixture of D-threonine (0.15 g, 1.25 mmol) and NaHCO3 (0.16 g, 1.25 mmol) in H2O (3.0 mL), the crude isomeric mixture containing 2-phenethyloxyethyl-2-pyridyl carbonate and 2-phenethyloxyethyl-2-oxopyridine-1-carboxylate (0.54 g, 1.89 mmol) in THF (3.0 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×5 mL). The aqueous phase was acidified with 2.0 M HCl solution to pH 2-3 and subsequently extracted with EtOAc (3×10 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.38 g, 94%) as transparent oil, which was used in the next step without further purification. MS (ESI) m/z: 312 [M−H]+; (ESI) m/z: 310 [M−H]−. 1H NMR (DMSO-d6): δ 1.09 (d, J=6.4 Hz, 3H), 2.81 (t, J=7.1 Hz, 2H), 3.55-3.66 (m, 4H), 3.93 (dd, J=3.4, 8.9 Hz, 1H), 4.00-4.15 (m, 3H), 6.83 (d, J=8.9 Hz, 1H), 7.14-7.32 (m, 5H), 12.20 (s, 1H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:10][C:11](=[O:38])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:22][C:21]=2[O:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>CO>[CH2:3]([NH:10][C:11](=[O:38])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][C:21]=2[O:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCC(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCCC(C)C)c1
Temperature: 55 °C
Yield: 84 %

Procedure:
281 mg (7.03 mmol, 10 eq) of sodium hydroxide are added to a solution of 400 mg (0.703 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-(3-methylbutoxy)biphenyl-4-yl]propanoate in 10 ml of methanol. The reaction mixture is heated at 55° C. for 1 hour. The reaction medium is evaporated to dryness, taken up in water, acidified with 2N hydrochloric acid solution and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over magnesium sulfate. The solvent is evaporated off and the oil obtained is chromatographed on silica gel (10 g FlashSmart column) eluted with 30/70 heptane/ethyl acetate. The product is crystallized from heptane and 284 mg of 3-[3′-(3-heptyl-1-methylureido)-2-(3-methylbutoxy)biphenyl-4-yl]propanoic acid are obtained in the form of white crystals (m.p.=60-62° C.). Yield=84%
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].[Li]CCCC.[CH3:18][C:19]([CH3:21])=[O:20].Cl>C1COCC1.[OH-].[Na+]>[OH:20][C:19]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12])([CH3:21])[CH3:18]
Reactant: CC(C)=O
Reactant: COc1cc(C(=O)O)ccc1Br
Agent: Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1C(C)(C)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
4-Bromo-3-methoxy-benzoic acid (2.00 g, 8.67 mmol) was dissolved in THF (50 mL) and the solution was cooled to −78° C. n-BuLi in hexanes (7.6 mL of 2.5 M, 19 mmol) was added dropwise over 15 minutes. The reaction mixture was allowed to stir for 30 minutes at −78° C. and then acetone (640 μL, 8.9 mmol) was added in a dropwise manner. The reaction mixture was allowed to stir for 30 minutes at −78° C., and then it was allowed to warm to room temperature. The reaction mixture was then diluted with 100 mL of 1M aqueous sodium hydroxide. The organic layer was discarded and the aqueous layer was made acidic with 4M aqueous hydrochloric acid. The aqueous layer was then extracted 3 times with ethyl acetate. The combined extracts were dried over sodium sulfate and then evaporated to dryness. The crude material was purified by column chromatography utilizing a gradient of 0-5% methanol in dichloromethane to give 4-(2-hydroxypropan-2-yl)-3-methoxybenzoic acid (618 mg, 34%). ESI-MS m/z calc. 210.1, found 209.1 (M−1)−; Retention time: 0.68 minutes (3 min run).
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].[C:21]1([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35]Cl)[CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]\[C:40]([OH:42])=[O:41]>C(O)C>[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]\[C:40]([OH:42])=[O:41].[C:21]1([N:27]2[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][CH2:35][N:9]3[C:8](=[O:13])[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:11][C:10]3=[O:12])[CH2:31][CH2:32]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCCCN1CCN(c2ccccc2)CC1
Reactant: O=C1NC(=O)C(c2ccccc2)(c2ccccc2)N1
Agent: O=C(O)/C=C\C(=O)O
Agent: [Na]
Solvent: CCO
Product: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1CCCN1CCN(c2ccccc2)CC1
Reaction time: 16 h

Procedure:
5,5-diphenylhydantoin, 25.2 g (0.1 mole), was added to a solution of 2.3 g (0.1 mole) of sodium in 300 ml of anhydrous ethanol and the suspension was heated under reflux for half an hour. 4-phenyl-1-(3-chloropropyl)piperazine, (23.9 g, 0.1 mole) slowly was added to the suspension and the mixture was heated under reflux with stirring for 16 hours. The solvent was removed in vacuo, the concentrate was suspended in water, and the free base was extracted with chloroform. The dried extracts were concentrated in vacuo to an oil. The oil was dissolved in hot methanol and 14 g (0.12 mole) of maleic acid was added. The hot solution was filtered and the filtrate was cooled. The resulting solid was collected and recrystallized from an aqueous-methanol solution.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13]2[NH:18][C:17]([CH3:20])([CH3:19])[N:16]=[C:15]([O:21]CC)[N:14]=2)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.C[Si](I)(C)C.Cl>S1(CCCC1)(=O)=O>[NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13]2[NH:18][C:17]([CH3:19])([CH3:20])[N:16]=[C:15]([OH:21])[N:14]=2)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1
Reactant: CCOC1=NC(C)(C)NC(NC(=O)c2nc(Cl)c(N)nc2N)=N1
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: O=S1(=O)CCCC1
Product: CC1(C)N=C(O)N=C(NC(=O)c2nc(Cl)c(N)nc2N)N1
Temperature: 45 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 3,5-diamino-6-chloro-N-(3,4-dihydro-4,4-dimethyl-6-ethoxy-1,3,5-triazin-2-yl)-2-pyrazinecarboxamide (0.55 g., 0.0016 mole) in sulfolane (10 ml.) is added trimethylsilyl iodide (1.5 ml.). The reaction mixture is stirred for 5 hours at 45° C., poured into ice water (30 ml.) containing hydrochloric acid (1.5 ml.), then extracted with chloroform (2×15 ml.) The aqueous layer is made basic with ammonia to give 420 mg. of 3,5-diamino-6-chloro-N-(3,4-dihydro-4,4-dimethyl-6-hydroxy-1,3,5-triazin-2-yl)-2-pyrazinecarboxamide which melts at 266°-8° C. after reprecipitation from dilute hydrochloric acid with ammonia.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]#[C:16][C:17](=O)[CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:27][NH2:28]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]2[NH:28][N:27]=[C:17]([CH3:18])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)C#CC(=C1CCN(C(=O)OC(C)(C)C)CC1)c1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2)[nH]n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
A mixture of 4-[1-phenyl-1-(3-oxo-1-butyn-1-yl)methylene]-piperidine-1-carboxylic acid tert-butyl ester(0.365 g, 1.069 mmol) and hydrazine hydrate (0.065 mL, 1.14 mmol) in EtOH (5 mL) was allowed to stir at rt for 2 h and then it was heated at 80° C. for 14 h. The solvent was subsequently removed under reduced pressure and the residue was purified by preparative HPLC affording the title compound (0.151 g, 40%) as a colorless solid