Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[C:15](=O)[CH:10]([CH2:11][O:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19].N1C=CC=CC=1>C(O)C>[CH2:1]([N:8]1[CH2:14][CH:13]2[C:15](=[N:18][OH:19])[CH:10]([CH2:11][O:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C2COC1CN(Cc1ccccc1)C2
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C1C2COC1CN(Cc1ccccc1)C2
Temperature: 100 °C
Yield: 41.2 %

Procedure:
A mixture of (rac)-3-benzyl-6-oxa-3-aza-bicyclo[3.2.1]octan-8-one (500 mg, 2.30 mmol), hydroxylamine hydrochloride (224 mg, 3.22 mmol) and pyridine (0.32 mL) in ethanol (5 mL) was heated to 100° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. 2.5 N Aqueous sodium hydroxide solution (10 mL) was added to the residue. The resulting solution was extracted with ethyl acetate (50 mL), washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel with 5-10% ethyl acetate/hexane mixture as eluent to afford the title compound as a brown sticky liquid (220 mg, 43%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[CH3:6][C:7]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([O-:20])=[O:19])[C:10]=2[O:9][C:8]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Na+]>CN(C)C=O.O>[Br:1][CH2:2][CH2:3][CH2:4][O:20][C:18]([C:17]1[C:10]2[O:9][C:8]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[C:7]([CH3:6])[C:12](=[O:13])[C:11]=2[CH:14]=[CH:15][CH:16]=1)=[O:19]
Reactant: BrCCCBr
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)[O-])cccc2c1=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccccc2)oc2c(C(=O)OCCCBr)cccc2c1=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 69.6 %

Procedure:
30 g of 1,3-dibromopropane was added dropwise at ambient temperature to a suspension of 30 g of sodium 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylate in 150 ml of dimethylformamide and 35 ml of water. The reaction mixture was stirred at ambient temperature for 5 days. 100 ml of water was added and stirring was continued for a further 15 minutes. The precipitate was filtered off by suction, washed with water and purified by flash chromatography on silica gel, eluting with chloroform:ethyl acetate 95:5. The collected fractions were evaporated to dryness in vacuo and the residue was recrystallized from ethanol to give 27.7 g of the title compound, m.p. 114°-115° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][O:22][CH3:23].[CH3:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:34](O)=[O:35])=[N:32][CH:33]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][O:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:34]([C:31]3[CH:30]=[CH:29][C:28]([CH2:27][CH2:26][CH2:25][CH3:24])=[CH:33][N:32]=3)=[O:35])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: CCCCc1ccc(C(=O)O)nc1
Product: CCCCc1ccc(C(=O)NCCCCn2c(CCOC)nc3c(N)nc4ccccc4c32)nc1

Procedure:
According to the general method of Example 50, 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin4-amine and fusaric acid were combined to provide N2-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-5-butyl-2-pyridinecarboxamide as a tan solid, m.p. 54.9-55.2° C. 1H NMR (300 MHz, DMSO-d6) δ 8.81 (t, J=6.1 Hz, 1H), 8.44 (m, 1H), 7.98 (d, J=7.3 Hz, 1H), 7.94 (dd, J=8.0, 0.7 Hz, 1H), 7.80 (dd, J=8.0, 2.2 Hz, 1H), 7.60 (dd, J=8.3, 1.2 Hz, 1H), 7.39-7.34 (m, 1H), 7.16-7.10 (m, 1H), 6.52 (broad s, 2H), 4.55 (t, J=6.9 Hz, 2H), 3.79 (t, J=6.7 Hz, 2H), 3.23 (s, 3H), 3.18 (t, J=6.7 Hz, 2H), 2.67 (t, J=7.6 Hz, 2H)., 1.83-1.72 (m, 4H), 1.63-1.53 (m, 2H), 1.34-1.24 (m, 2H), 0.90 (t, J=7.3 Hz, 3H); MS(EI) m/e 474.2750 (474.2743 calcd for C27H34N6O2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][OH:6].CO[C:18](OC)([CH3:20])[CH3:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][O:6][C:18]([CH3:20])([CH3:19])[N:7]1[C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])=[O:15]
Reactant: COC(C)(C)OC
Reactant: COC(=O)C(CO)NC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (34) in CH2Cl2 stirring under nitrogen at 0° C., was added 2,2-dimethoxypropane (29,5 mL, 237.9 mmol) and p-toluene sulfonic acid monohydrate (9.050 g, 47.58 mmol). The mixture was removed from the ice bath after 15 minutes and stirred at room temperature for 1.5 hours. The reaction mixture was poured into 50 mL of saturated NaHCO3 (aq) and extracted with diethyl ether (3×50). The organic layer was extracted with NaHCO3 and brine, then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on SiO2 (1:1 EtOAc/Hexanes) to yield 7.659 g (62%, 3 steps) of a clear liquid.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[N:4]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[N:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[N:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=3)[N:4]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:3]=2)=[CH:35][CH:34]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C(O)c1ccc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: O=C(O)c1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C

Procedure:
3-bromo-1-trityl-1H-indazole-5-carboxylic acid (500 mg, 1.04 mol) was added to a vial containing pyridin-4-ylboronic acid (128 mg, 1.04 mol) and tetrakis(triphenyl-phosphine)palladium (120 mg, 0.104 mol). After purging the vial with nitrogen gas, dioxane (5 mL) and 2M sodium carbonate (5 mL) was added to the vial respectively. The reaction mixture was stirred and was heated to 80° C. for overnight. Upon completion, the mixture was concentrated under vacuo. Water (30 mL) was added and pH was adjusted to 7 by HCl. The mixture was extracted using dichloromethane (3×100 mL). The extracts were combined and dried using anhydrous sodium sulfate. The resulting suspension was filtered and concentrated. The crude product was purified using prep LC/MS.
Reaction SMILES: Br[C:2]1[C:6]2[C:7]([NH2:19])=[N:8][CH:9]=[C:10]([C:11]3[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[C:5]=2[S:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:23]=1[NH:37][C:38]([C:40]1[N:41]([CH3:49])[C:42]2[C:47]([CH:48]=1)=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:19][C:7]1[C:6]2[C:2]([C:26]3[CH:25]=[CH:24][C:23]([NH:37][C:38]([C:40]4[N:41]([CH3:49])[C:42]5[C:47]([CH:48]=4)=[CH:46][CH:45]=[CH:44][CH:43]=5)=[O:39])=[C:22]([O:21][CH3:20])[CH:27]=3)=[CH:3][S:4][C:5]=2[C:10]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[CH:9][N:8]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: COc1ccc(-c2cnc(N)c3c(Br)csc23)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2cnc(N)c3c(-c4ccc(NC(=O)c5cc6ccccc6n5C)c(OC)c4)csc23)cn1
Reaction time: 0.08 h

Procedure:
A mixture of Example 215 (1.0 eq) in 1,2-dimethoxyethane (10 mL) and water (5 mL) was reacted with N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-indole-2-carboxamide (1.2 eq), Na2CO3 (2.4 eq), and Pd(PPh3)4 (0.06 eq) at 95° C. for 18 hours. The organic solvent was removed in vacuo and the the mixture was extracted with dichloromethane. The extract was dried (MgSO4), filtered, and concentrated. The residue was purified by preparative reverse phase HPLC (Rainin C18, 8 mm, 300 Å, 25 cm; 40% acetonitrile/0.1M ammonium acetate isocratic for 5 minutes, then 40–100% acetonitrile/0.1M ammonium acetate over 30 minutes, 21 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyophilized to provide the desired product. 1H NMR (DMSO-d6, 400 MHz) δ 9.52 (s, 1H), 8.45 (s, 1H), 8.02 (t, 1H), 7.91 (s, 1H), 7.71 (d, 1H), 7.55–7.63 (m, 2H), 7.28–7.38 (m, 2H), 7.23 (s, 1H), 7.08–7.18 (m, 2H), 7.03 (d, 1H), 5.57–5.69 (br s, 2H), 4.04 (s, 3H), 3.93 (s, 3H), 3.92 (s, 3H); reverse phase HPLC (Delta Pak C18, 5 μm, 300 Å, 15 cm; 50%-100% acetonitrile/0.1M ammonium acetate over 10 min, 1 mL/min) Rt=9.30 min.; MS m/e 536 (M+H)+.
Reaction SMILES: Cl[CH2:2][Si:3]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Na].[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.O>CN(C)C=O>[CH3:13][C:12]([CH3:15])([O:11][Si:3]([CH2:2][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)([CH3:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:14]
Reactant: CC(C)(C)O[Si](C)(CCl)c1ccccc1
Reactant: c1c[nH]cn1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)O[Si](C)(Cn1ccnc1)c1ccccc1
Reaction time: 3 h
Yield: 92.3 %

Procedure:
A mixture of 3.6 g (0.015 mol) of chloromethyl(1,1-dimethylethoxy)methyl(phenyl)silane and 1.3 g (0.015 mol) of imidazole sodium salt in 10 ml of dimethylformamide was stirred at 50° for 3 hours, allowed to stand at room temperature for 72 hours, poured into water, and extracted with ether. The ether extracts were washed three times with water and once with brine, dried over magnesium sulfate, and evaporated to leave 3.8 g of an oil. Impurities were removed by Kugelrohr distillation at 90° (airbath)/0.05 mm to leave 2.9 g (71%) of the title compound as a pale yellow oil: nD20 15291; ir (neat) 3105, 3070, 3045, 2970, 1590, 1500, 1425, 1360, 1250, 1235, 1185, 1110, 1055, 1020, 900, 805, 740, 700, 660 cm-1 ; nmr (CDCl3): 0.6 (3H, s), 1.3 (9H, s), 3.6 (2H, s), 6.8 (1H, s), 7.0 (1H, s) and 7.3-7.7 (6H, m).
Reaction SMILES: CS(C)=O.Cl[C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]#[C:15][CH3:16])[N:9]=[CH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23]([NH:26][CH2:27][CH2:28][CH3:29])[CH2:24][CH3:25]>C(OCC)(=O)C>[CH2:13]([O:12][C:10]1[CH:11]=[C:6]([N:26]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:24][CH3:25])[N:7]=[CH:8][N:9]=1)[C:14]#[C:15][CH3:16]
Reactant: CCCNCCC
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC#CCOc1cc(N(CCC)CCC)ncn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To 2 ml of dimethylsulfoxide were added 183 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 166 mg of potassium carbonate, and 152 mg of dipropylamine, followed by stirring at 80° C. for 8 hours. The reaction mixture was then left for cooling to room temperature, diluted with ethyl acetate, and washed twice with an aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel thin layer chromatography to give 179 mg of 4-(2-butynyloxy)-6-(dipropylamino)pyrimidine (the present compound (113)).
Reaction SMILES: C([O:5][C:6](=[O:15])[NH:7][CH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][NH:10]1)(C)(C)C.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([C:29](O)=[O:30])=[N:25][N:26]([CH3:28])[CH:27]=2)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:24]([C:29]([N:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]3[CH2:8][NH:7][C:6](=[O:15])[OH:5])=[O:30])=[N:25][N:26]([CH3:28])[CH:27]=2)=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCCCN1
Reactant: Cn1cc(-c2ccc(F)cc2)c(C(=O)O)n1
Product: Cn1cc(-c2ccc(F)cc2)c(C(=O)N2CCCC[C@H]2CNC(=O)O)n1
Yield: 110 %

Procedure:
The title compound (3.96 g) was prepared from (S)-1-piperidin-2-ylmethyl-carbamic acid tert butyl ester (2.14 g) and 4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl carboxylic acid (2.20 g) according to the method of D40.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH3:11][C:12]1[N:13]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:14]([CH3:17])=[CH:15][CH:16]=1>ClCCCl>[CH3:17][C:14]1[N:13]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:12]([CH3:11])=[CH:16][C:15]=1[CH:8]=[O:9]
Reactant: CN(C)C=O
Reactant: COC(=O)Cn1c(C)ccc1C
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)Cn1c(C)cc(C=O)c1C

Procedure:
17 ml (0.18 mol) of phosphorus oxychloride, 14 ml (0.18 mol) of anhydrous dimethylformamide and 30 g (0.18 mol) of methyl (2,5-dimethyl-pyrrol-1-yl)-acetate are reacted in 140 ml of 1,2-dichloroethane as described above.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:27][C:23]5[S:22][CH:26]=[CH:25][CH:24]=5)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: OCc1cccs1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4cccs4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), 2-thienylmethanol (100 μL) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, and the DCM layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (60 mg) as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[CH:22]([N:25]=[C:26]=[O:27])([CH3:24])[CH3:23]>>[CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH:21][C:26]([NH:25][CH:22]([CH3:24])[CH3:23])=[O:27])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CC(C)N=C=O
Reactant: Nc1ccc2c(c1)COC(Nc1cccc(C3CC3)c1)=N2
Product: CC(C)NC(=O)Nc1ccc2c(c1)COC(Nc1cccc(C3CC3)c1)=N2
Yield: 51.3 %

Procedure:
Prepared from N2-(3-cyclopropyl-phenyl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 119) (215 mg, 0.77 mmol) and isopropyl isocyanate (72 mg, 0.84 mmol) according to the procedure described for Example 16. Obtained the title compound as a white solid (144 mg, 51%), MS (ISP) m/e=363.5 [(M−H)−].
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][N:16]([CH3:19])[C:15]1=[O:20])[CH2:6]2.[N:21]#[C:22][NH2:23]>O1CCOCC1.Cl>[ClH:1].[CH3:19][N:16]1[CH2:17][CH2:18][N:14]([CH2:13][CH2:12][N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[C:3]([NH:2][C:22]([NH2:23])=[NH:21])[CH:4]=3)[CH2:8]2)[C:15]1=[O:20]
Reactant: CN1CCN(CCN2Cc3ccc(N)cc3C2)C1=O
Reactant: N#CN
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCN(CCN2Cc3ccc(NC(=N)N)cc3C2)C1=O

Procedure:
0.4 g I.21 (1-[2-(5-amino-1,3-dihydro-isoindol-2-yl)-ethyl]-3-methyl-imidazolidin-2-one hydrochloride) was added to a mixture of 0.37 g cyanamide in 3 ml dioxane and 1 ml 4 N hydrochloric acid in dioxane. The mixture was irradiated at 140° C. in a microwave for 30 min. The solvent was evaporated and the residue was used in the next step without purification.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:24](=[O:30])[NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:15]=1)[C:24]([NH:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:30]
Reactant: CC(C)(C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reaction time: 0.33 h
Yield: 91.3 %

Procedure:
A solution of (S)-[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-carbamic acid tert-butyl ester (6.0 g, 14.1 mmol, Example 2, Step B) in CH2Cl2 (28 mL) was treated with trifluoroacetic acid (28 mL). The resulting solution was stirred for 20 minutes and then concentrated. The residue was diluted with EtOAc (300 mL), washed with saturated bicarbonate solution (2×300 mL) and brine (300 mL), dried over Na2SO4, and concentrated to give 4.2 g (91%) of (S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide.
Reaction SMILES: Cl.C(O[C:7]([N:9](C)[S:10]([NH:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:12])=[O:11])=O)CCC>CO>[CH3:7][NH:9][S:10]([NH:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:12])=[O:11]
Reactant: CCCCOC(=O)N(C)S(=O)(=O)NCC(=O)OCC
Agent: Cl
Solvent: CO
Product: CCOC(=O)CNS(=O)(=O)NC
Reaction time: 3 h

Procedure:
To a solution of HCl in methanol (2 M) is added ethyl 2-((N-(butyloxycarbonyl)-N-methylsulfamoyl)amino)acetate from the previous step (5.0 mmol) in portions at RT and the mixture is stirred for 3 h. After the solvent is removed in vacuo, the residue is washed with diethyl ether to afford ethyl 2-((N-methylsulfamoyl)amino)acetate
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([N+:12]([O-])=O)=[C:10]([N+:15]([O-])=O)[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]>CO.[Pd]>[CH3:1][O:2][C:3]1[C:11]([NH2:12])=[C:10]([NH2:15])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1c(C(=O)O)ccc([N+](=O)[O-])c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1c(C(=O)O)ccc(N)c1N

Procedure:
2-methoxy-3,4-dinitrobenzoic acid (1.0 g) was dissolved in methanol (50 mL) and treated with 100 mg 10% palladium on carbon. The reaction mixture was purged with nitrogen and placed in an ice bath. Upon treatment with 5 mL formic acid, brisk effervescence was noticed which subsides upon further cooling. The reaction mixture was filtered through celite and concentrated to give a tan solid. (Decolorization occurs rapidly upon keeping) EIMS M+ 182, Exp. 182.
Reaction SMILES: C([Li:5])CCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10](Br)[CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15]>CCOCC>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([Li:5])[CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15]
Reactant: [Li]CCCC
Reactant: COc1cc(Br)cc(OC)c1OC
Solvent: CCOCC
Product: [Li]c1cc(OC)c(OC)c(OC)c1
Reaction time: 1 h

Procedure:
To a stirred solution of n-butyllithium (3.7 mL, 1.6 M in hexane solution, 6.0 mol) in dry ether (40 mL), a solution of 3,4,5-trimethoxyphenylbromide (0.74 g, 3.0 mol) in ether (20 mL) was added under dry nitrogen at −78° C. The solution was stirred for 1 h in order to form 3,4,5-trimethoxyphenyllithum (“TPL”). Substituted tetralone reagent (3.0 mol) was added at −20° C., and the stirring was continued for 2 h (−20° C.—RT). The mixture was partitioned between CH2Cl2 and water, the organic layer was dried over anhydrous sodium sulfate, and, after filtration, the organic layer was concentrated in vacuo to provide a tetrahydronaphthalen-1-ol as a yellow oil. Each compound was purified by column chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:17])[NH:14][CH:13]([C:15]#[N:16])[CH2:12][O:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH3:17])[NH:14][CH:13]([CH2:15][NH2:16])[CH2:12][O:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2(C)COCC(C#N)N2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C2(C)COCC(CN)N2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.25 mmol of 5-(4-methoxyphenyl)-5-methylmorpholin-3-carbonitrile (Example 3f2) in 10 ml of tetrahydrofuran is cooled to 0-5° C. in an ice bath. 6.75 mmol of lithium aluminium hydride are added in portions, and the reaction mixture is then stirred at room temperature for 1 hour. The reaction mixture is quenched with 0.5 ml of methanol and mixed with 40 ml of dichloromethane and 0.060 g of solid potassium carbonate, and 0.60 ml of water. The suspension is filtered through Hyflo and the filter cake is washed with dichloromethane. The filtrate is evaporated. The title compound is obtained as a colourless oil from the residue by flash chromatography (SiO2 60 F). Rf=0.26 (dichloromethane-methanol-25% aqueous ammonia solution 200:20:1), Rt=2.13 (gradient I)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH2:48][CH2:49][CH2:50][CH3:51]>CN(C=O)C>[CH2:48]([N:25]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:24][CH2:23][CH2:22][N:21]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:12]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:11][CH2:10][CH2:9][N:8]([CH2:13][CH2:14][CH2:15][CH3:16])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:49][CH2:50][CH3:51]
Reactant: CCCCI
Reactant: CC(C)(C)OC(=O)NCCCN(CCCCCCCCN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: CCCCN(CCCN(CCCCCCCCN(CCCN(CCCC)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 64.6 %

Procedure:
Combine 3.5 gm (0.0053 mol) of the product of Step C of Example 1, 2.7 gm (0.024 mol) of KtBuO, 2.57 ml (0.024 mol) of 1-iodobutane in 10 ml of DMF and allow the mixture to stir for 18 hours. Evaporate the volatiles (0.5 mm at 45° C.), dissolve the residue in 500 ml of EtOAc, water-wash (2× with 100 ml) the organic layer and dry the organic layer over MgSO4. Evaporate off the solvents and subject the residue to flash chromatography (silica gel eluted with 20% EtOAc/hexane to yield 1.32 gm of the title compound. Rf is 0.36 (silica gel plates eluted with 20% EtOAc/hexane).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]([F:21])([F:20])[CH:17]1[O:19][CH2:18]1>>[O:1]([C:8]1[CH:9]=[C:10]([NH:11][CH2:18][CH:17]([OH:19])[C:16]([F:21])([F:20])[F:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(Oc2ccccc2)c1
Reactant: FC(F)(F)C1CO1
Product: OC(CNc1cccc(Oc2ccccc2)c1)C(F)(F)F
Temperature: 100 °C
Yield: 70.6 %

Procedure:
EX-588B) A mixture of solid 3-phenoxyaniline (2.96 g, 16 mmol) and 1,1,1-trifluoro-2.3-epoxypropane (1.30 mL. 15.0 mmol) was placed in a sealed tube and heated to 100° C. giving a dark solution. The stirred solution was heated 18 h and cooled to give a dark oil. Purification by flash chromatography on silica gel eluting with dichloromethane gave 3.15 g (71%) of the desired 3-[(N-3-phenoxy-phenyl)amino]-1,1,1-trifluoro-2-propanol product as a colorless oil. Anal. calcd. for C15H14NO2F3.0.05 CH2Cl2: C, 59.92; H, 4.71; N, 4.64. Found: C. 59.92; H, 4.53; N, 4.73. HRMS calcd. 298.1055 [M+H]+, found: 298.1056.