Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[O:9][CH2:8]1)([O-:3])=[O:2].[N+:18]([O-])([OH:20])=[O:19]>>[N+:1]([O:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:10]=2[O:9][CH2:8]1)([O-:3])=[O:2]
Reactant: O=C1c2ccccc2OCN1CCO[N+](=O)[O-]
Reactant: O=[N+]([O-])O
Product: O=C1c2cc([N+](=O)[O-])ccc2OCN1CCO[N+](=O)[O-]

Procedure:
50 ml of 100% fuming nitric acid were dropped into 50 g (0.21 mole) of 2,3-dihydro-3-(2'-nitrooxyethyl)-4H-1,3-benzoxazin-4-one, at a temperature of -10° C. At the end of the addition, the reaction mixture was stirred for minutes, then poured in ice and sequentially extracted with chloroform. The organic layer was washed with water, sodium hydroxide 0.1N and again with water, then dried over sodium sulphate and concentrated to dryness. The resulting oil was taken up with warm ethyl ether yielding 42.5 g of the title compound as white solid. m.p. 97°-99° C. (ethyl ether).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C@H:6]1[CH2:11][CH:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:9](=[O:19])[CH2:8][N:7]1[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[OH:19][CH:9]1[CH2:8][N:7]([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])[C@@H:6]([CH2:5][O:4][CH2:3][O:2][CH3:1])[CH2:11][CH:10]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: C=CCOC(=O)N1CC(=O)C(C(=O)OC(C)(C)C)C[C@@H]1COCOC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C=CCOC(=O)N1CC(O)C(C(=O)OC(C)(C)C)C[C@@H]1COCOC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-allyl 4-tert-butyl (2R)-2-[(methoxymethoxy)methyl]-5-oxo-1,4-piperidinedicarboxylate (1.21 g, 3.4 mmol) in methanol (40 ml) was added acetic acid (0.235 ml, 4.1 mmol) and sodium cyanoborohydride (0.255 g, 4.1 mmol) and the mixture were stirred at room temperature for 20 minutes. The solvent was removed in vacuo and it was confirmed whether a starting material run out by TLC. When the starting material remained, methanol (40 ml) was added thereto to dissolve the reaction mixture and then the solvent was again removed. Until the starting material run out, the procedure was repeated. After the starting material run out, the residue was purified by silica gel (30 g) chromatography to give 1-allyl 4-tert-butyl (2R)-5-hydroxy-2-[(methoxymethoxy)methyl]-1,4-piperidinedicarboxylate (1.22 g, quantitatively).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][C@H:26]5[CH2:28][O:27]5)=[CH:20][CH:19]=4)[N:15]=[C:14]3[CH2:29][O:30][CH2:31][CH3:32])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:35]([NH2:37])[CH3:36]>CO>[Cl:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][C@H:26]([OH:27])[CH2:28][NH:37][CH2:35][CH3:36])=[CH:20][CH:19]=4)[N:15]=[C:14]3[CH2:29][O:30][CH2:31][CH3:32])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCN
Reactant: CCOCc1nc(-c2ccc(OC[C@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: CO
Product: CCNC[C@@H](O)COc1ccc(-c2cn(-c3ccc(Oc4ccc(Cl)cc4)cc3)c(COCC)n2)cc1

Procedure:
A solution of 1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-4-[4-((R)-1-oxiranylmethoxy)-phenyl]-1H-imidazole (50 mg, 0.11 mmol, from intermediate B2) in 4 mL of ethylamine in MeOH (2M) was stirred at 60° C. overnight in a teflon-capped vial. Upon completion (determined by LC/MS), the reaction was dried in vacuo and purified by silica gel flash column chromatography using a gradient of EtOAc to 4% ammonia/MeOH (2.0M) in EtOAc as an eluent to afford (R)-1-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenoxy)-3-ethylamino-propan-2-ol.
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1.[NH2:31][CH2:32][CH2:33][OH:34]>C(O)C>[OH:34][CH2:33][CH2:32][NH:31][C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1
Reactant: NCCO
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Solvent: CCO
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(NCCO)no2)C1
Reaction time: 2 h

Procedure:
To a solution of 150 mg (0.337 mmol) of the oxadiazole from Example 23A in 2.25 ml of ethanol were added 412 mg (6.74 mmol) of 2-aminoethanol, and then the reaction mixture was stirred in the microwave at 80 for 2 h. The solvent was removed under reduced pressure and the crude product was purified by means of preparative HPLC. Yield: 82.2 mg (52% of theory)
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([OH:11])=[C:6]([C:12]([CH3:16])([CH3:15])[CH2:13]Cl)[CH:5]=1>O1CCCC1>[Br:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]2[O:11][CH2:13][C:12]([CH3:16])([CH3:15])[C:6]=2[CH:5]=1
Reactant: Cc1cc(O)c(C(C)(C)CCl)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc2c(cc1Br)C(C)(C)CO2
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
To a stirred, cooled (ice bath) suspension of sodium hydride (60% dispersion in mineral oil, 1.23 g, 30.85 mmol) in 50 mL of anhydrous tetrahydrofuran under argon, a solution of 4-bromo-2-(2-chloro-1,1-dimethyl-ethyl)-5-methyl-phenol (Compound 46, 6.2 g, 25.7 mmol) in 10 mL of anhydrous tetrahydrofuran was added. After 0.5 hour, the excess sodium hydride was quenched with methanol and the reaction mixture was evaporated in vacuo. The residue was diluted with water, extracted with ether and the organic phase was washed with brine. The organic extract was dried over anhydrous sodium sulfate, filtered and evaporated to an oil. Flash column chromatography of the oil over silica gel using hexanes as the eluent afforded the title compound as a clear oil (5.25 g, quantitative). 1H NMR (300 MHz, CDCl3): δ 7.23 (s, 1H), 6.70 (s, 1H), 4.24 (s, 2H), 2.35 (s, 3H), 1.33 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[CH3:13][O:14][C:15]([CH2:17]P(OC)(OC)=O)=[O:16]>>[CH3:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1/[CH:4]=[CH:17]/[C:15]([O:14][CH3:13])=[O:16]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: Cc1ccc([N+](=O)[O-])cc1C=O
Product: COC(=O)/C=C/c1cc([N+](=O)[O-])ccc1C

Procedure:
Methyl(E)-3-(2-methyl-5-nitro-phenyl)prop-2-enoate (15a) is prepared from commercial 2-methyl-5-nitro-benzaldehyde (5j) (for a synthesis of (5j) see also Example 5, Method B) and commercial trimethyl phosphonoacetate as described in Example 2.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:20])OCC(Cl)(Cl)Cl)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:21]1([C:27]2[N:31]=[C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13]([N:35]3[CH2:36][CH2:37][N:32]([C:30]4[S:29][N:28]=[C:27]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:31]=4)[CH2:33][CH2:34]3)=[O:20])=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(Nc1ccc(-n2ccnc2)cc1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(-n2ccnc2)cc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1

Procedure:
A solution of 2,2,2-trichloroethyl [4-(1H-imidazol-1-yl)phenyl]carbamate (200 mg, 0.598 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (147 mg, 0.598 mmol), diisopropylethylamine (0.104 ml, 0.598 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to obtain the desired product (71.0 mg, 35.4%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.C(N(CC)C(C)C)(C)C.[I-].[Na+].[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[C:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[N:21]=1>CN(C=O)C>[Cl:19][C:20]1[N:21]=[C:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[N:23]=[C:24]([NH:7][C:4]2[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=2)[CH:25]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Clc1cc(Cl)nc(-c2ccccc2Cl)n1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2cc(Cl)nc(-c3ccccc3Cl)n2)n[nH]1
Temperature: 110 °C
Yield: 70.1 %

Procedure:
A mixture containing 5-methyl-1H-pyrazol-3-amine 187 mg, 1.93 mmol), N,N-diisopropylethylamine (503 μl, 2.89 mmol), sodium iodide (289 mg, 1.93 mmol) and DMF (50 mL) was treated with 4,6-dichloro-2-(2-chlorophenyl)pyrimidine (500 mg, 1.93 mmol). The reaction mixture was then heated at 110° C. for 48 h before being cooled to room temperature and concentrated in vacuo. The resulting residue was purified by column chromatography (eluting with MeOH/DCM, 5/95) to give the title compound as a solid (433 mg, 70%). MS (ES+) m/e=320. 1H NMR: (DMSO) 2.18-2.23 (3H, m), 7.40-7.70 (6H, m), 10.32 (1H, s), 12.10 (1H, brs)
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:8]2[CH2:7][CH2:6][O:5][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21]([NH:17][C:14]1[CH:13]=[N:12][C:11]([C:10]2[C:2]([Cl:1])=[CH:3][C:4]3[O:5][CH2:6][CH2:7][C:8]=3[CH:9]=2)=[CH:16][N:15]=1)=[O:22]
Reactant: Nc1cnc(-c2cc3c(cc2Cl)OCC3)cn1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cnc(-c2cc3c(cc2Cl)OCC3)cn1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
To a solution of 5-(6-chloro-2,3-dihydrobenzo[3,4-b]furan-5-yl)pyrazine-2ylamine (147) (7.8 mg, 0.031 mmol) in 1 ml DCM was added 2,6-difluorobenzoyl chloride (12 μl, 3 eq) followed by addition of DIEA (27 μl). The resulting solution was stirred at r.t. for overnight. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (100 μl) at 60° C. for 1 h and before worked up with EA/aq. NaHCO3. Prep HPLC purification furnished (2,6-difluorophenyl)-N-[5-(6-chloro(2,3-dihydrobenzo[b]furan-5-yl))pyrazin-2-yl]carboxamide (148) (4.2 mg, yield: 34.9%, purity>90%) as pale yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[C@H:6]([CH2:7][OH:8])[C:5]1([CH3:23])[C:9]1[CH:18]=[CH:17][C:16]2[C:15]([CH3:20])([CH3:19])[CH2:14][CH2:13][C:12]([CH3:22])([CH3:21])[C:11]=2[CH:10]=1.[Si](OCC1[C@@H](CO)C1(C)C1C=CC2C(C)(C)CCC(C)(C)C=2C=1)(C(C)(C)C)(C)C.CI>>[CH3:1][O:2][CH2:3][CH:4]1[C@@H:6]([CH2:7][OH:8])[C:5]1([CH3:23])[C:9]1[CH:18]=[CH:17][C:16]2[C:15]([CH3:20])([CH3:19])[CH2:14][CH2:13][C:12]([CH3:22])([CH3:21])[C:11]=2[CH:10]=1
Reactant: COCC1[C@H](CO)C1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: CC1(C)CCC(C)(C)c2cc(C3(C)C(CO[Si](C)(C)C(C)(C)C)[C@H]3CO)ccc21
Solvent: CI
Product: COCC1[C@@H](CO)C1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 40 %

Procedure:
Following a procedure similar to that for the preparation of Intermediate 6a using Intermediate 5 as the starting material and methyl iodide as the alkylating reagent provided the title compound as a colorless oil (67 mg, 40% yield):
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:41][C@:42]1([C:47]([NH:49][S:50]([CH:53]2[CH2:55][CH2:54]2)(=[O:52])=[O:51])=[O:48])[CH2:44][C@H:43]1[CH:45]=[CH2:46].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CO.CN(C=O)C>[CH:53]1([S:50]([NH:49][C:47]([C@@:42]2([NH:41][C:24]([C:23]3[CH:22]=[C:21]([C:18]4[CH:19]=[CH:20][C:10]5[O:9][C:8]([C:5]6[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=6)=[C:12]([C:13]([NH:14][CH3:15])=[O:16])[C:11]=5[CH:17]=4)[CH:29]=[CH:28][CH:27]=3)=[O:25])[CH2:44][C@H:43]2[CH:45]=[CH2:46])=[O:48])(=[O:52])=[O:51])[CH2:55][CH2:54]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=C[C@@H]1C[C@]1(NC(=O)c1cccc(-c2ccc3oc(-c4ccc(F)cc4)c(C(=O)NC)c3c2)c1)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 55.4 %

Procedure:
In a 7 mL scintillation vial were combined 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (30 mg, 0.077 mmol), (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide 4-methylbenzenesulfonate (30 mg, 0.075 mmol), and HATU (40 mg, 0.10 mmol). DMF (0.4 mL) and DIPEA (0.1 mL, 0.57 mmol) were added, the vial was capped, and the solution was stirred at r.t. for 45 min. The reaction was diluted with MeOH, filtered, purified by prep HPLC, and the collected fractions were concentrated on a SPEEDVAC® to afford the title compound (25 mg, 54% yield) as a white powder. 1H NMR (500 MHz, CDCl3) δ ppm 8.01 (s, 1H) 7.97 (s, 1H) 7.88 (dd, J=8.85, 5.19 Hz, 2H) 7.80 (d, J=7.63 Hz, 1H) 7.74 (d, J=7.63 Hz, 1H) 7.59 (br. s., 1H) 7.52 (s, 2H) 7.48 (t, J=7.63 Hz, 1H) 7.18 (t, J=8.55 Hz, 2H) 6.00 (d, J=3.97 Hz, 1H) 5.61-5.73 (m, 1H) 5.39 (d, J=17.09 Hz, 1H) 5.20 (d, J=10.99 Hz, 1H) 3.02 (d, J=4.88 Hz, 3H) 2.91-2.99 (m, 1H) 2.34 (q, J=8.44 Hz, 1H) 2.05-2.09 (m, 1H) 1.49 (dd, J=9.31, 5.95 Hz, 1H) 1.41 (dd, J=5.80, 4.58 Hz, 1H) 1.30-1.35 (m, 1H) 1.22-1.30 (m, 1H) 1.04-1.12 (m, 1H) 0.96-1.04 (m, 1H). LC/MS was performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters MICROMASS®. LC/MS method: solvent A=10% CH3CN/90% H2O/0.1% TFA, solvent B=90% CH3CN/10% H2O/0.1% TFA, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm; HPLC Rt=1.73 min, (ES+) m/z (MH+)=602. Analytical HPLC were performed using a Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: solvent A=5% CH3OH/95% H2O/10 mM NH4HCO3, solvent B=95% CH3OH/5% H2O/10 mM NH4HCO3, start % B=10, final % B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column: PHENOMENEX® Gemini C18, 4.6 mm, 3 μm, Rt=16.26 min, purity=100%; column: Waters XBridge phenyl 4.6×150 mm, 3.5 μm, Rt=15.28 min, purity=100%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[S:17]([CH3:19])=[O:18])[N:10]3[CH2:20][CH2:21][CH2:22][CH:23]([CH2:24][C:25]([O:27]CC)=[O:26])[C:9]=23)=[CH:4][CH:3]=1.C1COCC1.CO.[Li+].[OH-].CC(O)=O>[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[S:17]([CH3:19])=[O:18])[N:10]3[CH2:20][CH2:21][CH2:22][CH:23]([CH2:24][C:25]([OH:27])=[O:26])[C:9]=23)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1CCCn2c1c(-c1ccc(Cl)cc1)c1c(S(C)=O)cccc12
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CS(=O)c1cccc2c1c(-c1ccc(Cl)cc1)c1n2CCCC1CC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the ester of Step 13 in a THF/MeOH (3:1) mixture at r.t. was added 1N LiOH (aqueous solution). The reaction mixture was stirred at r.t. for 2 hours and AcOH (0.5 mL) and brine (5 mL) were added. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4 and concentrated. The residue was swished in EtOAc/hexanes to give the desired acid as a white solid. Each isomer from Step 13 was hydrolyzed under these conditions. From the less polar diastereomer of Step 13: 1H NMR (methanol-d4) δ 7.65 (1H, d), 7.61 (1H, d), 7.51–7.35 (5H, m), 4.37–4.29 (1H, m), 4.09–4.02 (1H, m), 3.79–3.71 (1H, m), 2.40 (1H, dd), 2.24 (3H, s), 2.23–1.91 (5H, m). MS (−APCI) m/z 400.2 M-H)+.
Reaction SMILES: [C:1]1([CH:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[C:20]([C:28]([O:30]C)=[O:29])=[CH:21][C:22]4[N:23]([N:25]=[CH:26][N:27]=4)[N:24]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:32]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[C:20]([C:28]([OH:30])=[O:29])=[CH:21][C:22]4[N:23]([N:25]=[CH:26][N:27]=4)[N:24]=3)[CH2:13][CH2:14]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)c1cc2ncnn2nc1NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2ncnn2nc1NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51.3 %

Procedure:
1.58 g of methyl [6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[1,5-b]pyridazin-7-yl]carboxylate was dissolved in 10 ml of ethanol; 8.0 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by stirring at room temperature for 1.5 hours. After cooling, the mixture was concentrated under reduced pressure. The residue was diluted with water and washed with ethyl acetate; 1N hydrochloric acid was added to adjust pH 4.5. The mixture was saturated with saline and extracted with tetrahydrofuran; the extract was dried over magnesium sulfate. The crystal obtained by concentration under reduced pressure was washed with ethyl ether, collected by filtration and dried to yield 788 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[N:7]([CH2:11][CH3:12])[C:6](=[O:13])[CH2:5]2.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](Cl)=[O:20]>CN(C)C1C=CN=CC=1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[N:7]([CH2:11][CH3:12])[C:6](=[O:13])[CH:5]2[C:19](=[O:20])[C:15]1[S:14][CH:18]=[CH:17][CH:16]=1
Reactant: CCN1C(=O)Cc2cc(Cl)cnc21
Reactant: O=C(Cl)c1cccs1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C(=O)c2cccs2)c2cc(Cl)cnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-chloro-1-ethyl-7-azaoxindole (400 mg, 2.03 mmol) and 4-dimethylaminopyridine (537 mg, 4.4 mmol) in DMF (10 mL) at 0° C. was added thiophene-2-carbonyl chloride (0.24 mL, 2.24 mmol). The reaction mixture was stirred at room temperature for 2 hours and then poured into ice/water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried (magnesium sulfate) and concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with chloroform. Fractions containing only the desired product were combined and concentrated to afford the title compound as a solid which was recrystallized from hexanes. The yield of recrystallized material was 29 mg (50%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([F:16])([F:15])[F:14])=[CH:7][CH:6]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[C:17]1([C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:6][CH:7]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C1COCCN1
Reactant: Fc1ccc(C(=C(c2ccccc2)C(F)(F)F)c2ccc(OCCBr)cc2)cc1
Product: Fc1ccc(C(=C(c2ccccc2)C(F)(F)F)c2ccc(OCCN3CCOCC3)cc2)cc1
Yield: 92 %

Procedure:
3.25 g (7 mmoles) of 1-[4-(2-bromoethoxy)-phenyl]-2-phenyl-3,3,3-trifluoro-1-(4-fluorophenyl)-propene are reacted with morpholine as described in Example 1. The product is crystallized from hexane. 3.03 g (92%) of the aimed compound are obtained; m.p.: 95°-96° C.
Reaction SMILES: [O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:51])[NH:11][CH:12]([CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:13]([OH:43])[CH2:14][N:15]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[C:25]([NH:32][CH:33]3[CH2:37][CH2:36][N:35]([CH:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)[CH2:34]3)[CH:24]=2)(=[O:22])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1.C([O-])=O.[NH4+]>[Pd].CC1CCCO1>[O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:51])[NH:11][CH:12]([CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:13]([OH:43])[CH2:14][N:15]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([NH:32][CH:33]3[CH2:37][CH2:36][N:35]([CH:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)[CH2:34]3)[CH:24]=2)(=[O:21])=[O:22])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1
Reactant: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)S(=O)(=O)c1ccc([N+](=O)[O-])c(NC2CCN(C3CCCC3)C2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC1CCCO1
Product: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)S(=O)(=O)c1ccc(N)c(NC2CCN(C3CCCC3)C2)c1

Procedure:
(1-Benzyl-3-{[3-(1-cyclopentyl-pyrrolidin-3-ylamino)-4-nitro-benzenesulfonyl]-isobutyl-amino}-2-hydroxy-propyl)-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester (12) (0.36 g, 0.50 mmol, 1 equiv), ammonium formiate (0.16 g, 2.50 mmol, 5 equiv) and palladium on charcoal (10%, 0.106 g, 1.00 mmol, 2 equiv) were suspended in 2-methyl-tetrahydro-furan. The solution was heated to reflux for 2 h. The catalyst was filtered over a bed of dicalite and the filtrate was evaporated under reduced pressure. The crude product was purified by column chromatography on elution with dichloro-methane:ammonia in methanol (7N) (99:1 to 97.5:2.5). The solvent was evaporated under reduced pressure. (0.10, 0.50 mmol, 29%). LRMS (ES+): m/z 700 [M+H]+; HPLC (system 1) (272 nm) tR 6.95 min, 94%; 1H-NMR (CDCl3) δ 0.89 (d, 3H, CH3), 0.92 (d, 3H, CH3), 1.39-2.10 (m, 17H, CH2, H4, CH and CH2 (7x)), 2.70-3.21 (m, 9H, CH2—N, CH2—N (isobutyl), CH, H3a, CH—NH and CH—N), 3.59-3.78 (m, 3H, CH, H5, CH, H2 and CH), 3.78-3.99 (m, 3H, CH, H2, CH, H5 and CH—OH), 4.32-4.43 (brs, 1H, NH), 4.60-4.76 (brs, 1H, NH), 4.90-5.08 (m, 1H, CH, H3), 5.62 (d, 1H, CH, H6a), 6.62 (d, 1H, CHarom), 6.87 (s, 1H, CHarom), 7.07 (dd, 1H, CHarom), 7.18 (d, 1H, OH), 7.22-7.31 (m, 5H, C6H5).
Reaction SMILES: [Na].Cl.[CH3:3][C:4]([CH3:11])([CH3:10])[CH2:5][CH2:6][C:7]([NH2:9])=[NH:8].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[S:21])=[CH:15][CH:14]=1>CC(C)=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:8][C:7](=[NH:9])[CH2:6][CH2:5][C:4]([CH3:11])([CH3:10])[CH3:3])=[S:21])=[CH:15][CH:14]=1
Reactant: CC(C)(C)CCC(=N)N
Reactant: S=C=Nc1ccc(Cl)cc1
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CC(C)(C)CCC(=N)NC(=S)Nc1ccc(Cl)cc1

Procedure:
Following a procedure similar to that described in Example 42 but using 7.22 g. sodium in 705 ml. dry acetone, 51.7 g. 4,4-dimethylvaleramidine hydrochloride, and 53.2 g. 4-chlorophenyl isothiocyanate in 350 ml. dry acetone there was obtained 1-(4-chlorophenyl)-3-(4,4-dimethylpentanimidoyl)-2-thiourea; m.p. 135°-137°C. (from acetonitrile); hydrochloride (80.7 g.), m.p. 182°-186°C.