Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH4+].[C:11](=[S:14])([S-:13])[NH2:12]>CCO.CCOC(C)=O>[SH:14][C:11]1[S:13][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:12]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)[S-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1csc(S)n1
Reaction time: 16 h
Yield: 23.3 %

Procedure:
To a solution of ethyl 3-bromo-2-oxopropanoate (200 mg, 1.02 mmol) in EtOH (5.0 mL) was added dithiocarbamic acid ammonium salt (96 mg, 1.23 mmol) The reaction mixture was stirred for 16 h, then diluted with EtOAc and washed with H2O and brine. The organic fraction was dried (MgSO4), filtered, and concentrated. Purification by preparative TLC afforded the title compound (45.0 mg, 23%). 1H NMR (DMSO-d6) δ=1.23 (t, 3H), 4.23 (q, 2H), 7.78 (s, 1H); ESIMS: m/z 188 (M+H). mp=120-121° C.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:33])[CH:12]([C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:19]=[C:20]([OH:22])[CH:21]=1)[CH2:13][CH2:14][CH3:15])[CH3:9].[F:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>CC([O-])=O.CC([O-])=O.[Cu+2].C(Cl)Cl>[CH2:8]([O:10][C:11](=[O:33])[CH:12]([C:16]1[CH:17]=[C:18]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:27][CH:28]=2)[CH:19]=[C:20]([O:22][C:38]2[CH:39]=[CH:40][C:35]([F:34])=[CH:36][CH:37]=2)[CH:21]=1)[CH2:13][CH2:14][CH3:15])[CH3:9]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCCC(C(=O)OCC)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(C(=O)OCC)c1cc(Oc2ccc(F)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Reaction time: 24 h
Yield: 58.2 %

Procedure:
Triethylamine (100 μL, 0.72 mmol) was added to a stirred mixture of 2-(5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (90 mg, 0.25 mmol), Cu(OAc)2 (68 mg, 0.38 mmol), 4-fluorophenylboronic acid (70 mg, 0.57 mmol), 4 {acute over (Å)} molecular sieves (25 mg, powdered) and DCM (2 mL) at room temperature open to the air. After 24 h, the reaction mixture was loaded onto silica and purified (0-10% ethyl acetate in petrol) to give 2-(5-(4-fluorophenoxy)-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (67 mg) as a colourless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[C:41]([O:42][CH3:43])=[CH:40][C:24]2[CH2:25][CH2:26][N:27]([CH2:30][C:31]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[O:32])[CH2:28][CH2:29][C:23]=2[CH:22]=1>>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])=[N:7][C:2]([NH:20][C:21]2[C:41]([O:42][CH3:43])=[CH:40][C:24]3[CH2:25][CH2:26][N:27]([CH2:30][C:31]([N:33]4[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]4)=[O:32])[CH2:28][CH2:29][C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N1CCN(C)CC1)CC2
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n1)CCN(CC(=O)N1CCN(C)CC1)CC2
Yield: 32 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1-(4-methyl-piperazin-1-yl)-ethanone. Product was isolated as a white foam (38 mg, 32%). mp: 190° C. (glass 140), MS (ESI+): 595.5 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.20 (s, 1H), 7.91 (s, 1H), 7.42 (s, 1H), 6.65 (s, 1H), 6.57 (d, J=8 Hz, 1H), 5.60 (br s, 1H), 5.32 (s, 1H), 4.46 (t, J=9 Hz, 1H), 3.88 (s, 3H), 3.72 (m, 2H), 3.67 (m, 2H), 3.30 (s, 2H), 3.09 (s, 1H), 2.89 (s, 5H), 2.68 (s, 4H), 2.53 (d, J=8 Hz, 1H), 2.46 (m, 2 h), 2.41 (m, 2H), 2.34 (s, 3H), 2.28 (d, J=8 Hz, 1H), 1.67 (d, J=9 Hz, 1H), 1.27 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14]>C(O)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([N:15]([CH2:16][CH3:17])[CH2:13][CH3:14])=[C:3]([CH:6]=1)[C:4]#[N:5])([O-:12])=[O:11]
Reactant: CCNCC
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Solvent: CCO
Product: CCN(CC)c1ccc([N+](=O)[O-])cc1C#N
Reaction time: 1 h
Yield: 86.6 %

Procedure:
2-Chloro-5-nitrobenzonitrile (15 g) and diethylamine (15 g) were added to ethanol (100 ml) and the mixture was stirred at a refluxing temperature for 1 h. The solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from hydrous ethanol to give 5-nitro-2-diethylaminobenzonitrile (15.6 g), melting point: 98° C.
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:16]=[C:15]([C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)[C:14]2[C:23](=[O:37])[N:24](CC3C=CC(OC)=CC=3OC)[CH2:25][C:13]=2[C:12]=1[F:38].[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl>[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40].[NH2:1][C@H:2]1[C:7]([F:8])([F:9])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:16]=[C:15]([C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)[C:14]2[C:23](=[O:37])[NH:24][CH2:25][C:13]=2[C:12]=1[F:38]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC(F)(F)[C@@H]4N)nc(-c4cnn(C)c4)c3C2=O)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2nc(N[C@@H]3CCCC(F)(F)[C@@H]3N)c(F)c3c2C(=O)NC3)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 23.7 %

Procedure:
To a solution of 6-(cis-2-amino-3,3-difluorocyclohexylamino)-2-(2,4-dimethoxybenzyl)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (21 mg, 0.040 mmol) in DCM (300 μL) was added TFA (500 μL, 6.49 mmol). The reaction mixture was stirred at ambient temperature for 12 h then an additional 3 h at 50° C. The mixture was subsequently concentrated to a dark oil and diluted with DMF (1 mL) which was purified via preparative HPLC and lyophilized to give a TFA salt of the title compound as a fluffy white solid (3.6 mg, 19%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.89 (s, 1H), 8.43 (s, 3H), 8.16 (s, 1H), 6.89 (br s, 1H), 6.54 (br s, 1H), 4.65-4.52 (m, 1H), 4.49-4.32 (m, 2H), 4.17 (br s, 1H), 3.89 (s, 3H), 2.37-2.03 (m, 2H), 1.84 (br s, 3H), 1.63 (br s, 1H). [M+H] calc'd for C17H19F3N6O, 381. found, 381.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:9]=1[O:10][CH2:11][CH2:12][C:13]([OH:15])=O.CN(C=O)C.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Br:7][C:8]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[C:16]2[C:9]=1[O:10][CH2:11][CH2:12][C:13]2=[O:15]
Reactant: O=C(O)CCOc1cc(F)c(F)cc1Br
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCOc2c(Br)cc(F)c(F)c21
Reaction time: 1.5 h
Yield: 72.2 %

Procedure:
Oxalyl chloride (1.7 mL, 20 mmol) was added to the solution of 2.8 g (10 mmol) of 3-(2-bromo-4,5-difluorophenoxy)-propanoic acid in 40 mL of anhydrous DCM followed by a drop of DMF. After 1.5 hours, a drying tube was attached and the solution was cooled in an ice-water bath. AlCl3 (1.5 g, 11 mmol) was added and the dark red solution was allowed to slowly reach room temperature while being stirred for 16 hours. The mixture was poured into ice and the organic layer was separated. The aqueous layer was extracted with DCM twice. The combined organic layers were washed with 0.5 N NaOH and brine, then dried over Na2SO4 and concentrated. Column chromatography of this residue with hexane and EtOAc provided 1.9 g of the title compound as an off-white solid (73%). 1H NMR (300 MHz, CDCl3): δ 7.6 (t, 1H), 4.65 (t, 2H), 2.85 (t, 2H).
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:7]1[C:15]2[C:11](=[CH:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:14]=2)[CH:10]=[C:9]([Cl:24])[CH:8]=1)[CH3:6].[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2([CH2:48][OH:49])[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]2)=[CH:31][CH:30]=1>ClCCl.C1CCCCC1>[Cl:24][C:9]1[CH:8]=[C:7]([CH:5]([O:49][CH2:48][C:35]2([C:32]3[CH:31]=[CH:30][C:29]([F:28])=[CH:34][CH:33]=3)[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])[CH2:39][CH2:40]2)[CH3:6])[C:15]2[C:11](=[CH:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:21])[CH3:23])[N:14]=2)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Reactant: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-1-(5-Chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethyl 2,2,2-trichloroacetimidate (1.1 g, 2.33 mmol) and tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.79 g, 2.57 mmol) were combined in a dichloromethane/cyclohexane mixture (1:1, 10 mL) and cooled to 0° C. The reaction was treated with tetrafluoroboric acid-diethyl ether complex (64 μL, 0.47 mmol), stirred at 0° C. for 1 h, quenched by addition of saturated sodium bicarbonate, and diluted with diethyl ether. The layers were separated. The ethereal was washed with water (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (20% ethyl acetate/hexanes) gave 0.81 g (56%) as a clear film. 1H-NMR (CDCl3, 500 MHz) δ 8.00 (s, 1H), 7.49 (d, J=1.8 Hz, 1H), 7.30-7.33 (m, 2H), 7.01-7.05 (m, 2H), 6.77 (m, 1H), 5.62-5.68 (s, 2H), 4.93 (q, J=6.4 Hz, 1H), 3.72 (m, 2H), 3.58-3.61 (m, 2H), 3.33-3.39 (m, 2H), 3.03-3.08 (m, 2H), 2.08-2.22 (m, 2H), 1.87-1.97 (m, 2H), 1.44 (s, 9H), 1.43 (d, J=6.4 Hz, 3H), 0.91-0.92 (m, 2H), 0.05 (s, 9H). Mass spec.: 618.86 (MH)+.
Reaction SMILES: O.[F:2][C:3]1[C:8](F)=[CH:7][CH:6]=[CH:5][C:4]=1C1C=C2C(=CC=1)NN=C2C(NCC1CCN(CC2OC=C(C(O)=O)N=2)CC1)=[O:20].Br[C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[NH:44][N:43]=[C:42]2[C:48]([NH:50][CH2:51][CH:52]1[CH2:57][CH2:56][N:55]([CH2:58][C:59]2[O:63][C:62]([C:64]([O:66]CC)=[O:65])=[CH:61][CH:60]=2)[CH2:54][CH2:53]1)=[O:49].FC1C=CC=CC=1B(O)O>>[OH2:20].[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[NH:44][N:43]=[C:42]2[C:48]([NH:50][CH2:51][CH:52]1[CH2:53][CH2:54][N:55]([CH2:58][C:59]2[O:63][C:62]([C:64]([OH:66])=[O:65])=[CH:61][CH:60]=2)[CH2:56][CH2:57]1)=[O:49]
Reactant: O=C(O)c1coc(CN2CCC(CNC(=O)c3n[nH]c4ccc(-c5cccc(F)c5F)cc34)CC2)n1
Reactant: CCOC(=O)c1ccc(CN2CCC(CNC(=O)c3n[nH]c4ccc(Br)cc34)CC2)o1
Agent: OB(O)c1ccccc1F
Solvent: O
Product: O=C(O)c1ccc(CN2CCC(CNC(=O)c3n[nH]c4ccc(-c5ccccc5F)cc34)CC2)o1
Reaction time: 0.25 h

Procedure:
5-({4-[({[5-(2-Fluorophenyl)-1H-indazol-3-yl]carbonyl}amino)methyl]piperidin-1-yl}methyl)furan-2-carboxylic acid hydrate 20 was prepared, according to the procedure described for compound 12, from compound 15 and (2-fluorophenyl)boronic acid and using the following preparative HPLC parameters for the purification: channel A=CH3CN+0.1% formic acid; channel B=H2O+0.1% formic acid: flow=40 ml/min; gradient=10%-45% of eluent A in 15 minutes. Yield: 20 mg, 7%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12]O)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:38]I>C1(C)C=CC=CC=1>[I:38][CH2:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: II
Reactant: COc1ccc(CCCCO)cc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CCCCI)cc1
Temperature: 65 °C

Procedure:
To a stirred solution of 4-(4-methoxyphenyl)butan-1-ol (9.37 g, 52 mmol, Aldrich) in dry toluene (185 mL) under an argon atmosphere was added triphenylphosphine (17.8 g, 67.6 mmol) and imidazole (10.6 g, 156 mmol). After ten minutes I2 (17.1 g, 67.6 mmol) was added. The reaction was then heated at 65 ° C. for 30 minutes. Upon cooling to room temperature the reaction was concentrated to 1/4 volume. The remaining solution was diluted with Et2O and washed with H2O and brine and dried (MgSO4). The solvent was removed and the resulting residue was dissolved in CH2Cl2 and applied to a flash chromatography column (silica). Elution with 2% EtOAc in hexane provided a colorless oil: 1H NMR (250 MHz, CDCl3) δ7.08 (d, J=8.7 Hz, 2H, phenyl), 6.82 (d, J=8.7 Hz, 2H, phenyl), 3.78 (s, 3H, OMe), 3.17 (t, J=7.4 Hz, 2H, I-CH2), 2.54 (t, J=7.2 Hz, 2H, benzylic), 1.85 (m, 2H, CH2), 160 (m, 2H, CH2).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].[CH3:5][CH:6]1[CH2:11][CH2:10][CH:9]([CH:12]=[O:13])[CH2:8][CH2:7]1.[Cl-].[NH4+].Cl>O1CCCC1>[CH3:5][CH:6]1[CH2:11][CH2:10][CH:9]([CH:12]([OH:13])[CH2:1][CH3:2])[CH2:8][CH2:7]1
Reactant: CC[Mg]Cl
Reactant: CC1CCC(C=O)CC1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)C1CCC(C)CC1
Temperature: 22.5 °C
Reaction time: 16 h

Procedure:
180 ml (0.36 mol) of a 2 M ethylmagnesium chloride solution in tetrahydrofuran (THF) was first treated with a solution of 37.8 g (0.3 mol) of 4-methylcyclohexanecarbaldehyde (cis/trans) in 70 ml of THF and then stirred under protective gas atmosphere for approximately 16 hours at 20-25° C. After addition of 250 ml of 15% by weight ammonium chloride solution, the mixture was acidified with semiconcentrated hydrochloric acid and then extracted with methyl tert-butyl ether (MTBE). Washing of the combined organic phases with water and drying gave 44 g of 1-(4-methylcyclohexyl)propan-1-ol as a colorless oil. According to 1H NMR analysis, the ratio between the cis and trans isomers in the mixture amounted to approximately 35:65.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([O:19]C)[CH:3]=1.[OH-].[Na+]>C(O)C(O)C>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:7])=[C:4]([OH:19])[CH:3]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(O)CO
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Yield: 32.5 %

Procedure:
A mixture of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide (29.5 g, 0.1 mole), sodium hydroxide pellets (4.0 g, 0.1 mole) and 1,2-propanediol (70 ml) was stirred and heated under reflux for 20 hours followed by concentration in vacuo. The residue was treated with 1N HCl (100 ml) and again concentrated in vacuo. The residue was chromatographed on silica using methylene chloride (90), methanol (10), ammonia (0.5) solvent system. The appropriate fractions were combined and concentrated in vacuo and the residue crystallized from ether to give 9.3 g of product. This was dissolved in hot water, and the solution filtered over charcoal. The filtrate was cooled and filtered to give 6.7 g of tan colored title compound, mp 126°-7° (U.S. Pat. No. 3,357,978 reports mp 160° ).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[NH:5]([C:7]1[S:11][N:10]=[C:9]([C:12]([Cl:15])([Cl:14])[Cl:13])[N:8]=1)[NH2:6]>>[Cl:15][C:12]([Cl:13])([Cl:14])[C:9]1[N:8]=[C:7]([NH:5][N:6]=[C:2]([CH3:4])[CH3:1])[S:11][N:10]=1
Reactant: CC(C)=O
Reactant: NNc1nc(C(Cl)(Cl)Cl)ns1
Product: CC(C)=NNc1nc(C(Cl)(Cl)Cl)ns1
Yield: 79 %

Procedure:
A mixture of 5 ml (3.9 g, 0.068 mole) acetone and 2.4 g (0.01 mole) 5-hydrazino-3-trichloromethyl-1,2,4-thiadiazole was heated 0.5 hour on a steam bath. The solid that was left after evaporation of the excess acetone was recrystallized from ligroin to yield 0.95 g (mp. 75°-77° C.). A second crop of 1.2 g (mp. 66° C.) was obtained after concentration of the solvent. Total yield was 2.15 g (79% yield).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([O:23][NH:24][C@H:25]([C:30]([OH:32])=O)[CH2:26][CH:27]([CH3:29])[CH3:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ON1C(=O)CCC1=O.Cl.[NH2:42][CH:43]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[C:44]([O:46][CH2:47][CH3:48])=[O:45]>O1CCOCC1.C(N(CC)CC)C>[CH2:16]([O:23][NH:24][C@H:25]([C:30]([NH:42][CH:43]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:49]([O:51][CH2:52][CH3:53])=[O:50])=[O:32])[CH2:26][CH:27]([CH3:28])[CH3:29])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: CC(C)C[C@H](NOCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)[C@H](CC(C)C)NOCc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
22.90 g of dicyclohexylcarbodiimide was added to 300 ml of a solution of 26.39 g of N-benzyloxyleucine and 13.35 g of N-hydroxysuccinimide in anhydrous dioxane. The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered to remove the insoluble materials, whereby a colorless solution was obtained. Separately, 20 ml of triethylamine was added to 300 ml of a suspension of 28.57 g of diethyl aminomalonate hydrochloride in anhydrous dioxane. To the mixture was applied an ultrasonic wave for 1 hour. Thereto was added the above colorless solution. The mixture was stirred at room temperature for 16 hours and then at a bath temperature of 100° C. for 3.5 hours. The reaction mixture was subjected to distillation to remove the solvent. The residue was dissolved in 1,000 ml of ethyl acetate. The solution was washed with 1N hydrochloric acid, an aqueous solution saturated with sodium hydrogen carbonate and an aqueous solution saturated with sodium chloride in this order, then dried with anhydrous magnesium sulfate, and subjected to distillation to remove the solvent to obtain 39.22 g of diethyl N-(N-benzyloxyleucyl)aminomalonate as a yellow oily substance.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:6]([O:8][CH3:9])=[O:7])(=O)[CH3:2].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.FC(F)(F)C(O)=O>C(#N)CCC>[CH3:16][O:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:1]([CH3:2])=[N:4][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COCCCCC(=O)C(NC(C)=O)C(=O)OC
Reactant: Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCCC#N
Product: COCCCCc1c(C(=O)OC)nc(C)n1-c1ccccc1
Temperature: 25 °C

Procedure:
Methyl 2-(acetylamino)-7-methoxy-3-oxoheptanoate (5.45 g), aniline (3.01 ml) and trifluoroacetic acid (2.48 ml) were dissolved in butyronitrile (30 ml), and the reaction mixture was heated under reflux for 2 hr. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. 3.6M Aqueous potassium carbonate solution was added to the obtained residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (3.88 g).
Reaction SMILES: [CH:1](=[N:10][NH2:11])[C@H:2]([C@@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5])[OH:3].[H][H]>C(O)C.O.[Pt]=O>[NH:10]([CH2:1][C@H:2]([C@@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5])[OH:3])[NH2:11]
Reactant: NN=C[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: [H][H]
Agent: O=[Pt]
Solvent: O
Solvent: CCO
Product: NNC[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
A 1.5 portion of D-arabinose hydrazone in 40 ml of ethanol and 20 ml of water was reduced with 200 mg of platinum oxide and hydrogen for 4 hours. The mixture was then filtered and the filtrate evaporated to dryness. The residue was dissolved in 40 ml of methanol and then evaporated to dryness, giving 1.24 g of 1-deoxy-1-hydrazino-D-arabinitol.
Reaction SMILES: [N+](C1C=CC(C([O:10][C@@H:11]2[CH2:16][C@H:15]([CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@@H:14]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:13]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@H:12]2[NH:42]C(OC(C)(C)C)=O)=O)=CC=1)([O-])=O.C([O-])([O-])=O.[K+].[K+]>CO.CCOC(C)=O>[NH2:42][C@@H:12]1[C@@H:13]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C@H:14]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@@H:15]([CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][C@H:11]1[OH:10]
Reactant: CC(C)(C)OC(=O)N[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)C[C@H]1OC(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: N[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)C[C@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
A suspension of (1R,2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-((tert-butoxycarbonyl)amino)cyclohexyl 4-nitrobenzoate (2.80 g, 4.02 mmol) and anhydrous K2CO3 (0.70 g, 0.51 mmol) in MeOH (100 mL) was stirred at room temperature for 2 h. The resulted clear solution was concentrated, and DCM (80 mL) was added. The mixture was washed with saturated aqueous NaHCO3 (60 mL), and the aqueous layer was further extracted with DCM (2×40 mL). The combined extract was dried over anhydrous Na2SO4. After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:3 to 1:1), affording a white solid. The solid was dissolved in mixed MeOH and EtOAc (30 mL, 2:1). HCl (g) was bubbled into the solution for 30 sec, and the mixture was stirred at room temperature for 2 h. The solvent was then removed, water (30 mL) was added and the mixture was basified with diluted aqueous NaOH solution. Extraction with DCM (2×40 mL) was performed, and the combined extract was dried over anhydrous Na2SO4. After filtration the solvent was evaporated under reduced pressure, affording the title compound as an off-white solid (1.54 g, 94%). 1H NMR (400 MHz, CDCl3) δ 7.37-7.25 (m, 15H), 4.98 (d, J=11.3 Hz, 1H), 4.84 (d, J=10.8 Hz, 1H), 4.69 (d, J=11.3 Hz, 1H), 4.56 (d, J=10.8 Hz, 1H), 4.47 (s, 2H), 3.64 (dd, J=4.9, 8.9 Hz, 1H), 3.54-3.48 (m, 2H), 3.34-3.30 (m, 1H), 3.19 (t, J=9.4 Hz, 1H), 2.53-2.50 (m, 1H), 2.08-2.02 (m, 1H), 1.75-1.72 (m, 1H), 1.59-1.52 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[N:14]=[C:15]([C:17](O)=[O:18])[CH:16]=[C:11]2[CH:10]=[C:9]1[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[CH3:32]>>[CH2:1]([N:8]1[C:12]2=[C:13]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[N:14]=[C:15]([C:17]([N:36]3[CH2:37][CH2:38][N:33]([CH2:31][CH3:32])[CH2:34][CH2:35]3)=[O:18])[CH:16]=[C:11]2[CH:10]=[C:9]1[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN1CCNCC1
Reactant: Cc1cc2cc(C(=O)O)nc(N3CCc4ccccc4C3)c2n1Cc1ccccc1
Product: CCN1CCN(C(=O)c2cc3cc(C)n(Cc4ccccc4)c3c(N3CCc4ccccc4C3)n2)CC1

Procedure:
In accordance with the same procedures as in Step 1 of Example 756, except for using 1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Step 1 of Example 925 and 1-ethylpiperazine, the titled compound was obtained as a white solid. (Yield: 63%) The product was used in the subsequent step without further purification.