Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:14](=S)=[S:15].[H-].[Na+].IC.[CH3:21][S:22]([CH3:24])=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11](=[C:21]([S:15][CH3:14])[S:22][CH3:24])[C:12]#[N:13])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CS(C)=O
Reactant: N#CCS(=O)(=O)c1ccc(Cl)cc1
Reactant: S=C=S
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CSC(SC)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 65 %

Procedure:
To a solution of 2-(4-chlorobenzenesulfonyl) acetonitrile (600 mg, 2.78 mmol) in anhydrous DMSO (8 ml) under an argon atmosphere was added carbon disulfide (212 mg, 2.78 mmol). The reaction mixture was cooled to approximately 0° C. and 2 equivalents of sodium hydride (5.56 mmol) was added in one portion. The resulting thick reaction mixture was swirled until homogeneous and allowed to warm to room temperature for one hour with stirring. The reaction mixture was cooled again to 0° C. and 2 equivalents of iodomethane (5.56 mmol) was added under argon. The reaction mixture was allowed to gradually warm to room temperature and after 18 hours deionized water was added (30 ml) and the resulting slurry was stirred for 15 minutes. The solid was collected by filtration, washed with deionized water, and dried. The crude solid product thus obtained was dissolved in 25% hexanes/chloroform and purified via flash chromatography. The resulting solution was concentrated in vacuo to provide the titled compound as a light yellow solid in 65% yield.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[I:15]I>C(Cl)(Cl)Cl>[I-:15].[CH:11]1[C:12]2[C:7](=[S+:6][C:5]3[C:14]([N:13]=2)=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: II
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Solvent: ClC(Cl)Cl
Product: [I-]
Product: c1ccc2[s+]c3ccccc3nc2c1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
This compound was prepared according the procedure by B. Wilson et. al, Tetrahedron 64 (2008), 3429-3436. To the solution of 10H-phenothiazine in anhydrous chloroform (22 mL), at 5° C., surmounted with an addition funnel was added the solution of iodine (2.4 g, 9.40 mmol) in CHCl3 (55 mL) over a 1 h period. The resulting dark solution was stirred for an additional 1 h at 5° C. monitored by TLC. After the disappearance of the starting material, the cooling bath was removed, solid precipitate was filtered, washed several times with chloroform, dried, to afford a very dark solid.
Reaction SMILES: CC[C@@H]([C@H](N[C:34]([CH2:36][C@H:37]([OH:70])[C@@H:38]([NH:43]C([C@@H](N(C([C@@H](NC([C@H](O)[C@H](CC)C)=O)CC(C)C)=O)C)CCC(N)=O)=O)[CH2:39][CH:40]([CH3:42])[CH3:41])=[O:35])C(NCC(N([C@@H](C(N1[C@H](C(OC)=O)CCC1)=O)CC1C=CC=CC=1)C)=O)=O)C.CC(C[C@H](NC1C([N+]([O-])=O)=CC([N+]([O-])=O)=C(F)C=1)C(N)=[O:77])C.CO.C(O)=O>O>[NH2:43][C@H:38]([C@H:37]([CH2:36][C:34](=[O:35])[OH:77])[OH:70])[CH2:39][CH:40]([CH3:42])[CH3:41]
Reactant: CC(C)C[C@H](Nc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-])C(N)=O
Reactant: CC[C@H](C)[C@H](NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)N(C)C(=O)[C@H](CC(C)C)NC(=O)[C@H](O)[C@@H](C)CC)C(=O)NCC(=O)N(C)[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC
Solvent: CO
Solvent: O
Solvent: O=CO
Product: CC(C)C[C@H](N)[C@@H](O)CC(=O)O

Procedure:
Samples of both compounds 1 and 3 (35 μg) were subjected to acid hydrolysis, derivatized with L-FDLA, and analyzed by reversed-phase HPLC [column, Alltima HP C18 HL (4.6×250 mm), 5 μm, Alltech; flow rate, 0.5 mL/min; detection by ESIMS in negative ion mode (MRM scan, 468→408)], using a linear gradient of MeOH in H2O (both containing 0.1% HCOOH, 40-100% MeOH over 50 min). Two peaks, corresponding to (3S,4S)-Sta-L-FDLA and (3R,4S)-Sta-L-FDLA, were observed in both samples in a 1:1 ratio at tR 35.5 and 35.9 min, respectively. The retention times (tR, min) of the authentic standards were as follows: (3S,4S)-Sta-L-FDLA (35.5), (3R,4S)-Sta-L-FDLA (35.9), (3S,4S)-Sta-D-FDLA [corresponding to (3R,4R)-Sta-L-FDLA, 45.7], (3R,4S)-Sta-D-FDLA [corresponding to (3S,4R)-Sta-L-FDLA, 46.4]. The MS parameters used were as follows: DP −60.0, EP −7.0, CE −28.0, CXP −7.4, CUR 40, CAD High, IS −4500, TEM 750, GS1 40, GS2 40.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].CCN(C(C)C)C(C)C.[CH2:19]([O:21][C:22](=[O:44])[C@@H:23]([CH3:43])[CH2:24][CH:25]([N:40]=[C:41]=[O:42])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=2)=[CH:29][CH:28]=1)[CH3:20]>CN(C=O)C>[CH2:19]([O:21][C:22](=[O:44])[C@@H:23]([CH3:43])[CH2:24][CH:25]([NH:40][C:41]([NH:1][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:42])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=2)=[CH:29][CH:28]=1)[CH3:20]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)[C@@H](C)CC(Cc1ccc(-c2cccc(Cl)c2)cc1)N=C=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H](C)CC(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)NCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Next, to a solution of tert-butyl 2-aminoacetate (140 mg, 1.065 mmol) in DMF (5 mL) is added DIEA (344 mg, 2.66 mmol). The solution is stirred at room temperature for 5 minutes then (S)-5-(3′-chloro-biphenyl-4-yl)-4-isocyanato-2-methyl-pentanoic acid ethyl ester (330 mg, 0.887 mmol) is added. The mixture is stirred at room temperature for 2 hours then the solvent is removed under reduced pressure to give (S)-4-(3-tert-butoxycarbonylmethyl-ureido)-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester which is used directly in the following reaction.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:33]=1[CH2:34]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:34][C:33]3[CH:36]=[C:37]([F:40])[CH:38]=[CH:39][C:32]=3[F:31])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Reactant: Fc1ccc(F)c(CBr)c1
Product: Cc1nc2c(ccn2Cc2cc(F)ccc2F)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2,5-difluorobenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.50-7.41 (m, 1 H), 7.23-7.17 (m, 1 H), 7.14 (t, J=3.4 Hz, 1 H), 7.06 (td, J=4.5, 9.3 Hz, 1 H), 7.01-6.92 (m, 3 H), 6.32 (dd, J=3.5, 11.3 Hz, 1 H), 5.64-5.53 (m, 3 H), 4.29 (t, J=4.6 Hz, 2 H), 2.96-2.80 (m, 2 H), 2.79 (s, 3 H), 2.09 (d, J=5.3 Hz, 2 H), 1.03-0.90 (s, 9H); LC/MS (m/z) ES+=521.36 (M+1).
Reaction SMILES: O.[NH2:2][NH2:3].Br[CH:5]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)[CH2:6][CH2:7][CH3:8]>C(O)(C)C>[F:16][C:15]([F:18])([F:17])[C:12]1[CH:13]=[CH:14][C:9]([CH:5]([NH:2][NH2:3])[CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=1
Reactant: CCCC(Br)c1ccc(C(F)(F)F)cc1
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: CCCC(NN)c1ccc(C(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Hydrazine monohydrate (8.9 g) was dissolved in isopropanol (25 ml) and 1-(1-bromobutyl)-4-(trifluoromethyl)benzene (as prepared in WO 2005013985, 2.0 g, 7.12 mmol) added. The mixture was heated to 70° C. and stirred for 16 h. After this time the solvent was removed and the residue taken up in ethyl acetate and washed three times (H2O). The combined organics were dried (sodium sulfate) and concentrated to give the mixture of products as a white solid suspended in a clear oil. The mixture was triturated with diethyl ether to give a white solid; 1H NMR δ (ppm)(DMSO): 9.20 (1 H, s), 7.76 (2 H, d, J=8.1 Hz), 7.64 (2 H, s), 4.16 (1 H, s), 1.85 (1 H, s), 1.59 (1 H, s), 1.20-0.96 (2 H, m), 0.82 (3 H, t, J=7.3 Hz).
Reaction SMILES: C(N(CC)CC)C.[N:8]1([C:13](Cl)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:16][C:17]1[N:21]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)[N:20]=[CH:19][C:18]=1[C:32]([NH:34][C:35]1[CH:36]=[N:37][C:38]([C:42]2[CH2:43][CH2:44][NH:45][CH2:46][CH:47]=2)=[C:39]([CH3:41])[CH:40]=1)=[O:33]>ClCCl.O>[CH3:16][C:17]1[N:21]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)[N:20]=[CH:19][C:18]=1[C:32]([NH:34][C:35]1[CH2:36][N:37]([C:13]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:14])[C:38]([C:42]2[CH2:43][CH2:44][NH:45][CH2:46][CH:47]=2)=[C:39]([CH3:41])[CH:40]=1)=[O:33]
Reactant: O=C(Cl)N1CCCC1
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC1=C(C2=CCNCC2)N(C(=O)N2CCCC2)CC(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)=C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Triethylamine (38 μl) and 1-pyrrolidinecarbonyl chloride (30 μl) were added to a mixture of 5-methyl-N-[5-methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (100 mg) described in Reference Example 170 and dichloromethane (4.6 ml), and stirred at room temperature for six hours. Then, triethylamine (380 μl) and 1-pyrrolidinecarbonyl chloride (300 μl) were added and stirred at room temperature all night and all day. Triethylamine (95 μl) and water was added to the reaction solution, dichloromethane was evaporated in vacuo, and the precipitated solid was washed with ethanol to give the titled compound (99 mg) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=2)=[O:13])[CH2:5][CH2:4]1.[BH4-].[Na+]>CO>[OH:1][C:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=2)[OH:13])[CH2:5][CH2:4]1
Reactant: COC(=O)C(C)(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(C)(C)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Reaction time: 1 h

Procedure:
A solution of 13.5 g of methyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylacetate, prepared in accordance with Example 5, in 250 mL of CH3OH was cooled in an ice-CH3OH bath and 1.8 g of NaBH4 was added in portions. After 1 hr, the mixture was concentrated to a solid. The residue was partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous portion was extracted with EtOAc. The combined organics were washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated in vacuo to afford 9.5.g (70%) of methyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetate as a foam.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14].O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH3:12][Si:13]([C:16]#[C:17][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)([CH3:15])[CH3:14]
Reactant: Brc1cnc2ccccc2c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: O
Product: C[Si](C)(C)C#Cc1cnc2ccccc2c1
Temperature: 70 °C

Procedure:
A mixture of 3-bromoquinoline (10.40 g, 0.05 mol), trimethylsilylacetylene (8.48 mL, 0.06 mol), cuprous iodide (0.5 g) and trans-dichlorobis(triphenylphosphine)palladium (1 g) and TEA (15 mL) was heated at 70° C. in a sealed tube for 1 h. H2O (150 mL) was added, followed by Et2O (300 mL). The organic layer was separated and the aqueous layer extracted with Et2O (200 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (eluent: 100% DCM) to give 3-(trimethylsilylethynyl) quinoline as a brown oil. 3-(Trimethylsilylethynyl) quinoline was dissolved in anhydrous MeOH (100 mL) and K2CO3 (0.69 g, 5 mmol) was added. The mixture was stirred at rt for 1 h and DCM (250 mL) was added. The mixture was filtered over celite. The filtrate was evaporated and the residue was purified by flash column chromatography to give Compound 13b as an off-white solid.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:8]([NH2:11])[CH2:9][NH2:10]>CCOCC.C(O)(C)C>[NH3:5].[CH2:1]([NH:5][C:6]([NH:10][CH2:9][CH2:8][NH2:11])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN=C=O
Reactant: NCCN
Solvent: CCOCC
Solvent: CC(C)O
Product: CCCCNC(=O)NCCN
Product: N
Temperature: 25 °C
Reaction time: 3 h
Yield: 123.7 %

Procedure:
A solution of n-butylisocyanate (19.83 g, 0.2 m) in Et2O (50 ml) was added over 40 minutes to a vigorously stirred solution of ethylenediamine (48.08 g, 0.8 m) in isopropanol (1000 ml). After stirring at 25° C. for 3 hours, and standing for about 16 hours, the mixture was filtered and the filtrate evaporated to dryness under reduced pressure initially using water aspiration and finally high vacuum at 70° C. The residue was stirred for 1 hour in 12N HCl (20 ml) and H2O (200 ml), filtered and the filtrate rendered alkaline with 40% NaOH and evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel and eluted with 20% MeOH--CHCl3 saturated with NH3 to give 83 (19.7 g, 59%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]([CH2:11][OH:12])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[CH3:23][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:12][CH2:11][CH:8]2[CH2:7][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[C:10]=3[O:9]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1Cc2cccc(Br)c2O1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Yield: 80.5 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methanol (49.0 g, 0.214 mol) with p-toluenesulfonyl chloride (44.9 g, 0.235 mol) generally according to the procedure described for Intermediate 10 gave 66.00 g (80%) (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Rf=0.44 (silica, ethyl acetate:hexanes 1:4); mp 120-122° C.; Anal. calcd. for C16H15BrO4S: C, 50.14; H, 3.94. Found: C, 48.47; H, 4.03.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([CH2:12][OH:13])[N:11]=[C:4]2[N:3]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([CH:12]=[O:13])[N:11]=[C:4]2[N:3]=1
Reactant: Cc1cc(C)n2nc(CO)nc2n1
Solvent: ClCCl
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Product: Cc1cc(C)n2nc(C=O)nc2n1
Temperature: 25 °C

Procedure:
To a 10 L reactor was sequentially charged CH2Cl2 (5.1 L), (5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methanol (680 g, 3.816 mol), and iodobenzene diacetate (1352 g, 4.197 mol). As the iodobenzene diacetate dissolves, there is a significant endotherm (typically down to 15-16° C.). The jacket was set to 23° C. The mixture was warmed to ambient temperature and Tempo (2,2,6,6-tetramethyl-1-piperidinyloxy, free radical, 43.75 g, 0.28 mol) added in a single charge. The reaction was stirred until 5% of the starting alcohol remained by HPLC. Once the starting material is adjudged to be less than about −5%, the over-oxidized product begins to be observed. Allowing the reaction to run to further completion leads to an overall diminished yield of the desired product. For this reaction, the desired reaction completion was reached in 2.75 h. MTBE (5.1 L) was then slowly charged to the reactor, causing the product to precipitate, and the slurry stirred for an additional 30 mins. The mixture was filtered, washed twice with 1:1 DCM/MTBE (2×1L), and dried in a vacuum oven overnight at 50° C. to provide 500.3 g (74%) of 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde as an off-white solid. 1H NMR (300 MHz, d6-DMSO): 2.64 (s, 3), 2.78 (d, 3, J=0.8), 7.36 (d, 1, J=0.9), 10.13 (s, 1).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([NH2:23])[CH3:22])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:23]([CH:21]([C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=1)[CH3:22])[CH2:11]2
Reactant: COC(=O)c1c(Cl)cccc1CBr
Reactant: CC(N)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(c1ccc(Cl)cc1)N1Cc2cccc(Cl)c2C1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
A mixture of 2-bromomethyl-6-chloro-benzoic acid methyl ester (0.132 g, 0.5 mmol), 1-(4-chlorophenyl)-ethylamine (0.117 g, 0.6 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-chloro-2-[1-(4-chloro-phenyl)-ethyl]-2,3-dihydro-isoindol-1-one (0.132 g, 86%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.66 (d, 3H), 3.95 (d, 1H), 4.34 (d, 1H), 5.84 (q, 1H) 7.26-7.46 (m, 7H). GC-MS: m/z 306 (M)+.
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:33])[C@H:24]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:25][C@H:24]([C:23]([OH:33])=[O:22])[CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](CC2CCCCC2)C(=O)O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to β-cyclohexylalanine methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:10])=[N:4][N:5]([CH3:9])[C:6]=1[NH:7][CH3:8].[Cl-].[C:12]([O:18][CH3:19])(=[O:17])[CH2:13][C:14]([O-])=[O:15].[C:20]1(C)C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:19]([O:18][C:12]([CH2:13][C:14]([NH:1][C:2]1[C:3]([CH3:10])=[N:4][N:5]([CH3:9])[C:6]=1[NH:7][CH3:8])=[O:15])=[O:17])[CH3:20]
Reactant: COC(=O)CC(=O)[O-]
Reactant: Cc1ccccc1
Reactant: CNc1c(N)c(C)nn1C
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC(=O)Nc1c(C)nn(C)c1NC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.4 g (0.01 mole) of 4-amino-1,3-dimethyl-5-methylaminopyrazole are dissolved in 20 ml of toluene, 1 ml (0.012 mole) of monomethyl malonate chloride is slowly added dropwise, whilst cooling with ice, and the mixture is subsequently stirred at room temperature for one hour. The toluene is stripped off in vacuo, the residue is taken up in chloroform and the mixture is washed with ice-cold NaHCO3 solution and water and dried with Na2SO4. After evaporating off the solvent, a yellowish oil remains which does not crystallize.
Reaction SMILES: [C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)([O-:19])=[O:18].[P:28]([O:43]C1C=CC=CC=1)([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1C=CC=CC=1>C(Cl)(Cl)Cl>[C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](=[O:9])[NH:10][CH:24]([P:28](=[O:43])([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:23]2[CH:26]=[CH:27][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)N(c1ccccc1)c1ccccc1
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(NC(c1ccc([N+](=O)[O-])cc1)P(=O)(Oc1ccccc1)Oc1ccccc1)N(c1ccccc1)c1ccccc1
Temperature: 87 °C

Procedure:
A mixture of 21.2g (0.1 mole) of 1,1diphenylurea, 15.1g (0.1 mole) of 4-nitrobenzaldehyde, and 31.0g (0.1 mole) of triphenyl phosphite in 50g of benzene is stirred under nitrogen and warmed at reflux (87° C) for 2 hours to give a light yellow solution: 31P nmr -13.2 (d, J = 23Hz), 127.8 ppm (area ratio 5:1). Most of the benzene is removed at reduced pressure, and ether is stirred into the yellow oil remaining, causing 32g of solid to separate after a few minutes. A portion is recrystallized from acetonitrile to give a white solid: mp 157°-162°; 31P nmr -13.2 ppm (d, J = 24Hz); molecular weight (CHCl3) 565 (calcd 579).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:2]1.Br[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31].C(N(CC)C(C)C)(C)C>CN(C=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]3[C:25](=[O:26])[C:24]4[C:23](=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:22]3=[O:31])[CH2:14][CH2:15]2)=[N:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1CCCCN1CCN(c2nsc3ccccc23)CC1
Temperature: 80 °C
Yield: 65.4 %

Procedure:
An 18.01 g sample of 1-(1,2-benzisothiazol-3-yl)piperazine (83.7 mmol), 29.5 g of N-(4-bromobutyl)phthalimide (104.6 mmol) and 36 mL of N,N-diisopropylethylamine (375.4 mmol) were added to 400 mL of dry DMF. The solution was heated at 80° C. for 18 hours, and the solvent was then removed in vacuo. The residue was dissolved in 500 mL of methylene chloride and was washed with saturated aqueous sodium bicarbonate. The combined aqueous layers were re-extracted with 2 portions of methylene chloride. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was crystallized from isopropanol with the addition of 4N HCl/isopropanol to give 23.03 g of the title compound as the hydrochloride, quarter hydrate, m.p. 253°-255° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([CH:10](Cl)Cl)[CH:3]=1.C(O)=[O:14]>[Cl-].[Zn+2].[Cl-].O>[Br:1][C:2]1[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([CH:10]=[O:14])[CH:3]=1
Reactant: O=[N+]([O-])c1sc(Br)cc1C(Cl)Cl
Reactant: O=CO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Product: O=Cc1cc(Br)sc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
5-Bromo-3-(dichloromethyl)-2-nitrothiophene (60.5 g, 208 mmol) and zinc chloride (113 g, 832 mmol) were stirred in refluxing formic acid (800 mL) overnight. After cooling to ambient temperature, water was added and the mixture was extracted with EtOAc (4×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([Cl:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[C:14](Cl)=[O:15].O.[NH3:18].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([Cl:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[C:14]([NH2:18])=[O:15]
Reactant: N
Reactant: COc1cc2nccc(Cl)c2cc1C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2nccc(Cl)c2cc1C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
7-Methoxy-4-chloroquinoline-6-carbonyl chloride (2.7 g) was dissolved in tetrahydrofuran (150 ml), and the solution was cooled to 0° C. After adding 30% ammonia water (5 ml), the mixture was stirred at room temperature for 30 minutes. Water was added, extraction was performed 3 times with ethyl acetate, and then the organic layers were combined, washed with water and saturated brine, dried over sodium sulfate and dried under reduced pressure to obtain the title compound (1.35 g).