Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:30]([CH3:31])=[CH:29][C:5]2[N:6]([C:19](=[O:28])[CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[C:7]3[N:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C:9]3[N:10]([C:11](=[O:14])[NH:12][N:13]=3)[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:34][N:35]([CH3:40])[CH2:36][CH2:37][CH2:38]Cl>CN(C)C=O.C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[C:30]([CH3:31])=[CH:29][C:5]2[N:6]([C:19](=[O:28])[CH2:20][N:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)[C:7]3[N:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C:9]3[N:10]([C:11](=[O:14])[N:12]([CH2:38][CH2:37][CH2:36][N:35]([CH3:40])[CH3:34])[N:13]=3)[C:4]=2[CH:3]=1
Reactant: CN(C)CCCCl
Reactant: Cc1cc2c(cc1C)-n1c(n[nH]c1=O)-c1cccnc1N2C(=O)CN1CCN(C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1C
Product: Cc1cc2c(cc1C)-n1c(nn(CCCN(C)C)c1=O)-c1cccnc1N2C(=O)CN1CCN(C)CC1
Reaction time: 22 h

Procedure:
In the manner given in Example 21, to 6,7-dimethyl-2,9-dihydro-9-[(4-methylpiperazino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one in dimethylformamide is added a solution of sodium hydride in mineral oil. The mixture is allowed to react at about 95° C. for 40 minutes and after cooling [3-(dimethylamino)propyl]chloride in xylene is added. The mixture is kept at 95°-100° C. for a period of 22 hours, evaporated and worked up as in example 25 to give 6,7-dimethyl-2,9-dihydro-2-[3-(dimethylamino)propyl]-9-[(4-methylpiperazino)-acetyl]-3-H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one.
Reaction SMILES: [CH3:1]/[C:2](/[C:6]#[C:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH:3]\[CH2:4][OH:5].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH2:45]([O:47][C@@H:48]([CH2:54][C:55]1[CH:60]=[CH:59][C:58](O)=[CH:57][CH:56]=1)[C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH3:46]>C1C=CC=CC=1>[CH2:52]([O:51][C:49](=[O:50])[C@@H:48]([O:47][CH2:45][CH3:46])[CH2:54][C:55]1[CH:60]=[CH:59][C:58]([O:5][CH2:4]/[CH:3]=[C:2](\[CH3:1])/[C:6]#[C:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:57][CH:56]=1)[CH3:53]
Reactant: C/C(C#Cc1ccccc1)=C\CO
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)C#Cc2ccccc2)cc1)OCC
Yield: 70.3 %

Procedure:
The title compound was prepared from of (E)-3-methyl-5-phenyl-pent-2-en-4-yn-1-ol (0.172 g, 1.0 mmol), (J. Med. Chem. 1998, 41(14), 2524-2536), tributylphosphine (0.370 mL, 1.5 mmol), 1,1′-(azodicarbonyl)dipiperidine (0.378 g, 1.5 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxy-phenyl)-propionate (0.262 g, 1.1 mmol) in dry benzene (20 mL) by a procedure analogous to that described in example 3, yielding 0.276 g (68%) of (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid ethyl ester. 1H NMR (300 MHz, CDCl3) δ: 1.1-1.25 (6H, m), 1.98 (3H, d), 2.95 (2H, d), 3.29-3.4 (1H, m), 3.53-3.65 (1H, m), 3.95 (1H, t), 4.15 (2H, q), 4.60 (2H, dd), 6.15 (1H, dt), 6.8 (2H, d), 7.15 (2H, d), 7.20-7.3 (3H, m), 7.35-7.45 (2H, m).
Reaction SMILES: [CH:1]1([C:4]([OH:12])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][C:6]#[CH:7])[CH2:3][CH2:2]1.N1C=CN=C1.Cl[Si:19]([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O>[CH:1]1([C:4]([O:12][Si:19]([CH3:22])([CH3:21])[CH3:20])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][C:6]#[CH:7])[CH2:2][CH2:3]1
Reactant: C#CCC(O)(CCCC)C1CC1
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C#CCC(CCCC)(O[Si](C)(C)C)C1CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a stirred solution of 27.8 g. of 4-cyclopropyl-4-hydroxy-1-octyne (Example 9) and 33.3 g. of imidazole in 130 ml of dimethylformamide at 5° C. is added 24 ml. of chlorotrimethylsilane during 5 minutes. The solution is stirred at ambient temperature for 17 hours and then partitioned with 600 ml of hexane and 250 ml of ice-water. The hexane phase is separated and washed successively with water and brine. The solution is dried over magnesium sulfate and evaporated to give a liquid, p.m.r. spectrum (C D Cl3):δ0.12 (singlet, trimethylsiloxy group), 2.02 (triplet, HC≡C), and 2.45 (doublet, C≡CH2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=3)=[N:10][NH:11][C:12]=2[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]#[CH:33]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=3)=[N:10][N:11]([CH2:33][C:32]#[CH:31])[C:12]=2[C:13]([F:15])([F:16])[F:14])=[CH:4][CH:3]=1
Reactant: CSc1ccc(-c2n[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCn1nc(-c2ccc(SC)cc2)c(-c2ccc(F)cc2)c1C(F)(F)F
Yield: 21.1 %

Procedure:
4-(4-Fluorophenyl)-3-[4-(methylthio)phenyl]-5-(trifluoromethyl)-1H-pyrazole (0.15 g) from step 1 was added to potassium carbonate (0.14 g) and propargyl bromide (0.45 g) in 5 mL of DMF. HPLC purification gave 4-(4-fluorophenyl)-3-[4-(methylthio)phenyl]-1-propargyl-5-(trifluoromethyl)pyrazole (35 mg, 22%) in the first fraction (mp 144.5°-146° C.) and 4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-1-propargyl-3-(trifluoromethyl)-1H-pyrazole in the second fraction (87 mg, 56%, mp 135.5°-138.5° C.).
Reaction SMILES: O1C2CCCC([NH2:10])C=2C=C1.[S:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=O)[CH2:13][CH2:12]1>>[S:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]([NH2:10])[CH2:13][CH2:12]1
Reactant: O=C1CCSc2ccccc21
Reactant: NC1CCCc2occc21
Product: NC1CCSc2ccccc21

Procedure:
Following the procedure for the preparation of 4,5,6,7-tetrahydro-1-benzofuran-4-amine but substituting 2,3-dihydro-4H-thiochromen-4-one and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ 7.30, 7.07, 4.07, 3.28, 2.96, 2.16, 1.61; (MS/CI) calcd for C9H11NS+H 166.3, found 166.3.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:8]2=[O:18])=[C:4]([Cl:21])[CH:3]=1.[C:22]([O:26][C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27]([C:29]1[CH:34]=[C:33]([C:2]2[CH:20]=[CH:19][C:5]([CH2:6][CH:7]3[CH2:11][CH2:10][N:9]([CH:12]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]4)[C:8]3=[O:18])=[C:4]([Cl:21])[CH:3]=2)[CH:32]=[CH:31][CH:30]=1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: O=C1C(Cc2ccc(Br)cc2Cl)CCN1C1CCCCC1
Reactant: CC(C)(C)OC(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)OC(=O)c1cccc(-c2ccc(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)c1
Yield: 80.1 %

Procedure:
Using the procedure to synthesize Example 81 and using reagents 3-(4-bromo-2-chloro-benzyl)-1-cyclohexyl-pyrrolidin-2-one (500 mg, 1.35 mmol) and 3-(tert-butoxycarbonyl)phenylboronic acid (900 mg, 4.0 mmol) affords 506 mg (80%) of the title compound: Mass spectrum (apci) m/z=468.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([N+:8]([O-])=O)[CH:7]=1.O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([NH2:8])[CH:7]=1
Reactant: Cc1c([N+](=O)[O-])cc(Cl)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1c(N)cc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
5-Chloro-2-methyl-1,3-dinitro-benzene (1.96 g, from above) was suspended in methanol (80 mL) and water (20 mL) under N2. Sodium dithionite (5.51 g) was added portionwise and the mixture was stirred at room temperature for 3 hr. The reaction mixture was filtered and washed with methanol. The filtrate was then removed under reduced pressure and the residue was partitioned between ethyl acetate (150 mL) and brine (150 mL). The organic layer was dried over magnesium sulfate and evaporated to afford 5-chloro-2-methyl-3-nitro-phenylamine (1.45 g).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[CH:31]1([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:37]5[CH2:38][CH2:39][N:34]([CH:31]6[CH2:33][CH2:32]6)[CH2:35][CH2:36]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:29])([F:30])[F:28])[CH:3]=1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: C1CN(C2CC2)CCN1
Product: O=C1N=C(N2CCN(C3CC3)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-cyclopropyl-piperazin-1-yl)-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 1-cyclopropyl-piperazine following General Procedure B.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:25](=[O:26])[C:24]4[CH:28]=[CH:29][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:22][CH:23]=4)[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1ccc(C(F)(F)F)cc1
Yield: 61 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 4-(trifluoromethyl)benzoyl chloride to afford the title compound as a brown solid (33 mg, 61%). 1H-NMR (δ, ppm, DMSO-d6): 6.50 (d, 1H, HPy,5, J=6.0 Hz), 6.93 (d, 1H, Harom, J=7.0 Hz), 7.44 (t, 1H, Harom, J=8.0 Hz), 7.63 (s, 1H, Harom), 7.64-7.68 (m, 1H, Harom), 7.82 (d, 1H, HPy,6, J=6.0 Hz), 7.91 (d, 2H, Harom, J=8.0 Hz), 8.12 (d, 2H, Harom, J=8.0 Hz), 10.55 (s, 1H, NHamide), 11.20 (s, 1H, NHPy3), 11.38 (s, 1H, NHPy2).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][C:11]([C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[O:21])=[N:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH:34](Br)([CH3:36])[CH3:35]>CN(C)C=O>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:12][C:11]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([CH:34]([CH3:36])[CH3:35])[CH2:24][CH2:23]3)=[O:21])=[N:10]2)=[CH:5][CH:4]=1
Reactant: CC(C)Br
Reactant: COc1ccc(-n2nc(C(=O)N3CCNCC3)cc2-c2ccccc2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(C(=O)N3CCN(C(C)C)CC3)cc2-c2ccccc2)cn1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of 1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]piperazine (0.446 g) obtained in Example 16 in N,N-dimethylformamide (7.5 mL), potassium carbonate (0.505 g) and isopropyl bromide (0.30 mL) were added at room temperature, and the mixture was stirred at 60° C. for 16 hours, and then cooled in air. The reaction mixture was partitioned between water and ethyl acetate. Subsequently, the aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate anhydrate. After filtration, the solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography (chloroform-methanol), to thereby give the title compound as an oily product (0.283 g, 57%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH:16]2[CH2:27][CH2:26][C:19]3([N:23]=[C:22]([CH3:24])[NH:21][C:20]3=[O:25])[CH2:18][CH2:17]2)(=[O:14])=[O:13])=[CH:8][C:7]=1[CH3:28])[CH3:4].Br[CH:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:31]>CN(C=O)C.C(=O)(O)[O-].[Na+]>[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH:16]2[CH2:17][CH2:18][C:19]3([N:23]=[C:22]([CH3:24])[N:21]([CH:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH3:31])[C:20]3=[O:25])[CH2:26][CH2:27]2)(=[O:13])=[O:14])=[CH:8][C:7]=1[CH3:28])[CH3:4]
Reactant: CC(Br)c1ccccc1
Reactant: CCOc1ccc(S(=O)(=O)NC2CCC3(CC2)N=C(C)NC3=O)cc1C
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(S(=O)(=O)NC2CCC3(CC2)N=C(C)N(C(C)c2ccccc2)C3=O)cc1C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
Sodium hydride (4.74 mg, 0.119 mmol) was added at room temperature to 4-ethoxy-3-methyl-N-(2-methyl-4-oxo-1,3-diazaspiro[4.5]dec-1-en-8-yl)benzenesulfonamide (Example 471, 30 mg, 0.079 mmol) in DMF (988 μl). The reaction was stirred five minutes then a solution of (1-bromoethyl)benzene (16.18 μl, 0.119 mmol) in 200 ul DMF was added and the reaction stirred overnight at room temperature. After 16 hours, LCMS and HPLC indicated approximately 4:1 product:smarting material. The reaction was diluted with saturated sodium bicarbonate and extracted with multiple volumes ethyl acetate. The combined organics were rinsed 1× brine and dried over sodium sulfate. TLC (ethyl acetate) gave a product Rf 0.38 and starting material on the baseline. The crude was chromatographed on Biotage 12S by manual step gradient 7-100% EtOAc/heptane to yield the product as an off-white solid (21 mg). LCMS [M+H]=484.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].Cl.[Cl:19][CH2:20][CH2:21][NH2:22].C(N(CC)CC)C>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:22][CH2:21][CH2:20][Cl:19])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: NCCCl
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cnc2c(cnn2CC)c1NCCCl
Yield: 41.8 %

Procedure:
2.54 g (10 mmol) of 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (J. Med. Chem. 2001, 44, 1025) and 1.28 g (11 mmol) 2-chloroethylamine hydrochloride were added to 40 ml of anhydrous ethanol. Then 7 ml (50 mmol) of triethylamine were added. The mixture was heated at reflux until the reaction was completed (4 hours). The reaction mixture was concentrated under reduced pressure and 20 ml of saturated aqueous sodium carbonate solution was added. The mixture was extracted with 3×20 ml ethyl acetate. The combined organic layers were washed with 15 ml of water and 15 ml of brine, dried over Na2SO4 and evaporated in vacuo. The crude product (2.88 g) was first purified by flash chromatography on silica gel (petrol ether/ethyl acetate 5:1) and then crystallized from 20 ml of hexane/ethyl acetate=1/1 to afford 1.24 g (42%) of the desired product as a white crystalline solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)([OH:11])[C:7]([O:9][CH3:10])=[O:8].[CH3:17][N:18]1[C@@H:23]2[C@@H:24]3[O:26][C@@H:25]3[C@H:19]1[CH2:20]C(O)[CH2:22]2.[Na]>C1(C)C=CC=CC=1>[CH3:17][N:18]1[C@@H:23]2[C@@H:24]3[O:26][C@@H:25]3[C@H:19]1[CH2:20][CH:10]([O:9][C:7]([C:6]([OH:11])([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH2:22]2
Reactant: CN1[C@@H]2CC(O)C[C@H]1[C@@H]1O[C@@H]12
Reactant: COC(=O)C(O)(c1cccs1)c1cccs1
Agent: [Na]
Solvent: Cc1ccccc1
Product: CN1[C@@H]2CC(OC(=O)C(O)(c3cccs3)c3cccs3)C[C@H]1[C@@H]1O[C@@H]12
Reaction time: 5 h

Procedure:
50.87 g (0.2 mole) of methyl di-(2-thienyl)glycolate and 31.04 g (0.2 mole) of scopine are dissolved in 100 ml of absolute toluene and reacted at a bath temperature of 90° C. with addition of 1.65 g (0.071 gram atom) of sodium in several portions. The resulting methanol is distilled off at a reaction mixture temperature of 78°-90° C. under a pressure of 500 mbar. After a reaction time of about 5 hours, the reaction mixture is stirred into a mixture of ice and hydrochloric acid. The acid phase is separated off, rendered alkaline using sodium carbonate and the free base is extracted using methylene chloride. After drying over sodium sulphate, the methylene chloride is distilled off under reduced pressure and the residue is recrystallised from acetonitrile; beige-coloured crystals (from acetonitrile).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:26][O:27][C:28](=[O:31])[CH2:29]Br>CC(C)=O>[CH3:26][O:27][C:28](=[O:31])[CH2:29][N:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:10]1
Reactant: COC(=O)CBr
Reactant: Fc1ccc(-c2n[nH]c(-c3ccc(F)cc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Reaction time: 24 h
Yield: 91.1 %

Procedure:
26.5 g 3,5-bis-(4-fluoro-phenyl)-1H-(1,2,4)triazole, 62.6 g K2CO3 and 15.7 g 2-bromoacetic acid methyl ester were dissolved in 1 L acetone and stirred for 24 h under reflux. K2CO3 was filtered and the solvent was removed to yield 30.8 g of the desired product.
Reaction SMILES: [OH:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:11]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH3:11][O:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc2ocnc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cccc2ocnc12
Yield: 90.6 %

Procedure:
To a suspension of 4-hydroxybenzoxazole (2.00 g, 14.8 mmol) (Musser et al., J. Med. Chem., 30, pp. 62-67 (1987)) in acetone (80.0 ml) was added dried K2CO3 (2.25 g, 16.3 mmol) followed by iodomethane (1.38 ml, 22.2 mmol). The reaction was heated under reflux under N2 for 4.5 h, then filtered and reduced in vacuo to afford the crude product. The resulting residue was purified by flash chromatography (25:75 ethyl acetate/hexane) to give 2.0 g (91%) of the title compound as a white crystalline solid: m.p. 72-74° C.; IR (KBr) 3089, 1619, 1610, 1503, 1496, 1322, 1275, 1090, 1071, 780, 741; 1H NMR (CDCl3) δ 8.02 (1H, s), 7.32 (1H, t, J=8.0), 7.18 (1H, d, J=8.0), 6.81 (1H, d, J=8.0), 4.04 (3H, s). Anal. Calcd. for C8H7NO2: C, 64.42; H, 4.73; N, 9.39. Found: C, 64.40; H, 4.84; N, 9.31; m/z (EI) 149 (M++1, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([NH:9][NH2:10])=[O:8])([O-:3])=[O:2].[CH2:14](OC(OCC)(OCC)C)[CH3:15]>>[CH3:14][C:15]1[O:8][C:7]([C:6]2[CH:11]=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[N:9][N:10]=1
Reactant: NNC(=O)c1cccc([N+](=O)[O-])c1
Reactant: CCOC(C)(OCC)OCC
Product: Cc1nnc(-c2cccc([N+](=O)[O-])c2)o1

Procedure:
3-Nitrobenzoic acid, hydrazide, 24.5 g, (Chemical Abstracts, Vol. 102, 148507r (1983)) and 1,1,1-triethoxyethane are refluxed overnight. The mixture is cooled, filtered, and washed with hexane to give 21.9 g of 2-methyl-5-(3-nitrophenyl)-1,3,4-oxadiazole after recrystallization from 2-propanol; mp 154°-156° C.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:27](O)=[O:28])[CH2:3][CH2:4][C:5](=[O:26])[NH:6][C:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH2:83][C@H:84]([C:88]([NH:90][C@H:91]([C:96]([OH:98])=[O:97])[CH2:92][CH:93]([CH3:95])[CH3:94])=[O:89])[C@@H:85]([CH3:87])[OH:86]>CN(C=O)C>[NH2:1][C@H:2]([C:27]([NH:83][C@H:84]([C:88]([NH:90][C@H:91]([C:96]([OH:98])=[O:97])[CH2:92][CH:93]([CH3:94])[CH3:95])=[O:89])[C@@H:85]([CH3:87])[OH:86])=[O:28])[CH2:3][CH2:4][C:5](=[O:26])[NH:6][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)[C@@H](C)O)C(=O)O
Reactant: O=C(CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CCC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](C)O)C(=O)O
Reaction time: 0.03 h

Procedure:
In an RBF were mixed Fmoc-Gln(Trt)-OH (44.7 g, 73.2 mmol), BOP (40.4 g, 91.5 mmol) and 250 ml of DMF. The mixture was stirred for 2 min and then DIPEA (18.9 g, 146.4 mmol) was added. The resulting mixture was added in one portion to the pre-swollen H-Thr-Leu-Resin and the reaction mixture was stirred for 2.5 h, the Kaiser test was negative, then the reaction was considered to be complete and the reaction medium was removed via filtration.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C@@H:11]1[C:17](=[O:18])[N:16]2[C@H:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:21][CH2:22][N:15]2[C:14](=[O:30])[CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([NH:10][C@@H:11]1[C:17](=[O:18])[N:16]2[C@H:19]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:20][CH2:21][CH2:22][N:15]2[C:14](=[O:30])[CH2:13][CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](N)C(=O)N12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](NC(=O)c3ccccc3)C(=O)N12
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
A solution of benzoyl chloride (1.61 g, 11.47 mmol) in CH2Cl2 (15 ml) was added dropwise to a stirred ice cold mixture of (1S, 9S) t-butyl 9-amino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate (GB 2,128,984; 3.1 g, 10.43 mmol), dry CH2Cl2 (20 ml) and diisopropylethylamine (4.54 ml, 26.06 mmol). The mixture was kept cold for 1 h then left at room temperature for 0.5 h. The mixture was diluted with CH2Cl2, washed twice with brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography (0-5% methanol in CH2Cl2) to afford 211e (4.0 g, 96%) of a colourless glass: mp 74°-76 ° C.; [α]D+ -75.0° (c 0.12, CH2Cl2). IR (KBr) 3350, 2979, 2938, 1736, 1677, 1662, 1536, 1422, 1276, 1250, 1155; 1H NMR (CDCl3) δ8.72 (2H, m), 7.53-7.40 (3H, m), 7.07 (1H, d, J=7.2), 5.30 (1H, dd, J=3.0, 5.8), 5.12 (1H, m), 4.66 (1H, m), 3.51 (1H, m), 2.90 (2H, m), 2.38 (1H, dd, J 13.2, 6.8), 2.25 (1H, m), 1.9 (2H, m), 1.70 (1H, m). Anal. Calcd for C21H27N3O5 0.5H2O: C, 61.45; H, 6.88; N, 10.24. Found C, 61.69; H, 6.71; N, 10.18.
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Br:18][C:19]1[CH:26]=[C:25](F)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22].O>CN(C=O)C>[C:14]([O:13][C:3](=[O:12])[CH:4]([C:25]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([Br:18])[CH:26]=1)[C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])([CH3:17])([CH3:16])[CH3:15]
Reactant: N#Cc1ccc(F)cc1Br
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc(C#N)c(Br)c1
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (0.37 g, 15.4 mmol, 60.0% dispersion in oil) in DMF (40 mL) was added a solution of di-t-butyl malonate (3.6 g, 16 mmol) in DMF (10 mL) at 0° C. and this was stirred for 15 minutes. Subsequently, 2-bromo-4-fluorobenzonitrile (3.0 g, 15.0 mmol) was added in one portion and the reaction mixture was stirred for 8 hours at 80° C. and three hours at room temperature. Water (50 mL) was added and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over MgSO4 and filtered. After evaporation in vacuo, the residue was purified by flash chromatography (20% EtOAc in hexane) to give di-tert-Butyl(3-bromo-4-cyanophenyl)malonate as a light brown solid. 1H NMR (500 MHz, DMSO-d6) δ 7.97 (d, J=8 Hz, 1H), 7.88 (s, 1H), 7.60 (d, J=8 Hz, 1H), 4.95 (s, 1H), 1.42 (s, 18H). LC-MS (IE, m/z): 398 [M+1]+.