Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:45]=[CH:44][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH2:37])[CH:31]=2)\[C:25]([O:27]CC)=[O:26])=[CH:19][CH:18]=1.CO.Cl>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:45]=[CH:44][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH2:37])[CH:31]=2)\[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=1
Reactant: C=C(c1ccccc1)c1cccc(/C(=N/OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)C(=O)OCC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(c1ccccc1)c1cccc(/C(=N/OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)C(=O)O)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of ethyl Z-2-[4(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-[3-(1-phenylvinyl)phenyl]acetate (780 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at 40° C. for 2 hours. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain Z-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-[3-(1-phenylvinyl)phenyl]acetic acid (701 mg, yield 95%) as colorless crystals. m.p. 171-172° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[C:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][C:26]1[C:30]([S:31](Cl)(=[O:33])=[O:32])=[C:29]([CH3:35])[O:28][N:27]=1.C(N(CC)CC)C>>[CH3:25][C:26]1[C:30]([S:31]([N:22]2[CH2:21][CH2:20][CH:19]([C:10]3[C:9]4[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:8]=4)[NH:12][CH:11]=3)[CH2:24][CH2:23]2)(=[O:33])=[O:32])=[C:29]([CH3:35])[O:28][N:27]=1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3=CCNCC3)c[nH]c12
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: Cc1noc(C)c1S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1

Procedure:
Following the general procedure in example 267, 5-phenyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole-7-carboxamide (32 mg, 0.1 mmol), 3,5-dimethyl-4-isoxazolesulfonyl chloride (22.9 mg, 0.15 mmol) and triethylamine (0.06 mL, 0.3 mmol) were reacted to form the desired product which was purified by Gilson HPLC (CH3CN/Water, 0.1% TFA) (11 mg, 23%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][CH2:7][NH2:8].[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][N:20]([C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][N:24]=3)[C:21]=2[OH:22])=[C:13]([CH3:32])[CH:12]=1)#[N:10]>>[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][N:20]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH:8][CH2:7][CH2:6][CH:2]4[CH2:3][CH2:4][CH2:5][O:1]4)=[O:28])=[CH:25][N:24]=3)[C:21]=2[OH:22])=[C:13]([CH3:32])[CH:12]=1)#[N:10]
Reactant: NCCC1CCCO1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCCC3CCCO3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 227 using 2-(tetrahydrofuran-2-yl)ethanamine and 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid. 1H NMR (400 MHz, DMSO-d6) δ 1.21-1.29 (m, 1 H) 1.37-1.51 (m, 1 H) 1.68-1.89 (m, 4 H) 1.99 (dddd, J=11.8, 8.2, 6.6, 5.2 Hz, 1 H) 2.44 (s, 3 H) 3.26-3.47 (m, 3 H) 3.61 (td, J=7.9, 6.4 Hz, 1 H) 3.70-3.88 (m, 2 H) 7.63-7.68 (m, 1 H) 7.71-7.81 (m, 2 H) 8.18 (br. s., 1 H) 8.41 (d, J=6.3 Hz, 1 H) 8.72 (t, J=5.4 Hz, 1 H) 8.88-8.95 (m, 1 H). MS m/z [M+H]+ 418.4.
Reaction SMILES: [NH2:1][CH:2]([CH2:10][CH3:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[N:12]([CH:15]([CH2:21][CH2:22]Br)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N+:13]=[N-:14].C(N(CC)CC)C>C(#N)C>[N:12]([CH:15]([CH2:21][CH2:22][NH:1][CH:2]([C:3]([O:5][C:6]([CH3:7])([CH3:9])[CH3:8])=[O:4])[CH2:10][CH3:11])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N+:13]=[N-:14]
Reactant: CCC(N)C(=O)OC(C)(C)C
Reactant: CCOC(=O)C(CCBr)N=[N+]=[N-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C(CCNC(CC)C(=O)OC(C)(C)C)N=[N+]=[N-]
Temperature: 50 °C
Yield: 52.5 %

Procedure:
To a solution of tert-butyl 2-amino-butanoate (0.397 g) and ethyl 2-azido-4-bromo-butanoate (0.286 g) in acetonitrile (5 ml) was added triethylamine (0.347 ml). The mixture was heated at 50° C. for 18 h, cooled and evaporated onto silica gel (Merck.7734). The pre-absorbed material was purified by flash column chromatography (Merck. 9385, eluting with cyclohexane:ethyl acetate 6:1) to give the title compound (0.200 g) as a mixture of four diastereomers.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:18]([F:21])([F:20])[F:19])([O-:3])=[O:2].[H-].[Na+].[C:24]([O:28][C:29](=[O:32])[CH2:30]Br)([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[C:24]([O:28][C:29](=[O:32])[CH2:30][O:17][CH:14]1[CH2:15][CH2:16][CH:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:18]([F:19])([F:20])[F:21])[CH:6]=2)[CH2:12][CH2:13]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(NC2CCC(O)CC2)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.2 %

Procedure:
In a 250 ml round-bottomed flask under nitrogen, a solution of 4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (10 g, 33 mmol) in 150 ml of THF was cooled using an external ice bath. Sodium hydride (3.65 g, 152 mmol, 3 eq) was then added and the mixture was stirred at ˜0° C. for 30 minutes before adding the tert-butyl-2-bromoacetate (9.6 g, 49.2 mmol, 1.5 eq). The solution was allowed to warm to room temperature while stirring overnight. The reaction was then diluted using 500 ml of ice-water. The mixture was then extracted with 3×200 ml of ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under vacuum. The crude material was purified by silica gel chromatography using 10% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to provide 5 g (36%) of the desired ester as a yellow oil. Repeating this reaction on a larger scale yielded 51% of the desired product.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].C(N(CC)CC)C.Cl[C:19]([O:21][CH3:22])=[O:20].[Cl-].[Na+]>C(Cl)(Cl)Cl>[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:19](=[O:20])[O:21][CH3:22]
Reactant: NCc1cccc(Br)c1
Reactant: COC(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)NCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a suspension of 10.0 g of 3-bromobenzylamine hydrochloride in chloroform (100 ml), 9.55 g of triethylamine was added at room temperature. To this solution, 4.67 g of methyl chloroformate was dropwise added under cooling with ice, followed by stirring at room temperature for 2 hours. The reaction solution was poured into a sodium chloride aqueous solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 9.54 g of methyl N-(3-bromobenzyl)carbamate as white crystals.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]=[C:9]([CH2:11][C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:20][C:21]([F:29])([F:28])[C:22]1[S:26][C:25]([NH2:27])=[N:24][N:23]=1.[H-].[Na+].O>CN(C=O)C>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[CH2:11][C:9]1[S:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:27][C:25]3[S:26][C:22]([C:21]([F:29])([F:28])[F:20])=[N:23][N:24]=3)[C:3]=2[N:10]=1
Reactant: Nc1nnc(C(F)(F)F)s1
Reactant: Clc1cccc(Cl)c1Cc1nc2c(Cl)ncnc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1nnc(Nc2ncnc3sc(Cc4c(Cl)cccc4Cl)nc23)s1
Reaction time: 12 h
Yield: 34.5 %

Procedure:
To a solution of 7-chloro-2-(2,6-dichloro-benzyl)-thiazolo[5,4-d]pyrimidine (83 mg, 0.3 mmol) and 5-trifluoromethyl-[1,3,4]thiadiazol-2-ylamine (63 mg, 0.4 mmol) in DMF (1 mL) was added NaH (60% dispersion in oil; 20 mg, 0.5 mmol) at rt. After 12 h, the reaction mixture was poured into H2O (5 mL) and the resulting solid was collected by vacuum filtration and washed with 1:1 (IPA-H2O) to afford the title compound as a yellow solid (48 mg, 41%). MS (ESI): mass calcd. for C15H7Cl2F3N6S2, 462.0; m/z. found, 462.9 [M+H]+. 1H NMR ((CD3)2SO): 8.45 (s, 1H), 7.58 (d, J=8.0 Hz, 2H), 7.46-7.41 (m, 1H), 4.72 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[CH2:7][CH:8]([CH3:12])[O:9]2)=[CH:4][CH:3]=1.[N+:14]([O-])([OH:16])=[O:15].O>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[CH2:7][CH:8]([CH3:12])[O:9]2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: CC1CC(=O)c2ccc(Cl)cc2O1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC1CC(=O)c2cc([N+](=O)[O-])c(Cl)cc2O1
Temperature: 0 °C

Procedure:
7-Chloro-2-methylchroman-4-one (4.56 g, 23.2 mmol) was dissolved in 7 ml concentrated sulfuric acid at 0°-5° C. and cooled in an acetone-ice bath. Nitric acid (1.41 ml, s.g. 1.5, 90%) in 3 ml concentrated sulfuric acid was added dropwise over 20 minutes. The resulting viscous mixture was poured into 150 ml ice and water and extracted with 200 ml ethyl acetate. The organic layer was separated, washed 4×50 ml water and then brine, dried over magnesium sulfate, and stripped to a tan solid, 5.8 g. The latter was chromatographed on 500 cc silica gel, initially eluting with 5 liters 1:10 diethyl ether:hexane to remove starting material and then with 5 liters of 1:5 diethyl ether:hexane to obtain title product as a white solid, 2 g (36%); m/e 241(P+), 226, 199, 183, 169, 154, 141. 1H-NMR indicates contamination with about 44% of the 7-chloro-8-nitro isomer.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=1.C(N(CC)CC)C>CN(C)C=O>[O:4]1[CH2:5][CH2:6][N:1]([C:8]2[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=2)[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1csc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(N2CCOCC2)n1

Procedure:
The reaction described in Preparation 26 was repeated, but using 1.4 g of morpholine, 3 g of ethyl 2-chlorothiazole-4-carboxylate. 3 g of triethylamine and 12 ml of dimethylformamide, giving the title compound as colorless needles.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]1[CH:12]([CH2:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[NH:13][CH2:14][CH2:15][C:6]2=1.Cl.[CH:28]1(C2C=C3C(NC=C3CCN)=CC=2)[CH2:33][CH2:32]C[CH2:30][CH2:29]1>Cl>[ClH:1].[CH:2]1([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7]2[CH:12]([CH2:16][C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH:20]=[CH:19][CH:18]=4)[NH:13][CH2:14][CH2:15][C:6]3=2)[CH2:32][CH2:33][CH2:28][CH2:29][CH2:30]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCNC3Cc1cccc2ccccc12
Reactant: NCCc1c[nH]c2ccc(C3CCCCC3)cc12
Agent: Cl
Product: c1ccc2c(CC3NCCc4c3[nH]c3ccc(C5CCCCC5)cc43)cccc2c1
Temperature: 25 °C
Yield: 34.9 %

Procedure:
A suspension of azalactone (prepared as described in Example 5) (1.09 g, 4.59 mmol) and 5-cyclohexyltryptamine hydrochloride (1.28 g, 4.59 mmol) in 1N HCl (70 mL) was heated to reflux for 14 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and the crude product isolated by filtration. The solid was recrystallized from ethanol (2×) to afford 690 mg of desired product as a pale solid hydrochloride salt.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[O:5](C(OC(C)(C)C)=O)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=O>C(Cl)Cl>[C:9]([O:8][C:6](=[O:5])[NH:4][CH2:1][C:2]#[CH:3])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C#CCN
Solvent: ClCCl
Product: C#CCNC(=O)OC(C)(C)C

Procedure:
A solution of propargylamine (1 g, 18 mmol) in DCM (10 mL) was treated with (BOC)2O (4.0 g, 18 mmol) at rt for 3 h. Evaporation gave the title compound as an oil. 1H NMR (CDCl3) δ 4.80 (s, 1H), 3.93 (s, 2H), 2.23 (t, 1H), 1.47 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH3:12])[CH:3]=1.[N+:13]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)([O-:15])=[O:14]>C(O)C>[CH2:11]([C:4]1[CH:3]=[C:2]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=1)[CH3:12]
Reactant: CCc1cc(Cl)n2nccc2n1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: CCc1cc(Nc2ccc([N+](=O)[O-])cc2)n2nccc2n1

Procedure:
4.5 g (24.8 mmol) of 7-Chloro-5-ethylpyrazolo[1,5-a]pyrimidine (Example 1, Step B) and 3.5 g (25.3 mmol) 4-nitroaniline were heated in 75 ml dry ethanol for 5 h. During evaporation of the mixture in vacuo crystals precipitated, which were dissolved in dichloromethane. The solution was washed with saturated sodium bicarbonate solution, dried over sodium sulfate, and evaporated to dryness in vacuo to give the title compound as a yellow powder, m.p. 158°-160° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[C:15](=[O:16])[NH:14][CH2:13][C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[CH2:10][N:9]1[S:21]([C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)(=[O:23])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:36]I>C1COCC1.O>[CH2:1]([C@@H:8]1[C:15](=[O:16])[N:14]([CH3:36])[CH2:13][C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[CH2:10][N:9]1[S:21]([C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)(=[O:22])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=C1NCc2ccccc2CN(S(=O)(=O)c2cccc3cccnc23)[C@@H]1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN1Cc2ccccc2CN(S(=O)(=O)c2cccc3cccnc23)[C@H](Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a solution of 8 (50 mg, 0.11 mmol) in THF (3 mL) at −10° C. was slowly added NaH (5.2 mg, 0.12 mmol). The mixture was warmed to rt and stirred for 1 h. To it was added CH3I (50 mg, 0.33 mmol). The reaction mixture was stirred at rt for 16 h, diluted with H2O (10 mL) and extracted with EA (2×20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC to give 9 (50 mg, 96% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 9.14-9.11 (m, 1H), 8.24-8.19 (m, 2H), 7.92 (d, J=8.0 Hz, 1H), 7.59-7.54 (m, 1H), 7.44-7.36 (m, 3H), 7.22-7.13 (m, 5H), 7.08-7.04 (m, 1H), 6.72 (d, J=7.2 Hz, 1H), 5.80-5.76 (m, 1H), 5.43-5.30 (m, 2H), 4.20 (d, J=16.8 Hz, 1H), 3.46-3.30 (m, 2H), 3.06-3.00 (m, 1H), 2.75 (s, 3H); MS (ESI+) m/z: 472 [M+H]+.
Reaction SMILES: [C:1]([N:5]([CH2:13][CH2:14][CH2:15][O:16][CH2:17][C:18]#[C:19][C:20]1[S:24][CH:23]=[N:22][CH:21]=1)[C:6](=[O:12])[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>O1CCOCC1.O>[C:1]([N:5]([CH2:13][CH2:14][CH2:15][O:16][CH2:17][C:18]#[C:19][C:20]1[S:24][CH:23]=[N:22][CH:21]=1)[C:6](=[O:12])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)N(CCCOCC#Cc1cncs1)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)N(CCCOCC#Cc1cncs1)C(=O)C(=O)O
Temperature: 55 °C
Reaction time: 1 h

Procedure:
A solution of 272 mg of 8a in 3 ml of dioxane was mixed with 170 mg of KOH in 1.5 ml of water. The mixture was stirred for 1 h at 55° C. after which all starting material had disappeared, as judged by TLC analysis. The reaction mixture was cooled, diluted with 10 ml of water and acidified to pH3 by addition of cold 0.5N HCl. The product was extracted with ethyl acetate. The combined organic layers were washed once with water, dried and concentrated. The product 8b, 210 mg, thus obtained was used without further purification in the next step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][N:13]=3)[NH:9][N:8]=2)=[N:3][CH:2]=1.[H-].[CH3:19]I>O1CCCC1>[CH3:19][N:8]1[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][N:3]=2)=[N:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)=[N:9]1
Reactant: CI
Reactant: c1cc(-c2n[nH]c(-c3ccncn3)n2)ncn1
Agent: [H-]
Solvent: C1CCOC1
Product: Cn1nc(-c2ccncn2)nc1-c1ccncn1

Procedure:
To 3,5-bis(4-pyrimidinyl)-1,2,4-triazole (2.3 g.) in dry tetrahydrofuran (125 ml.) is added 57% sodimm hydride in mineral oil (0.46 g.). After refluxing 0.5 hour, methyl iodide (1.4 g.) is added and the mixture is heated at reflux an additional three hours. The reaction mixture is cooled, filtered and concentrated to a solid which after recrystallization yields substantially pure 1-methyl-3,5-bis(4-pyrimidinyl)-1,2,4-triazole.
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[NH2:11][C:12]1[S:13][C:14]([CH:20]=[O:21])=[C:15](Cl)[C:16]=1[C:17]#[N:18]>O>[NH2:11][C:12]1[S:13][C:14]([CH:20]=[O:21])=[C:15]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[C:16]=1[C:17]#[N:18]
Reactant: N#Cc1c(N)sc(C=O)c1Cl
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: O
Product: N#Cc1c(N)sc(C=O)c1S(=O)(=O)c1ccccc1
Reaction time: 8 h
Yield: 83 %

Procedure:
A solution of 82 parts of sodium phenylsulfinate in 500 parts of water is added to a mixture of 93.3 g of 2-amino-4-chloro-3-cyano-5-formylthiophene an 500 parts of methylglycol, and the reaction mixture is heated at the boil for 6 hours. Thereafter, the solution is filtered while hot and the filtrate is left to stand overnight. The precipitated product is then filtered off under suction, washed with water and dried. 121 parts (83% of theory) of 2-amino-3-cyano-5-formyl-4-phenylsulfonylthiophene are obtained.
Reaction SMILES: [C:1]([Si:5]([CH3:20])([CH3:19])[O:6][CH:7]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:17]=[C:16](I)[CH:15]=[N:14]2)[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.CO[B:28]1[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]1.[NH4+].[Cl-]>C1COCC1>[Si:5]([O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH:17]=[C:16]([B:28]3[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]3)[CH:15]=[N:14]2)[CH2:9][CH2:8]1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:20])[CH3:19]
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(n2cc(I)cn2)CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2)OC1(C)C
Temperature: 0 °C

Procedure:
To a stirred THF (30.00 mL) solution of 1-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-4-iodo-1H-pyrazole (Compound 137B, 1.1400 g, 2.8053 mmol) was added 2.00 M of isopropylmagnesium chloride in THF (2.31 mL, 4.63 mmol) dropwise under an atmosphere of Nitrogen in 5 min at 0° C. The reaction mixture was stirred at 0° C. for another hour. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.9577 mL, 5.610 mmol) was added at 0° C. and then the mixture was stirred at room temparature for another hour. The mixture was treated with saturated NH4Cl (10 ml), extracted with EtOAc (20 ml×3). The extracts were washed with water (10 ml), brine (15 ml), dried over Na2SO4. Solvent was removed under reduced pressure to give a residue which was purified by flash chromatography (10% EtOAc/hexane). MS (ES+): m/z=407.18 [MH+]. HPLC: tR=3.21 min (polar—5 min, ZQ3).
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]2[N:7]=[C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])[S:9][C:5]=2[CH:4]=1)#[N:2].Cl.NO.C(=O)([O-])[O-:22].[Na+].[Na+]>>[CH2:14]([NH:13][C:11]([NH:10][C:8]1[S:9][C:5]2[CH:4]=[C:3]([C:1]([NH2:2])=[O:22])[CH:17]=[CH:16][C:6]=2[N:7]=1)=[O:12])[CH3:15]
Reactant: O=C([O-])[O-]
Reactant: CCNC(=O)Nc1nc2ccc(C#N)cc2s1
Agent: Cl
Agent: NO
Agent: [Na+]
Product: CCNC(=O)Nc1nc2ccc(C(N)=O)cc2s1
Temperature: 25 °C

Procedure:
About 1 g of N-(6-cyano-1,3-benzothiazol-2-yl)-N′-ethylurea was charged into about 30 mL of aqueous alkanol. Added about 0.6 g hydroxylamine hydrochloride and about 0.45 g sodium carbonate then heated to reflux. The solution was refluxed for about 4–8 hours then cooled to room temperature. The precipitate was recovered by filtration and washed well with water. LC/MS indicated a mixture of two products identified as the following after further purification by preparative HPLC:
Reaction SMILES: C(OC([N:6]1[CH2:21][CH2:20][C:10]2[C:11]3[C:12](=O)[CH2:13][CH2:14][C:15]=3[C:16]([Cl:18])=[CH:17][C:9]=2[CH2:8][CH2:7]1)=O)C.[C:22]1([Mg]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Cl:18][C:16]1[C:15]2[CH2:14][CH2:13][CH:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11]=2[C:10]2[CH2:20][CH2:21][NH:6][CH2:7][CH2:8][C:9]=2[CH:17]=1
Reactant: CCOC(=O)N1CCc2cc(Cl)c3c(c2CC1)C(=O)CC3
Reactant: Br[Mg]c1ccccc1
Product: Clc1cc2c(c3c1CCC3c1ccccc1)CCNCC2

Procedure:
Example 10 was prepared in a similar fashion to Example 4, except Intermediate 4 was used as the starting material and phenylmagnesium bromide (3M in diethyl ether) was used instead of cyclopropylmagnesium bromide (Example 4, step (a)). NMR (300 MHz, CDCl3) δ 7.26-7.21 (m, 2H); 7.19-7.13 (m, 1H); 7.01 (s, 1H); 6.99-6.96 (m, 2H); 4.51-4.47 (m, 1H); 3.07-2.82 (m, 6H); 2.69-2.53 (m, 4H); 2.47-2.42 (m, 1H); 2.24-2.17 (m, 1H); 2.08-2.05 (m, 1H); MS: ESI (positive): 298, (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]O.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([CH3:20])[CH:11]=1.[I-].[K+]>C(N(CC)CC)C>[CH3:20][C:12]1[CH:11]=[C:10]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:13]2[CH2:14][CH2:19][CH2:10][CH2:11][CH2:12]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: NCCCCCCO
Reactant: Cc1cc(Cl)c2ccccc2n1
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Product: Cc1cc(NCCCCCCN2CCCCC2)c2ccccc2n1

Procedure:
Synthesis and purification were performed according to the procedure stated in example 152 using reagents 6-aminohexanol (15 mmol), 4-chloro-2-methylquinoline (15 mmol), 5 ml of triethylamine, and catalytic amounts of potassium iodide in the first step. The final product was purified by column chromatography (eluent: ethyl acetate/triethylamine (95/5)). The solvent was removed under reduced pressure. The residue was crystallized with oxalic acid from diethyl ether/ethanol.