Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:8])([CH2:6][CH3:7])[C:4]#[CH:5].C(N(CC)CC)C.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17]>C(Cl)Cl>[CH3:8][C:3]([NH:2][C:23](=[O:24])[C:22]1[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:27][CH:26]=1)([CH2:6][CH3:7])[C:4]#[CH:5]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: C#CC(C)(N)CC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CC(C)(CC)NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a three-necked, round-bottomed flask fitted with a mechanical stirrer, nitrogen inlet and thermometer were placed 4 grams (g) (0.03 mole) of 3-amino-3-methyl-1-pentyne hydrochloride (4 grams (g) (0.03 mole) suspended in 100 milliliters (mL) of methylene chloride in a three-necked, round-bottomed flask fitted with a mechanical stirrer, nitrogen inlet and thermometer. Triethylamine (6.82 g, 9.4 mL) was added slowly, keeping the temperature between 5° C. and 10° C. 4-nitrobenzoyl chloride 5 g (0.027 mole) was added to the resulting mixture at a rate to keep the reaction temperature between 5° C. and 10° C. After the addition was complete the reaction mixture was stirred at room temperature for 0.5 hours, and was then sequentially washed with water (2×100 mL), 5% aqueous hydrochloric acid, (2×100 mL), water (1×50 mL), 5% aqueous sodium hydroxide (2×100 mL) and finally with water (1×100 mL) before being dried over anhydrous magnesium sulfate. The solvent was removed in the rotary evaporator, yielding N-(3-methylpent-1-yn-3-yl)-4-nitrobenzamide, used as such in the next step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](=O)[CH3:17])=[CH:11][CH:10]=2)[CH:2]=1.[OH:19][CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1)[CH2:21][NH2:22]>O>[Cl:29][C:25]1[CH:24]=[C:23]([CH:20]([CH2:21][NH:22][CH:16]([CH3:17])[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:10][CH:11]=2)[OH:19])[CH:28]=[CH:27][CH:26]=1
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: CC(=O)Cc1ccc(OCc2cccnc2)cc1
Solvent: O
Product: CC(Cc1ccc(OCc2cccnc2)cc1)NCC(O)c1cccc(Cl)c1
Reaction time: 1 h
Yield: 54.3 %

Procedure:
A mixture of 1-[4-(3-pyridylmethyloxy)phenyl]propan-2-one (7.2 g) and 2-hydroxy-2-(3-chlorophenyl)ethanamine (5.1 g) was boiled under reflux with azeotropic removal of water until the reaction was complete. The solvent was evaporated, the residue dissolved in methanol (150 ml), cooled in an ice-bath and treated with sodium borohydride (5 g). After stirring for 1 hour the methanol was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with water, dried and evaporated to give an oil which was chromatographed on Kieselgel 60. Elution with 3% methanol in chloroform gave a yellow oil (6.4 g). Bulb to bulb distillation of this oil gave 3-chloro-β-[[[2-[4-(3-pyridylmethyloxy)phenyl]-1-methylethyl]amino]methyl]benzenemethanol b.p. 120°-130° C./0.4 mm, as a 1:1 mixture of diastereoisomers.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[N:23]1([CH2:32][C:33](O)=[O:34])[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]1=[O:25].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:33](=[O:34])[CH2:32][N:23]1[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]1=[O:25])[CH3:2]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1cc(C)c(=O)[nH]c1=O
Reaction time: 5 h
Yield: 75 %

Procedure:
To the mixture of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (1.72 g, 5 mmol), (thymin-1-yl)-acetic acid (0.92 g, 5 mmol), HOBt (0.81 g, 6 mmol), and DCC (1.24 g, 6 mmol) in DMF (15 mL) was added N,N-diisopropylethylamine (1.31 mL, 7.5 mmol) at ambient temperature. The resulting reaction mixture was stirred for 5 h at the same temperature and the solvent was removed in vacuo to 5 mL. The residue was dissolved in dichloromethane (50 mL) and the precipitate was filtered. The filtrate was washed with 1N HCl aqueous solution, saturated sodium bicarbonate solution, and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was triturated with ethyl alcohol. The resulting solid was filtered off and dried in vacuo to give the title compound (1.91 g, 75%) as a white solid. 1H NMR (500 MHz; DMSO-d6) δ 11.29 (s, 0.6H), 11.28 (s, 0.4H), 8.99 (brs, 0.6H), 8.82 (brs, 0.4H), 8.28 (m, 1H) 8.18 (d, 1H) 7.66 (m, 2H) 7.31 (s, 0.6H) 7.42 (s, 0.4H) 4.66 (s, 1.2H) 4.47 (s, 0.8H) 4.31 (s, 0.8H), 4.05 (s, 1.2H), 4.04 (q, 1.2H), 3.55 (t, 1.2H), 3.40˜3.34 (m, 2.8H), 3.20 (t, 0.8H), 1.73 (s, 3H), 1.19 (t, 1.2H), 1.14 (t, 1.8H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]([NH2:16])=[O:15].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.N1CCCCC1>C(O)C>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[N:1][C:2]2[NH:6][N:5]=[C:4]([NH:7][C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[C:3]=2[C:14]([NH2:16])=[O:15])=[CH:21][CH:20]=1
Reactant: COc1ccc(C=O)cc1
Reactant: NC(=O)c1c(Nc2cccnc2)n[nH]c1N
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(C=Nc2[nH]nc(Nc3cccnc3)c2C(N)=O)cc1
Yield: 50 %

Procedure:
5-amino-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide (1.0 g) was suspended in 10 mL of ethanol and 4-methoxybenzaldehyde (559 mg, 1.0 eq.) and piperidine (0.10 eq, 47 μL) was added. Stirred the reaction at reflux until starting material was absent and confirmed by HPLC. After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 5-((4-methoxybenzylidene)amino)-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide as a yellow to orange powder. The product was washed with ethanol to remove any excess 4-methoxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr (800 mg, 50% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([O:14][CH3:15])[N:3]=1.[CH2:16]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26]([N:29]=[C:30]=[O:31])(=[O:28])=[O:27])[CH2:17][CH3:18]>C(Cl)Cl>[CH3:15][O:14][C:4]1[N:5]=[C:6]([O:8][CH2:9][C:10]([F:11])([F:13])[F:12])[N:7]=[C:2]([NH:1][C:30]([NH:29][S:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH2:16][CH2:17][CH3:18])(=[O:28])=[O:27])=[O:31])[N:3]=1
Reactant: CCCOc1ccccc1S(=O)(=O)N=C=O
Reactant: COc1nc(N)nc(OCC(F)(F)F)n1
Solvent: ClCCl
Product: CCCOc1ccccc1S(=O)(=O)NC(=O)Nc1nc(OC)nc(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2.0 g of 2-amino-4-(2,2,2-trifluoroethoxy)-6-methoxy-1,3,5-triazine suspended in 35 mL of dry methylene chloride was added 4.4 g of a 50% solution of 2-n-propoxybenzenesulfonyl isocyanate in methylene chloride. The mixture was stirred overnight at ambient temperature and the resulting solution stripped to an amber oil which was triturated with ethanol to give 1.42 g of white solid with m.p. 161°-163° (dec).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N+:3]=1[O-:20]
Reactant: COC(=O)c1ccc(C)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(C)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
To a solution of methyl 6-methylnicotinate (6.05 g) in methylene chloride (100 mL) was added m-chloroperbenzoic acid (77%, 13.5 g). The reaction mixture was stirred at room temperature for 2 h and then diluted with chloroform (100 mL). The mixture was washed successively with aqueous sodium sulfite, saturated sodium bicarbonate, and brine. The organic later was then dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide 6.21 g of methyl 6-methylnicotinate 1-oxide. A solution of methyl 6-methylnicotinate 1-oxide (4.35 g) in acetic anhydride (50 mL) was heated at 120° C. for 2 h and then concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 1:2 to 3:5 ethyl acetate/hexanes) provided 3.3 g of the title compound: 3H NMR (300 MHz, CDCl3) δ 9.18, 8.31, 7.44, 5.29, 3.96, 2.19.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:8]=1[C:9]#[N:10])(=[O:6])=[O:5])([CH3:3])[CH3:2]>C1COCC1.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[C:8]([CH:11]=1)[C:9]#[N:10]
Reactant: CC(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1C#N
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)c1ccc(N)cc1C#N
Yield: 98 %

Procedure:
To 2-(isopropylsulfonyl)-5-nitrobenzonitrile (15B) (1.26 g, 4.96 mmol) in THF (20 mL) was added Pd/C (cat.) and the mixture was hydrogenated at 50 psi overnight. The reaction was filtered to provide 15C (1.09 g). LC-MS: 225.3 (M+H)+.
Reaction SMILES: [C:1]([NH2:7])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1>C1C=CC=CC=1>[N:8]1([C:3]([CH3:5])=[CH:2][C:1]([NH2:7])=[O:6])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C1CCNC1
Reactant: CC(=O)CC(N)=O
Solvent: c1ccccc1
Product: CC(=CC(N)=O)N1CCCC1
Temperature: 25 °C

Procedure:
N-[5-(4'-(1,1-dimethylethyl)phenyl)thien-2-yl]-amine, as prepared in Preparation 5, was dis tetrahydrofuran (50 mL). The solution was then treated with diketene (3.0 mL) at 50° C. for 90 minutes. Evaporation of the solvent and chromatography of the residue on silica gel (100 g, elute with ethyl acetate/hexane mixtures) yielded the acetoacetamide, a compound of formula (C). The acetoacetamide (1.14 g) was then dissolved in benzene (30 mL). The solution was treated with pyrrolidine (0.90 mL) and then refluxed for 2 hours with a Dean Stark trap. The reaction mixture was then cooled to room temperature and the product isolated by filtration to yield 1.130 g of N-5-(4'-(1,1-dimethylethyl)phenyl)thien-2-yl]-3-pyrrolidyl-2-butenamide, m.p. 205°-207° C. B. In a similar manner, but replacing N-[5-(4'-(1,1-dimethylethyl)phenyl)thien-2-yl]amine with other appropriately substituted amines, the following compounds are made:
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10](Cl)(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[NH2:24]>>[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[NH:24][S:10]([C:6]1[C:3]2=[N:4][S:5][N:1]=[C:2]2[CH:9]=[CH:8][CH:7]=1)(=[O:12])=[O:11]
Reactant: COC(=O)c1ccc(C)cc1N
Reactant: O=S(=O)(Cl)c1cccc2nsnc12
Product: COC(=O)c1ccc(C)cc1NS(=O)(=O)c1cccc2nsnc12
Yield: 53 %

Procedure:
The title compound (1.22 g, 53%) was prepared from benzo[1,2,5]thiadiazole-4-sulfonyl chloride and 2-amino-4-methyl-benzoic acid methyl ester as in Example 10, Part A. 1H NMR (500 MHz, CDCl3): 11.28 (s, 1H), 8.36 (dd, J=7.1, 1.0, 1H), 8.19 (dd, J=8.8, 1.0, 1H), 7.73 (d, J=8.1, 1H), 7.68 (dd, J=8.8, 7.1, 1H), 7.51 (br s, 1H), 6.77 (dd, J=8.1, 0.9, 1H), 3.89 (s, 3H), 2.28 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8][NH:7][C:6]=2[CH:14]=1.[N:15]([O-])=O.[Na+].C(=O)(O)[O-].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-]>Cl.O.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8][N:7]([NH2:15])[C:6]=2[CH:14]=1
Reactant: O=N[O-]
Reactant: CN1CCNc2cc(Cl)ccc2CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCc2ccc(Cl)cc2N(N)CC1
Reaction time: 1 h
Yield: 94.4 %

Procedure:
To a solution of 9-chloro-4-methyl-1,2,3,4,5,6-hexahydro-benzo[e][1,4]diazocine (6.0 g, 0.023 mole approximately) in hydrochloric acid (1 N, 200 mL) cooled to 0° C. was added sodium nitrite (4.0 g, 0.058 mole) in water (20 mL). The mixture was stirred for 1 hour and treated with sodium bicarbonate, extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with saturated sodium chloride (200 mL), dried and concentrated to a light brown oil. The oil was redissolved in THF (50 mL) and added to a suspension of lithium aluminum hydride (4.0 g, 0.10 mole) in THF (100 mL) and the mixture refluxed for 3 hours. The excess hydride was destroyed at 0° C. by the cautious addition of ethyl acetate. The mixture was washed with aqueous potassium sodium tartrate (10% v/w, 200 mL) and saturated aqueous sodium chloride (150 mL), dried (sodium sulfate) and concentrated. Evaporation in vacuo provided 4.9 g of the title compound as a light yellow oil. This oil was used for indole formation without further purification. 1H NMR (CDCl3): 7.25 δ (s, 1H); 7.00 δ (d, 2H); 3.00 δ (m, 2H); 2.90 δ (m, 2H); 2.78 δ (m, 2H); 2.40 δ (s, 3H); 2.30 δ (t, 2H).
Reaction SMILES: [O:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[N:9][NH:8][C:7]=2[CH:11]=1)[CH3:2].[OH-].[Na+].[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[O:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[N:9][N:8]([CH2:18][CH2:17][CH2:16][CH2:15][Cl:14])[C:7]=2[CH:11]=1)[CH3:2]
Reactant: ClCCCCBr
Reactant: COc1ccc2nn[nH]c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2nnn(CCCCCl)c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
6-methoxyl-benzotriazole (14.9 g, 0.10 mol) is dissolved into 100 ml of 30% wt. sodium hydroxide, 4-chlorobromobutane (34.3 g, 0.20 mol), tetrabutyl ammonium bromide (0.8 g) are added, and mixed for 5 min. The reaction solution is gradually heated to 60° C., stirred for reaction for 2 hours. Then the reaction solution was cooled down to ambient temperature, 100 ml of dichloromethane was added for extraction and liquid separation. To the aqueous phase, 100 of dichloromethane was added for extraction. Organic phases were mixed, washed with 100 ml of saturated saline. Liquid was separated, and organic phase was evaporated to dryness to produce oily product. Oily products were separated and purified by chromatography with neutral Al2O3, and eluted with dichlormethane to produce 17.9 g of 6-methoxyl-1-(4-chlorobutyl)-1H-benzotriazole, with a yield of 75.0%.
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C(=C)CC5[C@]4(C)CCCC5)[C@@H]2C3)C)O1.C=[C:30]1[CH:47]2[C@:42]([CH3:49])([CH2:43][CH2:44][C:45](=[O:48])[CH2:46]2)[C@@H:41]2[C@H:32]([C@H:33]3[C@@:37]([CH2:39][CH2:40]2)([CH3:38])[C:36](=[O:50])[CH2:35][CH2:34]3)[CH2:31]1>>[CH2:1]=[C:31]1[CH2:30][CH:47]2[C@:42]([CH3:49])([CH2:43][CH2:44][C:45](=[O:48])[CH2:46]2)[C@@H:41]2[C@@H:32]1[C@H:33]1[C@@:37]([CH2:39][CH2:40]2)([CH3:38])[C:36](=[O:50])[CH2:35][CH2:34]1
Reactant: C=C1CC2CCCC[C@]2(C)[C@H]2CC[C@@]3(C)[C@@H](CC45OCCOC43OCCO5)[C@H]12
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Product: C=C1CC2CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Yield: 87 %

Procedure:
The title compound II-aw was prepared in 87% yield from 3,3:17,17-bis(ethylendioxy)-7-methyleneandrostane by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (I-ac, Prepn. 13). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.70 (1H, m), 4.62 (1H, m), 2.20-1.10 (20H, m), 1.00 (3H, s), 0.88 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[C:22]([N:24]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[N:25]2)[CH:21]=[CH:20][C:3]=1[O:4][CH:5]([C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][CH:10]=1)[CH2:6][CH2:7][CH3:8].O.[OH-].[Li+].CO.C1COCC1>O>[CH3:1][C:2]1[CH:23]=[C:22]([N:24]2[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[N:25]2)[CH:21]=[CH:20][C:3]=1[O:4][CH:5]([C:9]1[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCC(Oc1ccc(-n2cc(C(F)(F)F)cn2)cc1C)c1ccc(C(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCC(Oc1ccc(-n2cc(C(F)(F)F)cn2)cc1C)c1ccc(C(=O)O)cc1
Reaction time: 18 h
Yield: 100.4 %

Procedure:
A mixture of ethyl 4-(1-(2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzoate (90 mg, 0.2 mmol), lithium hydroxide monohydrate (24 mg, 1.0 mmol), methanol (2 ml), THF (3 ml), and water (1 ml) was stirred at +450 for 18 hours. The mixture was concentrated, diluted with 8 ml of water and 2 ml of 1 M potassium hydrogen sulfate. The mixture was extracted with ethyl acetate-heptane (1:1), extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated to obtain the target product as a white solid (84 mg, 99%). MS (M+1): 419.2.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH2:20][CH2:21][CH3:22])[CH2:3][CH2:4][C:5]([N:7]1[CH:11]([CH3:12])[CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:8]1=[O:19])=[O:6].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:34]([O:38][C:39](=[O:42])[CH2:40]Br)([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:39](=[O:42])[CH2:40][C@@H:4]([C:5]([N:7]1[C@@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:9][C:8]1=[O:19])=[O:6])[CH2:3][C:2]([CH3:1])([CH3:23])[CH2:20][CH2:21][CH3:22])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCC(C)(C)CCC(=O)N1C(=O)OC(c2ccccc2)C1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CCCC(C)(C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1C
Yield: 49.2 %

Procedure:
According to example 1, 5.07 g (16 mmol) of 3-(4,4-dimethyl-heptanoyl)-4-methyl-5-phenyl-oxazolidin-2-one, 18 mL (1N, 18 mmol) of NaHMDS solution and 4.72 mL (32 mmol) of bromo-acetic acid tert-butyl ester gave 3.40 g (49.3%) of the title compound as a crystalline solid. m.p.: 83-85° C.
Reaction SMILES: C([O:5][C:6](=[O:39])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([NH:36][CH2:37][CH3:38])=[O:35])=[CH:30][CH:29]=2)[C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:37]([NH:36][C:34]([C:31]1[CH:30]=[CH:29][C:28]([CH2:27][N:18]([C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:39])=[O:5])[S:12][CH:13]=2)=[CH:33][CH:32]=1)=[O:35])[CH3:38]
Reactant: CCNC(=O)c1ccc(CN(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)c2ncc(CC)cn2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)c1ccc(CN(CCc2csc(SC(C)(C)C(=O)O)n2)c2ncc(CC)cn2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.8 %

Procedure:
2-[(4-{2-[{4-[(Ethylamino)carbonyl]benzyl}(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (268 mg) synthesized in Example 437-3 was dissolved in dichloromethane (2.0 mL), trifluoroacetic acid (2.0 mL) was added, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (at this time point, the object product had been extracted in the ethyl acetate layer). The ethyl acetate layer was washed with aqueous 10% citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1) to give the title compound (159 mg) as a white amorphous solid.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[NH2:25][C:26]1[N:33]=[CH:32][C:31](Br)=[CH:30][C:27]=1[C:28]#[N:29]>>[NH2:25][C:26]1[N:33]=[CH:32][C:31]([C:13]#[C:12][C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:24])=[CH:4][C:5]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)=[N:6][C:7]=23)=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: N#Cc1cc(Br)cnc1N
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: N#Cc1cc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cnc1N

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 g, 1.0 mmol) and 2-amino-5-bromo-nicotinonitrile (example C.23 step 1) (200 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (240 mg, 52%). MS (ISP) 455.3 [(M+H)+]; mp 255° C.
Reaction SMILES: C[O-].[Na+].[NH:4]([CH2:11][CH2:12][C:13]#[N:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:15][NH:16][C:17]1[CH:18]=[C:19]([CH:27]=[C:28]([NH:30][CH3:31])[CH:29]=1)[CH:20](O)CS(C)(=O)=O.CS(C)=O>O>[NH:4]([CH:11]=[C:12]([CH2:20][C:19]1[CH:27]=[C:28]([NH:30][CH3:31])[CH:29]=[C:17]([NH:16][CH3:15])[CH:18]=1)[C:13]#[N:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CNc1cc(NC)cc(C(O)CS(C)(=O)=O)c1
Reactant: N#CCCNc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CNc1cc(CC(C#N)=CNc2ccccc2)cc(NC)c1

Procedure:
A mixture of 8.6 g. of sodium methylate, 12.4 g. of β-anilinopropionitrile and 20.4 g. of 3,5-bis(methylamino)-α-[(methylsulfonyl)methyl]benzyl alcohol in 100 ml. of absolute dimethylsulfoxide was stirred for 1 hour at 50° C. and then treated with 1 liter of water. The precipitated product was extracted with 3 liters of ethyl acetate. The ethyl acetate extract was washed with 1 liter of water, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on 1 kg. of silica gel with methylene chloride/ethyl acetate (3:1), there being obtained α-(anilinomethylene)-3,5-bis(methylamino)hydrocinnamonitrile as a brownish-colored oil.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.[CH:41]1[CH:46]=[CH:45][C:44](N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=[CH:43][CH:42]=1>C(Cl)Cl>[C:18]1([N:13]2[C:12]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCc2nn(-c3ccccc3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(-c2c3c(nn2-c2ccccc2)CCNCC3)cc1

Procedure:
2-Phenyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester. To a stirred solution of the above compound (1.79 g) in 35 mL of CH2Cl2 was added 3.0 mL of i-Pr2NEt and 3.05 g of N-phenyltrifluoromethanesulfonimide. The mixture was heated at reflux for 24 h and then was concentrated in vacuo. Chromatography on SiO2 (0 to 75% EtOAc/hexanes) afforded 1.88 g of the desired compound. MS (ESI): exact mass calculated for C19H22F3N3O5S, 461.12; found, m/z 407.1 [M+H]+.