Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:39])[CH2:35][C:36](O)=[O:37].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][N:30]([C:36](=[O:37])[CH2:35][N:34]([CH3:39])[CH3:33])[CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 23.2 %

Procedure:
A mixture of 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (150 mg, 0.33 mmol), N,N-dimethylglycine (40 mg, 0.39 mmol), EDCl (69 mg, 0.36 mmol), HOBt (48 mg, 0.36 mmol), and N,N-diisopropylethylamine (227 μL, 1.30 mmol) in DMF (2 mL) was stirred at rt for 6 h. An additional 0.5 eq. of N,N-dimethylglycine was added and the mixture continued to stir at rt for 16 hr. The crude reaction mixture was purified via preparative HPLC using a gradient elution from 15% to 40% acetonitrile in water to provide 39 mg (24%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1 H), 7.92 (s, 1 H), 7.81 (d, 1 H), 7.66 (s, 1 H), 7.28-7.39 (m, 5 H), 7.15 (dd, 1 H), 6.60 (s, 1 H), 5.67 (s, 2 H), 4.32 (dd, 1 H) 3.33-3.46 (m, 1 H), 3.01-3.20 (m, 4 H), 2.66-2.78 (m, 1 H), 2.19 (s, 6 H), 2.05 (d, 2 H), 1.44-1.75 (m, 2 H); ES-MS m/z 509.23 [M+H]+, HPLC RT (min) 2.12.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]([Cl:12])[N:6]=1.CS(C)=O.[CH2:17]([N:19]([CH2:24][CH3:25])[C:20](=[O:23])[CH2:21]Cl)[CH3:18]>CO>[CH2:17]([N:19]([CH2:24][CH3:25])[C:20](=[O:23])[CH2:21][O:11][C:10]1[C:5]([Cl:4])=[N:6][C:7]([Cl:12])=[CH:8][CH:9]=1)[CH3:18]
Reactant: CCN(CC)C(=O)CCl
Reactant: Oc1ccc(Cl)nc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: CCN(CC)C(=O)COc1ccc(Cl)nc1Cl
Temperature: 25 °C

Procedure:
A solution of 4.6 g of sodium methylate (0.2 mole) in 50 ml of absolute methanol is slowly added at room temperature to 33.4 g (0.2 mole) of 2,6-dichloropyridin-3-ol. There is then added, with gentle heating, 100 to 150 ml of dimethylsulphoxide until the cloudy solution becomes clear. The solution is then heated to 80°-90° and methanol is distilled off. The reaction solution is cooled and an addition is slowly made dropwise at 0°-10° C of a solution of 60 g (0.2 mole) of chloroacetic acid diethylamide (dissolved in 300 ml of dimethylsulphoxide). After the dropwise addition is completed, the reaction mixture is stirred at room temperature for a further hour. The solvent is distilled off under reduced pressure; the oil remaining is taken up in ether, washed with water, dried and freed from solvent to leave N,N-diethyl-(2,6-dichloro-3-pyridyl)-oxy-acetic acid amide, which boils at 137°/0.4 torr; yield: 35 g (62% of theory). Treatment with ethereal hydrochloric acid yields the hydrochloride, which is recrystallised from isopropanol.
Reaction SMILES: CC(O[C:6](=[O:22])[NH:7][C@@H:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15]([NH:17][CH:18]2[CH2:20][CH2:19]2)=[O:16])[C:9]1=[O:21])(C)C.C(O)(C(F)(F)F)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+].[Cl:47][C:48]1[CH:57]=[C:56]2[C:51]([C:52]([N:59]3[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]3)=[CH:53][C:54]([NH2:58])=[N:55]2)=[CH:50][CH:49]=1>>[NH2:58][C:54]1[CH:53]=[C:52]([N:59]2[CH2:60][CH2:61][N:62]([C:6]([NH:7][C@H:8]3[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15]([NH:17][CH:18]4[CH2:19][CH2:20]4)=[O:16])[C:9]3=[O:21])=[O:22])[CH2:63][CH2:64]2)[C:51]2[C:56](=[CH:57][C:48]([Cl:47])=[CH:49][CH:50]=2)[N:55]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCCN(C(=O)NC2CC2)C1=O
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(N2CCN(C(=O)N[C@H]3CCCCN(C(=O)NC4CC4)C3=O)CC2)c2ccc(Cl)cc2n1

Procedure:
As described for example 213, [(3R)-1-[(cyclopropylamino)carbonyl]hexahydro-2-oxo-1H-azepin-3-yl]-carbamic acid-1,1-dimethylethyl ester, TFA, triphosgene, NaHCO3 (sat.), and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product as a white solid. LC-MS: 500 (M++1). 1H NMR (CDCl3): δ 0.50˜0.62 (m, 2H), 0.72–0.84 (m, 2H), 1.42 (m, 1H), 1.60 (m, 1H), 1.82˜2.02 (m, 3H), 2.13 (m, 1H), 2.76 (ddd, 1H), 3.12 (br.dd, 4H), 3.24 (br.dd, 1H), 3.66 (m, 4H), 4.82˜4.94 (m, 2H), 5.02 (br.s, 2H), 5.86 (d, 1H), 6.16 (s, 1H), 7.16 (dd, 1H), 7.60 (d, 1H), 7.72 (d, 1H), 9.10 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][C:8]=2[CH3:16])=[N:3]1.Br[CH2:19][C:20]1[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=1>>[CH3:17][C:2]1([CH3:1])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:14])[CH3:15])=[CH:9][C:8]=2[CH2:16][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)=[N:3]1
Reactant: Cc1cc(C(C)C)ccc1C1=NC(C)(C)CO1
Reactant: Cc1cccc(CBr)c1
Product: Cc1cccc(CCc2cc(C(C)C)ccc2C2=NC(C)(C)CO2)c1

Procedure:
The subtitle compound was prepared from the product of step (ii) and 3-bromomethyltoluene (9.25 g) using the method of example 15 step (iv). Purification was by chromatography eluting with toluene. Yield 4.8 g.
Reaction SMILES: C1C2C(CC=CC=2)CCC1=O.C1C2C(=CC=CC=2)CCC1.[CH3:22][C:23]1([CH3:47])[CH2:32][CH2:31][C:30](=[O:33])[C:29]2[CH:28]=[C:27](/[CH:34]=[CH:35]/[C:36]3[CH:46]=[CH:45][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][CH:37]=3)[CH:26]=[CH:25][C:24]1=2.Br[CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51]>[Zn]>[CH3:47][C:23]1([CH3:22])[CH2:32][CH2:31][C:30]([OH:33])([CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[C:29]2[CH:28]=[C:27](/[CH:34]=[CH:35]/[C:36]3[CH:37]=[CH:38][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:45][CH:46]=3)[CH:26]=[CH:25][C:24]1=2
Reactant: CCOC(=O)c1ccc(/C=C/c2ccc3c(c2)C(=O)CCC3(C)C)cc1
Reactant: CCOC(=O)CBr
Agent: O=C1CCC2CC=CC=C2C1
Agent: [Zn]
Solvent: c1ccc2c(c1)CCCC2
Product: CCOC(=O)CC1(O)CCC(C)(C)c2ccc(/C=C/c3ccc(C(=O)OCC)cc3)cc21

Procedure:
Reaction Scheme 5 discloses another example for the preparation of compounds within the scope of Formula 3. In this example the substituent is introduced to replace the oxo function of tetrahydronaphthalene-2-one after the Z--Y(R2)--A--B group has already been coupled to the tetrahydronaphthalene nucleus. Thus, ethyl (E)-4-[2-(5,6-dihydro-5,5-dimethyl-naphthalen-8(7H)-one-2-yl)ethenyl]-benzoate (Compound A2) is reacted with ethyl bromoacetate in the presence of zinc metal in a Reformatsky reaction to provide (+/-) ethyl (E)-4-[2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-hydroxy-8-(carbethoxymethyl)naphthalen-2-yl)ethenyl]benzoate (Compound A32). Compound A32 is itself within the scope of the present invention, within the scope of Formula 1. Compound A32 is dehydrated, as shown in the example by treatment with (methoxycarbonyl sulfamoyl)triethylammonium hydroxide (Burgess reagent) to yield a mixture of ethyl (E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(carbethoxymethyl)naphthalen-2-yl)ethenyl]benzoate (Compound A33a), and ethyl (E)-4-[2-(5,6-dihydro-5,5-dimethyl-8(7H)-anti(carbethoxymethylidenyl)-naphthalen-2-yl)ethenyl]benzoate (Compound A33b). Compound A33a is within the scope of Formula 6, and Compound A33b is within the scope of Formula 3. ##STR20##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C@H:17]3[CH2:22][N:21]([CH:23]4[CH2:28][CH2:27][C:26]([OH:35])([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)[CH2:25][CH2:24]4)[CH2:20][CH2:19][N:18]3C(OC(C)(C)C)=O)=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C@@H:17]3[NH:18][CH2:19][CH2:20][N:21]([CH:23]4[CH2:28][CH2:27][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)([OH:35])[CH2:25][CH2:24]4)[CH2:22]3)=[O:16])[CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCC(O)(c3ccccn3)CC2)C[C@@H]1C(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C([C@H]1CN(C2CCC(O)(c3ccccn3)CC2)CCN1)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The faster running isomer of tert-butyl (2R)-2-{[4-(3,4-dichlorophenyl)piperazin-1-yl]carbonyl}-4-(4-hydroxy-4-pyridin-2-ylcyclohexyl)piperazine-1-carboxylate (45 mg) was dissolved in dichloromethane (6 ml). Trifluoroacetic acid (1 ml) was added and the solution stirred at room temperature for 2 hours and allowed to stand over the weekend. The mixture was partitioned between saturated aqueous sodium bicarbonate (10 ml) and dichloromethane (2×100 ml) and combined organics were concentrated in vacuo and adsorbed onto silica for purification by chromatography eluting with 0-15% methanol/dichloromethane. This gave one isomer of 4-((3R)-3-{[4-(3,4-dichlorophenyl)piperazin-1-yl]carbonyl}piperazin-1-yl)-1-pyridin-2-ylcyclohexanol as a light brown solid (31%, 85%).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[CH:15]1([N:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[Si:38]([CH3:41])([CH3:40])[CH3:39])[C:19]([C:21]2[C:22]([CH:28]([F:30])[F:29])=[N:23][N:24]([CH3:27])[C:25]=2[F:26])=O)[CH2:17][CH2:16]1.O>O1CCOCC1>[CH:15]1([N:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[Si:38]([CH3:41])([CH3:40])[CH3:39])[C:19]([C:21]2[C:22]([CH:28]([F:30])[F:29])=[N:23][N:24]([CH3:27])[C:25]=2[F:26])=[S:2])[CH2:17][CH2:16]1
Reactant: Cn1nc(C(F)F)c(C(=O)N(Cc2ccccc2[Si](C)(C)C)C2CC2)c1F
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Solvent: C1COCCO1
Product: Cn1nc(C(F)F)c(C(=S)N(Cc2ccccc2[Si](C)(C)C)C2CC2)c1F
Temperature: 100 °C

Procedure:
A solution of 140 mg (0.31 mmol) of phosphorus pentasulfide and 500 mg (1.26 mmol) of N-cyclopropyl-3-(difluoromethyl)-5-fluoro-1-methyl-N-[2-(trimethylsilyl)benzyl]-1H-pyrazole-4-carboxamide in 20 ml of dioxane was heated at 100° C. for 2.5 hours. 2 ml of water were then added and the reaction mixture was heated at 100° C. for another 1 hour.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[CH:22]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23]1>ClCCl>[Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:27][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(CBr)c1ccc(S(=O)(=O)Cl)cc1
Reactant: NC1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CBr)c1ccc(S(=O)(=O)NC2CCCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4-(2-Bromo-acetyl)-benzenesulfonyl chloride (150 mg, 0.17 mmol) was dissolved in 4 mL of dry dichloromethane. To this solution at 0° C., was added triethylamine (0.03 mL, 0.2 mmol), followed by cyclopentylamine (0.2 mmol, 0.011 g). Reaction mixture was stirred at 0° C. for 15 minutes and then quenched with H2O. The reaction mixture was extracted with H2O. The organic phase was isolated, dried over MgSO4 and evaporated. It was used in the next step without any further purification.
Reaction SMILES: CN(C=O)C.[S:6]([Cl:10])(Cl)(=[O:8])=[O:7].[CH3:11][C:12]1[O:13][C:14]([CH3:17])=[CH:15][CH:16]=1>>[CH3:11][C:12]1[O:13][C:14]([CH3:17])=[CH:15][C:16]=1[S:6]([Cl:10])(=[O:8])=[O:7]
Reactant: Cc1ccc(C)o1
Reactant: O=S(=O)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(S(=O)(=O)Cl)c(C)o1

Procedure:
2,5-dimethyl-furan-3-sulfonylchloride was prepared by the method of Example 40B with DMF (28 mmoles, 2.2 ml), sulfurylchloride (24 mmoles, 1.9 ml) and 2,5-dimethyl-furan (14 mmoles, 1.5 ml). Flash chromatography (5% ethyl acetate/hexanes) provided 0.61 g (22%) of a yellow liquid.
Reaction SMILES: [N+:1]([C:4]1[C:9]([NH2:10])=[C:8]([N+:11]([O-:13])=[O:12])[C:7]([N+:14]([O-])=O)=[C:6]([N+:17]([O-:19])=[O:18])[C:5]=1[N+:20]([O-])=O)([O-:3])=[O:2].N>C1C=CC=CC=1.C(Cl)Cl>[C:9]1([NH2:10])[C:8]([N+:11]([O-:13])=[O:12])=[C:7]([NH2:14])[C:6]([N+:17]([O-:19])=[O:18])=[C:5]([NH2:20])[C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Nc1c([N+](=O)[O-])c([N+](=O)[O-])c([N+](=O)[O-])c([N+](=O)[O-])c1[N+](=O)[O-]
Agent: N
Solvent: ClCCl
Solvent: c1ccccc1
Product: Nc1c([N+](=O)[O-])c(N)c([N+](=O)[O-])c(N)c1[N+](=O)[O-]

Procedure:
According to this invention, the 4-nitro group or trinitrotoluene (TNT) is selectively reduced by H2S in p-dioxane to produce 4-amino-2,6-dinitrotoluene. This latter compound is then nitrated with HNO3 in H2SO4 to produce pentanitroaniline. Finally the pentanitroaniline is reacted with NH3 in benzene, methylene chloride or another suitable solvent to produce a quantitative yield of TATB. The method of this invention is easily carried out and all reactants are inexpensive.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].Cl.O.[NH2:15][NH2:16]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:15][NH2:16])=[O:8])([O-:3])=[O:2]
Reactant: NN
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: O
Solvent: CO
Product: NNC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A mixture of 167g (1 mole) of m-nitrobenzoic acid and 160g (5 moles) of methanol was refluxed with stirring for 3 hours while a stream of dry HCl was bubbled in. A precipitate which formed on cooling to room temperature was filtered off, and dissolved in hot methanol. The solution was boiled for 10 minutes with a mixture of sodium carbonate and anhydrous calcium sulfate and was then filtered. The filtrate was stirred and refluxed while 118g (2 moles) of 85% hydrazine hydrate was added. The mixture was refluxed for 90 minutes and allowed to cool. The solid product was filtered off and recrystallized from water to give 258 g of m-nitrobenzhydrazide, m.p. 155°-155.5°C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH2:11].[I:12](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1.C(=O)([O-])[O-].[Ca+2]>ClCCl.CO>[NH2:11][C:3]1[C:4]2[O:8][CH2:7][O:6][C:5]=2[C:9]([I:12])=[CH:10][C:2]=1[F:1]
Reactant: Nc1c(F)ccc2c1OCO2
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: ClCCl
Product: Nc1c(F)cc(I)c2c1OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.1 %

Procedure:
5-Fluoro-1,3-benzodioxol-4-amine (1.1 g, 7.10 mmol), benzyltrimethylammonium dichloroiodate (2.7 g, 7.76 mmol) and calcium carbonate (0.92 g, 9.2 mmol) in a mixture of dichloromethane (10 ml) and methanol (5 ml) were stirred at room temperature for 3 hr. The mixture was filtered through Celite and then evaporated to a dark brown solid. The residue was purified by column chromatography on silica using a 1:1 mixture of methyl tert-butyl ether and iso-hexane as eluent to give 4-amino-5-fluoro-7-iodo-1,3-benzodioxole (1.14 g, 57%) as a pale brown solid; NMR Spectrum: (CDCl3) 3.61 (s, 2H), 6.00 (s, 2H), 6.81 (d, 1H).
Reaction SMILES: O=[C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:5]=[C:4]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)O1.[H-].[Na+].[CH2:23]1[CH2:27]O[CH2:25][CH2:24]1>>[N:10]1([C:6]2[CH:5]=[C:4]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[C:25]3[CH2:24][C:23]4[C:27]([C:2]=3[C:7]=2[C:8]#[N:9])=[CH:6][CH:5]=[CH:4][CH:16]=4)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2cccs2)oc1=O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2cccs2)c2c1-c1ccccc1C2

Procedure:
A mixture of 2-oxo-4-(piperidin-1-yl)-6-(thiophen-2-yl)-2H-pyran-3-carbonitrile (286 mg), indanone-1 (132 mg) and NaH (37 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent Yellowish solid; mp 152-154° C.; ESMS 357 (M++1); IR (KBr). 2217 cm−1 (CN); HRMS calcd. for C23H20N2S 356.1347 found 356.1139.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])C(O)=O.[P:16]([O-:33])([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.[CH3:41][O:42][C:43]1[CH:44]=[C:45]([Br:53])[CH:46]=[C:47]([O:51][CH3:52])[C:48]=1[O:49][CH3:50]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:41][O:42][C:43]1[CH:44]=[C:45]([Br:53])[CH:46]=[C:47]([O:51][CH3:52])[C:48]=1[O:49][CH3:50].[CH3:15][O:14][C:10]1[CH:9]=[C:5]([P:16](=[O:33])([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:11]=1[O:12][CH3:13]
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Agent: COc1cc(Br)cc(OC)c1OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc(P(=O)(OCc2ccccc2)OCc2ccccc2)cc(OC)c1OC

Procedure:
3,4,5-Trimethoxybromobenzene is prepared from 3,4,5-trimethoxybenzoic acid following the procedure of Tetrahedron Lett. 26 (1985):5939-5942. Dibenzyl phosphite is heated in the presence of tetrakis(triphenylphosphine) palladium (0), triethylamine and toluene with 3,4,5-trimethoxybromobenzene to give dibenzyl 3,4,5-trimethoxyphenylphosphonate 2 following the procedure of J. Med. Chem. 32 (1989):1580-1590.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH2:19][CH2:20][Cl:21].O>CN(C)C=O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH2:19][CH2:20][Cl:21])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: ClCCCBr
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 81 %

Procedure:
To a solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.54 g) in N,N-dimethylformamide (20 mL) was added cesium carbonate (4.89 g) under ice-cooling, and the mixture was stirred under ice-cooling for 20 min. 1-Bromo-3-chloropropane (1.89 g) was added and the mixture was stirred under ice-cooling for 1 hr and at room temperature for 32 hrs. The reaction mixture was poured into water (40 mL), and the mixture was extracted with ethyl acetate (60 mL×2). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→50:50) to give the title compound (1.87 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH:7][CH3:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:18](Br)[C:19]#[CH:20]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][N:7]([CH2:20][C:19]#[CH:18])[CH3:8])=[CH:4][CH:3]=1
Reactant: C#CCBr
Reactant: CNCc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C#CCN(C)Cc1ccc(Cl)cc1

Procedure:
To a solution of 31.1 g (0.2 mole) N-(4-chlorobenzyl)-methylamine and 30.3 g (0.3 mole) triethylamine in 150 ml dry benzene are added in portions at room temperature while stirring 23.8 g (0.2 mole) propargyl bromide. The solution is heated for 17 hours with reflux. After filtering off the solid phase, the the solvent is distilled under vacuum and the remaining residue fractionally distilled under reduced pressure. One thus obtains 30.9 g N-(4-chlorobenzyl)-N-methyl-2-propinylamine (79% of the theory as colorless liquid of the boiling point 86°-106° C./2 Torr.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[O:14][CH3:15].C(=O)([O-])[O-].[Na+].[Na+].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C1CCCCC1>[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=2[O:14][CH3:15])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: COc1cc(C#N)ccc1OCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCCCC1
Product: COc1cc(C#N)ccc1OCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 27.5 °C
Yield: 75 %

Procedure:
To 50 gms (0.24 mole) of 4-(3′-Hydroxypropoxy)-3-methoxy benzonitrile in 200 ml. of cyclohexane was added 26 gms (0.24 mole) of sodium carbonate and 46 gms (0.24 mole) of p-toluene sulfonyl chloride at once. The resultant reaction mixture was refluxed for about 4-6 hrs. After completion of the reaction, the reaction mass was cooled to about 25-30° C. and the inorganic salts were filtered off. and washed with cyclohexane. The solvents were distilled completely and solid obtained was recrystallized from 150 ml of ethyl acetate to afford the title compound as white crystalline powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[CH3:13][C:14]1[CH:15]=[C:16]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[C:17]([N:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[NH2:20])=[O:18]>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:20][N:19]([C:17](=[O:18])[C:16]1[CH:15]=[C:14]([CH3:13])[CH:27]=[C:26]([CH3:28])[CH:25]=1)[C:21]([CH3:24])([CH3:23])[CH3:22])=[O:8]
Reactant: COc1cccc(C(=O)O)c1C
Reactant: Cc1cc(C)cc(C(=O)N(N)C(C)(C)C)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1cccc(C(=O)NN(C(=O)c2cc(C)cc(C)c2)C(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
A solution of 3-methoxy-2-methylbenzoic acid (1.5 g, 0.01 tool) in thionyl chloride (10 mL) was refluxed for 45 minutes and then stripped under reduced pressure. The residue was dissolved in methylene chloride (50 mL) and added dropwise with cooling at 0° C. to a solution of N-(3,5-dimethylbenzoyl)-N-tertbutylhydrazine (4.4 g. 0.02 mol) in methylene chloride (50 mL). Following the addition, the solution was stirred overnight at room temperature and filtered. The filter-cake was washed extensively with water and ether, and then dried in vacuo to give 2.1 g (64.1% yield) of N-(3-methoxy-2-methylbenzoyl)-N'(3,5-dimethylbenzoyl)-N'-tert-butylhydrazine, melting at 204-204.5° C. 1H-NMR δppm 1.50 (s, 9H, tert-Bu), 1.63 (s, 3H, Ar-CH3), 2.25 (s, 6H, di-CH3) 3.75 (s, 6.26 (d, 1H, Ar), 6.93-7.20 (m, 5H, Ar).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:20])=[N:18][CH:19]=1.CON(C)[C:24]([C:26]1[N:27]([CH2:31][CH3:32])[N:28]=[CH:29][CH:30]=1)=[O:25]>O1CCCC1>[Br:13][C:14]1[CH:15]=[C:16]([C:24]([C:26]2[N:27]([CH2:31][CH3:32])[N:28]=[CH:29][CH:30]=2)=[O:25])[C:17]([F:20])=[N:18][CH:19]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CCn1nccc1C(=O)N(C)OC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCn1nccc1C(=O)c1cc(Br)cnc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diisopropylamine and tetrahydrofuran were combined and cooled to −20° C. n-Butyl lithium (2.5M in hexanes) was slowly added and the resulting mixture stirred at this temperature for 30 minutes. The temperature was lowered to −78° C. and neat 5-bromo-2-fluoropyridine was added (internal temperature was not allowed to exceed −68° C.). The reaction mixture was stirred at −78° C. for 40 minutes. The resulting mixture was added to a solution of 2-ethyl-2H-pyrazole-3-carboxylic acid methoxy-methyl-amide in tetrahydro-furan. The combined reaction mixture was stirred at −78° C. for 1 hour before the reaction mixture was slowly warmed to room temperature, and quenched with saturate aqueous ammonium chloride solution. The reaction mixture was extracted with dichloromethane, dried over sodium sulfate, and concentrated. The crude material was purified by flash chromatography on silica gel to afford (5-bromo-2-fluoro-pyridin-3-yl)-(2-ethyl-2H-pyrazol-3-yl)-methanone. MS: m/z 298.1+300.1 (M+H+).