Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:9]=[CH:8][CH:7]=[C:6]2[O:20][C:21]1[C:22]([CH3:31])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2>C(N(CC)CC)C.CN(C)C=O.[OH-].[Pd+2].[OH-]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:9]=[CH:8][CH:7]=[C:6]2[O:20][C:21]1[C:22]([CH3:31])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: CCOC(=O)C=Cc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
Ethyl 3-[6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yl]-acrylate (compound 413) (310 mg) was dissolved in triethylamine/N,N-dimethylformamide (2.5 ml/13 ml) to prepare a solution. 20% palladium hydroxide (1.27 g) was added to the solution, and the mixture was stirred under a hydrogen gas atmosphere at room temperature overnight. The reaction solution was filtered, and the solvent was then removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give ethyl 3-[6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yl]-propionate (80 mg, yield 26%).
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[N:19]([CH2:20][CH2:21][O:22][CH2:23][CH2:24][OH:25])[C:18]4[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=4[N:16]=3)[CH2:10][CH2:9]2)C=CC=CC=1.[H][H]>[Pd].CO>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:19]([CH2:20][CH2:21][O:22][CH2:23][CH2:24][OH:25])[C:18]3[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=3[N:16]=2)[CH2:10][CH2:9]1
Reactant: OCCOCCn1c(NC2CCN(Cc3ccccc3)CC2)nc2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: OCCOCCn1c(NC2CCNCC2)nc2ccccc21
Yield: 46 %

Procedure:
A mixture of 140 parts of 2-[2-[2-[[1-(phenylmethyl)-4-piperidinyl]amino]-1H-benzimidazol-1-yl]ethoxy]ethanol and 480 parts of methanol was hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over diatomaceous earth and the filtrate was evaporated. The residue was crystallized twice from acetonitrile. The product was filtered off and dried, yielding 53.3 parts (46.0%) of 2-[2-[2-(4-piperidinylamino)-1H-benzimidazol-1-yl]ethoxy]ethanol; mp. 163.7° C. (compound 38).
Reaction SMILES: [S:1]1(=O)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[N:2]1.CN1CCN(C)C1=O.[Cl:19]C1C=CC=CC=1>>[Cl:19][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][N:2]=1
Reactant: O=S1N=Cc2ccccc21
Reactant: Clc1ccccc1
Solvent: CN1CCN(C)C1=O
Product: Clc1nsc2ccccc12
Yield: 92.7 %

Procedure:
Example 5 was repeated, except that 4 kg of 93% by weight pure benzisothiazolone and 90 g of 1,3-dimethylimidazolidinone in 5 l of chlorobenzene were phosgenated. To obtain the reaction product, 200 ml of high boiling paraffin oil were added prior to the vacuum distillation, and a Vigreux column of 20 cm in length was used. 3-Chlorobenzisothiazole of a purity of 99.4% by weight was obtained in a yield of 92.7% of theory.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4]1)[CH3:2].FC(F)(F)C(O)=O.N1CC[C@@H](C(OCC2C=CC=CC=2)=O)C1>>[CH2:1]([N:3]1[CH2:7][CH2:6][C@@H:5]([C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])[CH2:4]1)[CH3:2]
Reactant: CCN1CC[C@H](C(=O)OCc2ccccc2)C1
Agent: O=C(OCc1ccccc1)[C@@H]1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: CCN1CC[C@@H](C(=O)OCc2ccccc2)C1

Procedure:
Prepared by proceeding in a simialr manner to Intermediate 190, starting from benzyl (R)-pyrrolidine-3-carboxylate trifluoroacetic acid salt (Intermediate 198).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[CH2:18][CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[BrH:32].BrBr>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH2:16][Br:32])=[CH:11][C:10]=1[CH2:18][CH2:19][O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(CCOCc2ccccc2)c1
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccc(OCc2ccccc2)c(CCOCc2ccccc2)c1
Temperature: 25 °C

Procedure:
4'-Benzyloxy-3'-(2-benzyloxyethyl)acetophenone (8.0 g) and 0.4 ml of 30% hydrogen bromide acetic acid solution were dissolved in 80 ml of chloroform, and a solution of 1.1 ml of bromine in 30 ml of chloroform was added to the solution dropwise during 2 hours with stirring at room temperature. The reaction solution was concentrated under reduced pressure and the resulting residue was purified by silica gel medium pressure liquid column chromatography (eluent: hexane/diethyl ether=2/1) to give 3.9 g of 4'-benzyloxy-3'-(2-benzyloxyethyl)-2-bromoacetophenone having a melting point of 53 to 56° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)([O-:13])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: ClCCCN1CCCCC1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(OCCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a three-necked flask fitted with an overhead mechanical stirrer, a mixture of 1-(3-chloropropyl)piperidine (49.8 g, 0.308 mol), 4-nitrophenol (42.8 g, 0.308 mol) and potassium carbonate (212 g, 1.53 mol), in anhydrous DMF (200 mL) was heated to 94° C. and stirred for 18 h. The mixture was cooled to room temperature, then diluted with 2 L water. The organics were taken up in ethyl acetate and washed twice with 2N sodium hydroxide and then brine. The combined organics were dried over magnesium sulfate then concentrated under reduced pressure to give the title compound as a yellowish oil.
Reaction SMILES: [Si:1]([O:18][C@@H:19]1[CH2:24][C@H:23]([O:25][Si](CC)(CC)CC)[CH2:22][C@@H:21]([OH:33])[C:20]1=[CH2:34])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])(=O)=O>ClCCl>[Si:49]([O:33][C@H:21]1[C:20](=[CH2:34])[C@H:19]([O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:24][C:23](=[O:25])[CH2:22]1)([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50]
Reactant: C=C1[C@H](O)C[C@@H](O[Si](CC)(CC)CC)C[C@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C=C1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)C[C@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
The compound of Example 13D (8.5 g, 17 mmol) was dissolved in 50 mL of dichloromethane; 4.4 mL of 2,6-lutidine was added, and the resultant solution was cooled to 0° C. tert-Butyldimethylsilyl trifluoromethanesulfonate (5.9 mL) was added, and the mixture was stirred for 1 hour. The reaction was quenched by the addition of saturated aqueous NH4Cl, the solvents were removed in vacuo, and the residue was partitioned between ethyl acetate and water. The organic phase was washed with 1 N aqueous HCl, then brine, and dried over Na2SO4. The solvents were removed in vacuo; the residue was purified by chromatography on an Analogix IntelliFlash 280™, eluting with a gradient of 2% to 5% ethyl acetate in hexanes. The product (9.3 g) was dissolved in 75 mL of ethanol; pyridinium p-toluenesulfonate (390 mg) was added, and the mixture was stirred at ambient temperature for 1 hour. The solvents were removed in vacuo; the residue was purified by chromatography on an Analogix Intelliflash 280™, eluting with a gradient of 9% to 17% ethyl acetate in hexanes. A sample of this product (5.8 of 6.8 g) was dissolved in 30 mL of dichloromethane; 3.0g of NaHCO3 was added, and the mixture was cooled to 0° C. Dess-Martin reagent (5.9 g) was added, and stirring was continued for 2 hours. The solvents were removed in vacuo, and the residue was partitioned between ethyl acetate and water. The organic phase was washed with 1 N aqueous HCl, then brine, and dried over Na2SO4. The organic phase was passed through a plug of silica gel and concentrated in vacuo, giving the titled compound (5.5 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH2:11][CH2:12][NH:13][C:14]([NH:18][C:19]#[N:20])=[N:15][CH2:16][CH3:17])=[N:7][C:6]=2[CH:21]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([CH2:11][CH2:12][NH:13][C:14]([NH:18][C:19]#[N:20])=[N:15][CH2:16][CH3:17])=[O:30])=[N:7][C:6]=2[CH:21]=1
Reactant: CCN=C(NC#N)NCCSc1nc2cc(Cl)ccc2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCN=C(NC#N)NCCS(=O)c1nc2cc(Cl)ccc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
Dissolved in 8 ml of methylene chloride were 0.20 g (0.59 mmol) of the compound obtained in Example 27, and 0.15 g (0.59 mmol) of m-chloroperbenzoic acid with a 70% purity were added to the solution, which was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue was purified by silica gel chromatography to obtain 0.20 g of white crystalline powders (95% yield).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:33])([CH3:32])[C:4]2[C:9]([C:10](=[O:23])[C:11]=1[C:12]([NH:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])=[O:13])=[CH:8][CH:7]=[C:6]([C:24]#[C:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:5]=2>C(O)(C(F)(F)F)=O>[OH:1][C:2]1[C:3]([CH3:33])([CH3:32])[C:4]2[C:9]([C:10](=[O:23])[C:11]=1[C:12]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])=[CH:8][CH:7]=[C:6]([C:24]#[C:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH:5]=2
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)C(C)(C)c2cc(C#Cc3ccccc3)ccc2C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(O)=C(C(=O)NCC(=O)O)C(=O)c2ccc(C#Cc3ccccc3)cc21

Procedure:
Tert-butyl 2-(2-hydroxy-1,1-dimethyl-4-oxo-7-(2-phenylethynyl)-1,4-dihydronaphthalene-3-carboxamido)acetate (68 mg, 153 μmol) was dissolved and stirred in TFA (2 mL) at room temperature for 30 minutes. The reaction was concentrated, suspended in hexanes, filtered, washed with hexanes, and dried in a vacuum oven to give the title compound. MS (ESI) m/z: Calculated; 389.4: Observed; 390.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:21][CH2:22][CH2:23][NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Cl)(=[O:27])=[O:26]>C(N(C(C)C)C(C)C)C>[OH:21][CH2:22][CH2:23][NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:14][CH2:13]1)(=[O:27])=[O:26]
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=S(=O)(CCCCCCCl)NCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1)NCCO
Yield: 91.5 %

Procedure:
1-[(4-Chlorophenyl)phenylmethyl]piperazine (573.6 mg, 2.00 mmol) and N-(2-hydroxyethyl)-6-chlorohexanesulfonamide (487.5 mg, 2.00 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-(2-hydroxyethyl)-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfonamide (904.4 mg) as a pale yellow oil (yield: 91.5%).
Reaction SMILES: C[O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:4]=1[C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=1)=[O:6].C(NCCCC)CCC.Cl.O>CN(C)C(=O)C>[CH3:23][O:22][C:20]1[C:19]([O:24][CH3:25])=[CH:18][C:4]([C:5]([NH:7][C:8]2[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=2)=[O:6])=[C:3]([OH:2])[CH:21]=1
Reactant: CCOC(=O)c1csc(NC(=O)c2cc(OC)c(OC)cc2OC)n1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCCCNCCCC
Product: CCOC(=O)c1csc(NC(=O)c2cc(OC)c(OC)cc2O)n1
Temperature: 0 °C
Yield: 92.5 %

Procedure:
A suspension (30 ml) of 2-[N-(2,4,5-trimethoxybenzoyl)amino]-4-(ethoxycarbonyl)-1,3-thiazole (10.0 g) in N,N-dimethylacetamide was allowed to dissolve with heat at a temperature of at least 150° C., and di-n-butylamine (8.8 g) was added dropwise to the solution, refluxed for 5 hours. The reaction mixture was allowed to cool, poured into a mixture of 1 N hydrochloric acid (100 ml) and ice water (100 ml), and further, water was added thereto. The crystals so precipitated were collected by filtration, washed with water, and then subjected to air drying and drying under reduced pressure to thereby obtain crude crystals (10.0 g). The crystals were followed by recrystallization from 1,4-dioxane, thereby 8.9 g of 2-[N-(4,5-dimethoxy-2-hydroxybenzoyl)amino]-4-(ethoxycarbonyl)-1,3-thiazole was obtained (yield: 82.3%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:19](O)=[O:20])=[N:4][C:5]2[C:17]=1[C:16]([CH3:18])=[C:15]1[C:7](=[N:8][C:9]3[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=2.[C:22](C1NC=CN=1)([C:24]1[NH:25]C=C[N:28]=1)=O.[N-]1C=CN=C1.[H-].[Na+]>O1CCCC1>[CH3:1][C:2]1[C:3]([C:19]2[O:20][N:28]=[C:24]([CH3:22])[N:25]=2)=[N:4][C:5]2[C:17]=1[C:16]([CH3:18])=[C:15]1[C:7](=[N:8][C:9]3[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:6]=2
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC1=c2c(cc3c(c2C)-c2ccccc2N=3)N=C1C(=O)O
Agent: [H-]
Agent: [Na+]
Agent: c1c[n-]cn1
Solvent: C1CCOC1
Product: CC1=c2c(cc3c(c2C)-c2ccccc2N=3)N=C1c1nc(C)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.8 %

Procedure:
3,4-Dimethylpyrrolo[2,3-b]carbazole-2-carboxylic acid (0.5 g, 1.8 mmol) and carbonyl diimidazole (0.34 g, 2 mmol) were dissolved in freshly distilled tetrahydrofuran (20 ml) in an oven-dried flask under a nitrogen atmosphere. The resulting orange solution was stirred at room temperature for two hours, by which time it was an orange suspension, and complete conversion of the acid to the imidazolide intermediate was verified by TLC. Meanwhile, in a second oven-dried flask, methylamidoxime (0.27 g, 3.6 mmol) was dissolved in THF (10 ml). To this was added crushed 3 Å sieves and the mixture was stirred at room temp for 45 mins. Sodium hydride (60% dispersion in mineral oil, 0.243 g, 6.12 mmol) was added and the mixture stirred for a further 2 hours. The contents of the two flasks were combined and stirred at room temp for 18 hours, by which time TLC showed complete consumption of the imidazolide intermediate. The solvent was removed in vacuo to give a yellow solid. Chromatography on silica (eluting with ethyl acetate/hexane 1:2) gave the pure yellow product (0.044 g, 8%) with m.p. 248°-249° C. (Found: C, 71.97; H, 5.07; N, 17.21. C19H16N4O.0.05EtOAc requires: C, 71.89; H. 5.15; N, 17.47%); δH [2H6 ]-DMSO 11.54 (1H s, 1-NH), 10.92 (1H, s, 9-NH), 8.17 (1H, d, J 7.5, 5-H), 7.41-7.28 (2H, m, 7-H, 8-H), 7.19 (1H, s, 10-H), 7.16-7.06 (1H, m, 6-H), 3.18 and 3.00 (2×3H, 2×s, 3-CH3 and 4-CH3), 2.43 (3H, s, 3'-CH3); m/z (%) 316 (100, M+), 260 (19), 232 (31).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[OH-].[K+].Cl.[CH2:17]([OH:19])[CH3:18]>O>[CH2:17]([O:19][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6])[CH3:18]
Reactant: CCO
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOc1cc(C(=O)O)ccc1[N+](=O)[O-]
Yield: 99 %

Procedure:
3-fluoro-4-nitrobenzoic acid (Apollo Scientific; 15 g, 81 mmol) and potassium hydroxide (10.5 g, 186.3 mmol) were stirred together in ethanol (150 mL) at ambient temperature. The reaction mixture was slowly heating to reflux over 10 minutes. The reaction refluxed vigorously and a solid precipitate formed. The reaction was cooled, diluted with water (100 mL) and acidified with 2N HCl to give a precipitate which was filtered, washed with water and air dried to yield the title compound as a pale brown solid (16.88 g, 99%)
Reaction SMILES: C[Li].O1CCCC1.[CH2:8]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[C:26]([NH:27][C:28]([C:31]#N)([CH3:30])[CH3:29])=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(OCC)C>[CH2:8]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[C:26]([NH:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C#N)Nc1cccnc1N1CCN(Cc2ccccc2)CC1
Agent: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)Nc1cccnc1N1CCN(Cc2ccccc2)CC1

Procedure:
Methyllithium (61 ml, 85 mmol) as a 1.4M solution in diethyl ether is added to 30 ml tetrahydrofuran and cooled to -78°. 1-Benzyl-4-[3-(1-cyano-1-methylethylamino)pyridyl]-piperazine (PREPARATION 95, 7.14 g, 21.28 mmol), dissolved in 30 ml cooled tetrahydrofuran, is cannulated into the methyllithium solution, rinsing in with 10 ml THF. The reaction is stirred at -78° and allowed to warm to 20°-25° overnight. The reaction is cautiously quenched with water, then extracted from water with methylene chloride. The extract is dried over sodium sulfate and concentrated. The concentrate is chromatographed on a 500 g silica gel column, eluting with ethyl acetate/hexane (2/3, v/v), the appropriate fractions are pooled and concentrated to give the title compound, NMR (300 MHz, CD3OD) 7.44, 7.43-7.07, 6.84-6.80, 3.49, 2.92, 2.52, 1.28 δ.
Reaction SMILES: [K].[CH3:2][S:3][C:4]1[C:9]([F:10])=[CH:8][NH:7][C:6](=[O:11])[N:5]=1.[CH2:12](Br)[C:13]#[CH:14]>CN(C)C=O>[CH2:14]([N:7]1[CH:8]=[C:9]([F:10])[C:4]([S:3][CH3:2])=[N:5][C:6]1=[O:11])[C:13]#[CH:12]
Reactant: C#CCBr
Reactant: CSc1nc(=O)[nH]cc1F
Agent: [K]
Solvent: CN(C)C=O
Product: C#CCn1cc(F)c(SC)nc1=O
Yield: 71 %

Procedure:
The potassium salt of 4-methylthio-5-fluoropyrimid-2-one (0.005 mol) and propargyl bromide (0.06 mol) were stirred together in dimethylformamide (20 ml) for 40 hrs at room temperature. The mixture was then filtered; the filtrate evaporated at reduced pressure (1 mm Hg) and the residue extracted with chloroform (60 ml). The chloroform solution was washed with 1 N NaOH, with water, and dried (MgSO4) before evaporation; yield 71%, m.p. 101°-102° C. (ethyl acetate). (Found: C, 48.50; H, 3.62. Calc. for C8H7SN2O: C, 48.48; H, 3.56).
Reaction SMILES: CP(C)C.C1(OP([N:21]2[C:29]3[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=3)[C:23]([C@H:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[C@H:33]([N:40]=[N+]=[N-])[CH2:32]3)=[CH:22]2)(=O)OC2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C.CO>N1C=CC=CC=1.[OH-].[NH4+].C(N(CC)CC)C>[Cl:30][C:26]1[CH:25]=[C:24]2[C:29](=[CH:28][CH:27]=1)[NH:21][CH:22]=[C:23]2[C@H:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C@H:33]([NH2:40])[CH2:32]1
Reactant: [N-]=[N+]=N[C@@H]1C[C@@H](c2cn(P(=O)(Oc3ccccc3)Oc3ccccc3)c3ccc(Cl)cc23)c2ccccc21
Agent: CP(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CO
Solvent: CCOC(C)=O
Product: N[C@@H]1C[C@@H](c2c[nH]c3ccc(Cl)cc23)c2ccccc21
Temperature: 25 °C

Procedure:
32 g Trimethyl phosphine was added over 2 hours to 19 g [3-((1R,3R)-3-azido-indan-1-yl)-5-chloro-indol-1-yl]-phosphonic acid diphenyl ester in 100 mL pyridine and 36 mL 9N ammonium hydroxide at room temperature. The reaction mixture was stirred over night at room temperature and concentrated in vacuo. Ethyl acetate and water were added. The mixture was made basic with aqueous NaOH and filtered. The organic phase was concentrated in vacuo and was dissolved in ethyl acetate again. The ethyl acetate solution was extracted with 2×250 mL 2N methanesulfonic acid. The aqueous phase was made basic with 9N NaOH to form a precipitate, which was subjected to flash chromatography (ethyl acetate, methanol, triethylamine, silica gel) to give 0.6 g (1R,3R)-3-(5-chloro-1H-indol-3-yl)-indan-1-ylamine. The ethyl acetate phase from above was concentrated in vacuo and was dissolved in 100 mL methanol and 10 mL 30% NaOMe in methanol was added. The reaction mixture was stirred 2 hours at room temperature, concentrated in vacuo and purified by flash chromatography (ethyl acetate, methanol, triethylamine, silica gel) to give further 0.45 g (1R,3R)-3-(5-chloro-1H-indol-3-yl)-indan-1-ylamine.
Reaction SMILES: [CH2:1]([Li])CCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19]([Cl:23])[N:18]=1.IC>O1CCCC1>[Cl:16][C:17]1[C:22]([CH3:1])=[N:21][CH:20]=[C:19]([Cl:23])[N:18]=1
Reactant: [Li]CCCC
Reactant: Clc1cncc(Cl)n1
Agent: CC1(C)CCCC(C)(C)N1
Solvent: C1CCOC1
Solvent: CI
Product: Cc1ncc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of n-butyl lithium (1.6M in hexanes; 29 mL, 47 mmol) in tetrahydrofuran (200 mL) at −30° C. was added 2,2,6,6-tetramethylpiperidine (8.6 mL, 50 mmol). This solution was allowed to warm to 0° C. over 20 minutes then cooled to −78° C. To this solution was added a solution of 2,6-dichloropyrazine (5 g, 34 mmol) in tetrahydrofuran (200 mL) dropwise via cannula. After 30 minutes, iodomethane (21 mL, 340 mmol.) was added. After 1 h, the reaction mixture was quenched with a mixture of EtOH (25 mL), THF (25 mL) and 1N aqueous HCl (5 mL). The reaction mixture was allowed to warm to room temperature then concentrated to a crude oil. The crude oil was partitioned between water (500 mL) and CH2Cl2 (500 mL). The organic layer was washed with brine (250 mL). The first aqueous layer was back-extracted with CH2Cl2 (500 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (EtOAc/Hexanes gradient) to afford 3,5-dichloro-2-methylpyrazine as a yellow oil. LRMS (ESI) calculated for C5H4Cl2N2 [M+H]+, 163.0; found 163.1.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.CO.[C:28]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[CH3:28][O:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Yield: 34.5 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (3.48 g, 10.0 mmol) in toluene (40 mL) was added with methanol (0.486 mL, 12.0 mmol), triphenylphosphine (3.93 g, 15.0 mmol) and a 40% solution of diethyl azodicarboxylate in toluene (6.53 g, 15.0 mmol), and the mixture was stirred at 110° C. for 5 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/ethyl acetate) to obtain tert-butyl 4-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (1.25 g, 34%).