Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:17])[CH:11]=3)[C:6](=[C:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:5]=2[CH:4]=1.[OH:26][C@@H:27]1[CH2:32][CH2:31][C@H:30]([CH2:33][C:34](O)=O)[CH2:29][CH2:28]1.C1(N=C=NC2CCCCC2)CCCCC1.C(NC1CCCCC1)(NC1CCCCC1)=O>C(Cl)Cl>[OH:26][C@@H:27]1[CH2:32][CH2:31][C@H:30]([CH2:33][CH2:34][N:21]2[CH2:20][CH2:19][C:18](=[C:6]3[C:5]4[CH:4]=[C:3]([C:2]([F:1])([F:24])[F:25])[CH:16]=[CH:15][C:14]=4[S:13][C:12]4[C:7]3=[CH:8][CH:9]=[C:10]([F:17])[CH:11]=4)[CH2:23][CH2:22]2)[CH2:29][CH2:28]1
Reactant: Fc1ccc2c(c1)Sc1ccc(C(F)(F)F)cc1C2=C1CCNCC1
Reactant: O=C(O)C[C@H]1CC[C@@H](O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Solvent: ClCCl
Product: O[C@H]1CC[C@@H](CCN2CCC(=C3c4ccc(F)cc4Sc4ccc(C(F)(F)F)cc43)CC2)CC1
Reaction time: 8 h

Procedure:
7.3 Grams of 4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)-piperidine were dissolved in 50 milliliters of dry methylene chloride. Then 3.8 grams of cis-4-hydroxycyclohexane acetic acid (J.Am.Ch.Soc. 70, pg. 1898-99 (1948) and 5 grams of dicyclohexylcarbodiimide were added. The mixture was heated at temperatures from 22 to 30 degrees Centigrade during which the dicyclohexylurea formed separated out and was then left standing overnight. The precipitate was filtered from the solution which was then evaporated, and the residue was dissolved in ether. The solution was washed with dilute hydrochloric acid, dried over anhydrous potassium carbonate, filtered and evaporated. The residue, which was an oil, wad dried by evaporation in vacuum with toluene and consisted of somewhat impure 1-(cis-4-hydroxycyclohexylmethylcarbonyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine which was used without further purification in the next step. The oil was dissolved in dry ether, and 2 grams of lithium aluminium hydride were added in small portions. The mixture was heated under reflux for one hour. Then water was added dropwise until the precipitate formed clotted. The ether phase was decanted, the precipitate washed thoroughly with ether, the combined ether phases were dried over anhydrous potassium carbonate and treated with active carbon and filtered. The ether was evaporated, and 1-(cis-4-hydroxycyclohexylethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine was obtained as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13](Cl)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[CH:4][CH:3]=1.[SH:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([S:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(S)cc1
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Br)cc1)c1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A solution of the product of Example 57a (553 mg, 1.557 mmol) in anhydrous DMF (15 mL) was treated with 4-mercaptophenol (196 mg, 1.557 mmol) and cesium carbonate (1.015 g, 3.114 mmol) at room temperature, then heated at 100° under a nitrogen atmosphere for 3 hours. The reaction was cooled to room temperature and the solvent concentrated under vacuum giving the title compound. The residue was taken up in H2O (30 mL) and the pH adjusted to 3 with 1N aqueous HCl. The aqueous was then extracted with ethyl acetate, and the combined organic extracts washed with brine (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated under vacuum giving the title compound. The residue was triturated with methylene chloride and purified by silica gel flash chromatography with a gradient of 6% to 30% ethyl acetate/methylene chloride to afford the title product as a dark yellow solid (517 mg, 1.16 mmol, 75%).
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:18])[O:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7].[Li+].[OH-]>C1COCC1.O>[O:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[C:8]([C:6]([NH:5][CH2:4][C:3]([OH:19])=[O:2])=[O:7])[C:9]1=[O:18]
Reactant: COC(=O)CNC(=O)c1cc2ccccc2oc1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1cc2ccccc2oc1=O
Temperature: 25 °C

Procedure:
A solution of coumarin-3-carbonylamino-acetic acid methyl ester (312 mg, 1.19 mmol), in THF (12 ml) under Ar atmosphere, at 0° C. (ice bath), a solution of LiOH in H2O (0.2 M) was added dropwise. The reaction mixture was stirred vigorously at room temperature until total conversion was observed by TLC (2 hours). The solution was partially concentrated and Et2O was added (10 ml). The organic layer was washed with NaHCO3 (10 ml, sat) and the combined aqueous layers were acidified with boo KHSO4 (pH=3-4) and extracted with ether (3×20 ml). The organic layer was concentrated at reduced pressure to afford 8G9C1 (280 mg, 95%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[C:6]([CH2:13][CH3:14])=[C:5]2[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].O.[CH2:30]([O:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>COCCOC>[CH2:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([C:2]2[CH:3]=[C:4]3[N:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=24)[C:6]([CH2:13][CH3:14])=[C:5]3[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:40][CH:39]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCc1c(-c2ccc(OC)cc2)c2cc(Br)c3cccc1n32
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCc1c(-c2ccc(OC)cc2)c2cc(-c3ccc(OCc4ccccc4)cc3)c3cccc1n32
Temperature: 87.5 °C
Reaction time: 0.17 h
Yield: 67.8 %

Procedure:
4-Bromo-1-ethyl-2-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine (0.354 g, 1.0 mmol), prepared in example 75, step 2, was dissolved in 15 ml of 1,2-dimethoxyethane under a nitrogen atmosphere. tetrakistriphenylphospine palladium(0) (0.06 g, 0.052 mmol) was added, and the mixture was stirred for 10 minutes. Sodium carbonate (0.65 g, 6.13 mmol) and water 2 ml was added and stirring was continued for 10 minutes. 4-Benzyloxyphenyl boronic acid (0.91 g, 3.99 mmol) dissolved in 10 ml of hot 1,2-dimethoxyethane was added and the mixture was heated to 85-90° C. for 18 hours. The suspension was poured into 100 ml of water and the organic material was extracted into dichloromethane (1×100 ml and 3×50 ml). The combined organic layers were washed with brine, dried overmagnesium sulfate, and evaporated. The crude product was purified by column chromatography over silica gel 60, using 3% of diethyl ether in hexane as the eluent to afford a yellow solid, which was recrystallised from dichloromethane and petroleum ether, to afford 0.31 g (68%) of 4-(4-benzyloxyphenyl)-1-ethyl-2-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine as yellow crystals. MS(SP): m/z 457 (M+). 1H--NMR (CDCl3, 400 MHz) δ: 1.48 (t, 3 H); 3.25 (q, 2 H); 3.91 (s, 3 H); 5.14 (s, 2 H); 7.07-7.13 (m,4 H); 7.31-7.51 (m, 5 H); 7.67 (dd, 1 H); 7.70 (s, 1 H); 7.73-7.82 (m, 4 H); 7.92 (d, 1 H); 8.13 (d, 1 H). Analysis: Calculated for C32H27N1O2 : C, 84.00; H, 5.95; N, 3.06%; Found: C, 84.07; H, 6.02; N, 2.90%.
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[S:9]([C:12]1[CH:27]=[CH:26][C:15]([C:16]([O:18]CC2C=CC=CC=2)=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[S:9]([C:12]1[CH:27]=[CH:26][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN(Cc2ccccc2)S(=O)(=O)c2ccc(C(=O)OCc3ccccc3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CN(Cc2ccccc2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Yield: 42.3 %

Procedure:
Benzyl 4-(N-benzyl-N-(4-methoxybenzyl)sulfamoyl)benzoate (Example 5-1a) (517 mg, 1 mmol) was stirred a 10/1/2 solution of 6N NaOH (aq)/THF/MeOH (27 mL) at ambient temperature for 6 hours. The solution was acidified with 3N HCl (aq) to a pH of ˜3 (ca. 50 mL), and the aqueous phase was extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate and concentrated on the rotovap. The residue was taken up in MeOH (15 mL) and purified by reverse phased HPLC (5-95% acetonitrile in H2O gradient:25 minutes) in three 5 mL aliquots. The pure fractions were combined and concentrated to a white solid. The product was dissolved in 15 mL of absolute ethanol and evaporated on the rotovap (4×) to provide pure 4-(N-benzyl-N-(4-methoxybenzyl)sulfamoyl)benzoic acid (174 mg, 42%) as a white solid. M.p 161-163° C. 1H NMR (CDCl3, 400 MHz): 3.78 (s, 3H), 4.32 (s, 2H), 4.36 (s, 2H), 6.78 (d, J=8.4 Hz, 2H), 6.99 (d, J=8.8 Hz, 2H), 709-7.07 (m, 2H), 7.27-7.24 (m, 3H), 7.93 (d, J=8.8 Hz, 2H), 8.24 (d, J=8 Hz, 2H). MS 412 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][C@@H:10]2[CH2:14][CH2:13][O:12][CH2:11]2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[NH2:16][CH:17]1[CH2:22][CH2:21][C:20]([CH3:24])([OH:23])[CH2:19][CH2:18]1>>[O:12]1[CH2:13][CH2:14][C@@H:10]([O:9][C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([NH:16][CH:17]3[CH2:22][CH2:21][C:20]([CH3:24])([OH:23])[CH2:19][CH2:18]3)[N:4]=2)[CH2:11]1
Reactant: Clc1ncc(Br)c(O[C@@H]2CCOC2)n1
Reactant: CC1(O)CCC(N)CC1
Agent: Cl
Product: CC1(O)CCC(Nc2ncc(Br)c(O[C@@H]3CCOC3)n2)CC1

Procedure:
Using the procedure of Example 78, Step 2, (R)-5-bromo-2-chloro-4-(tetrahydrofuran-3-yloxy)pyrimidine was reacted with 4-amino-1-methylcyclohexanol HCl salt to provide the title compound. MS (ESI) m/z: Found: 372 (M++1), Calc. 371 (M+).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](=[O:23])[N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:12][CH:11]=1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[O:23]=[C:17]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH2:8])=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CC(=O)N2CCCC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCc1ccc(CC(=O)N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.5 %

Procedure:
Dissolve N-(tert-butoxycarbonyl)-4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-benzylamine (267 mg, 0.8 mmol) in DCM (4 mL). Add 4M hydrogen chloride in dioxane (2 mL, 8 mmol) and stir at room temperature for 1 h. Concentrate in vacuo and elute the compound through a SCX column to obtain the title compound (179 mg, 98%). MS (ES+) m/z: 219 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[CH:15][C:14]=3[O:25][CH3:26])[N:10]=[CH:11][C:6]=2[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:33]1([SH:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>CN(C=O)C>[CH:33]1([S:39][C:2]2[C:7]3[N:8]=[C:9]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]5[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=5)=[CH:15][C:14]=4[O:25][CH3:26])[N:10]=[CH:11][C:6]=3[CH:5]=[CH:4][N:3]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: SC1CCCCC1
Reactant: COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(Cl)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(SC3CCCCC3)c2n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 94.6 %

Procedure:
A mixture of 8-chloro-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine (Example 94, 26 mg, 0.071 mmol) and potassium carbonate (15 mg, 0.109 mmol) in DMF (0.35 mL) was treated with cyclohexanethiol (12 μL, 0.098 mmol) and stirred at room temperature for 4 days. An additional batch of potassium carbonate (10 mg, 0.07 mmol) and thiol (12 μL, 0.098 mmol) were added and the mixture stirred at 50° C. for 18 hours. The reaction was quenched with brine and extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 80% EtOAc in cyclohexane to give the title compound (30 mg, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18](I)=[C:17]([O:22][CH3:23])[CH:16]=2)[N:10]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[C:32]#[CH:33].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:33]#[C:32][C:26]3[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=3[Cl:24])=[C:17]([O:22][CH3:23])[CH:16]=2)[N:10]=1
Reactant: C#Cc1cc(Cl)ccc1Cl
Reactant: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C#Cc1cc(Cl)ccc1Cl
Yield: 18.6 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using 3-(2-chloro-6-fluorophenyl)-1-(4-iodo-3-methoxyphenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-32, 0.050 g, 0.11 mmol), 1,4-dichloro-2-ethynylbenzene (Intermediate-23, 0.029 g, 0.16 mmol), TBAF (0.101 g, 0.33 mmol), bis(triphenylphosphine)palladium(II) chloride (0.005 g, 0.04 mmol) and DMSO (3.0 mL) at 80° C. to afford 0.010 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 3.89 (s, 3H), 7.49-7.56 (m, 3H), 7.59-7.73 (m, 6H), 12.90 (br s, 1H); MS (m/z): 487.95 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[CH2:16]O.P(Br)(Br)[Br:19].C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[C:10]1([CH2:9][O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:16][Br:19])[CH:4]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrP(Br)Br
Reactant: OCc1cc(OCc2ccccc2)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Clc1ccc(OCc2ccccc2)cc1CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.6 %

Procedure:
To a solution of 4-chloro-3-(hydroxymethyl)phenol (for as preparation see Intermediate 12) (3.3 g, 20.8 mmol) in ethanol (30 ml) was added 2 M sodium hydroxide (10 ml, 20 mmol). To the mixture was added dropwise a solution of benzyl bromide (2.48 ml, 20.8 mmol, Aldrich) in ethanol (30 ml). The reaction was stirred under nitrogen overnight at ambient temperature. The ethanol was removed in vacuo to leave a cream solid and the residue partitioned between water (80 ml) and dichloromethane (60 ml). The phases were separated and the aqueous phase extracted with dichloromethane (40 ml). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate (40 ml) and the solvent removed in vacuo to leave a white solid (4.6 g). The sample was loaded in dichloromethane and purified on silica (2×100 g) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give {2-chloro-5-[(phenylmethyl)oxy]phenyl}methanol as a clear oil (4.12 g). To a solution of {2-chloro-5-[(phenylmethyl)oxy]phenyl}methanol (1.22 g, 4.91 mmol) in DCM (25 ml) at −10 to −15° C., under nitrogen, was added a solution of phosphorus tribromide (0.463 ml, 4.91 mmol, Aldrich) in DCM (10 ml) dropwise. The solution was allowed to warm to ambient temperature and stirred for 3 h under nitrogen. To the reaction mixture in an ice-bath was added dropwise saturated aqueous sodium hydrogen carbonate (15 ml). The mixture was diluted with water (80 ml) and DCM (100 ml). The phases were separated and the aqueous phase washed with DCM (60 ml). The combined organic extracts were washed with water (50 ml). The organic extract was dried (MgSO4), filtered and the solvent removed in vacuo to give 3-(bromomethyl)-4-chlorophenyl phenylmethyl ether as a colourless gum (1.11 g).
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C:8](=[O:15])[CH2:7]2.[CH:16](OCC)=[O:17]>C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C:8](=[O:15])[C:7]2=[CH:16][OH:17]
Reactant: COc1cc2c(cc1OC)NC(=O)C2
Reactant: CCOC=O
Agent: [Na]
Solvent: CCO
Product: COc1cc2c(cc1OC)C(=CO)C(=O)N2

Procedure:
To a warm solution of 1.5 g. sodium in 35 ml. ethanol was added 10 g. of 5,6-dimethoxy oxindole [J. Am. Chem. Soc. 77 3844 (1955)]. Then 30 ml. ethyl formate was added. A solid formed. The mixture was stirred and heated 10 minutes. A stream of nitrogen was blown over the mixture to evaporate as much solvent as possible. Then a solution of 6.5 ml. concentrated hydrochloric acid and 50 ml. water was added. The resulting clear solution was concentrated in vacuum and the resulting solid filtered and washed with ice water. Yield: 10.55 g., m.p. 216°-217° C.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:11][C:12]1[CH:13]=[C:14]([NH:18][C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:15]=[CH:16][CH:17]=1>CN1CCCC1=O.C(=O)([O-])O.[Na+]>[CH2:22]([NH:21][C:19]([NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([NH:11][C:2]2[C:3]3[NH:10][CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:13]=1)=[O:20])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cccc(NC(=O)NCc2ccccc2)c1
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(NCc1ccccc1)Nc1cccc(Nc2ncnc3cc[nH]c23)c1
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 41.6 %

Procedure:
To a solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (100 mg) in 1-methyl-2-pyrrolidone (1.3 mL), was added N-(3-aminophenyl)-N′-benzylurea (220 mg), and the mixture was heated to 140° C. and stirred for 1.5 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (20 mL), and extracted with a mixed solvent (30 mL×3) of ethyl acetate/tetrahydrofuran (1/1). The organic layer washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluent:ethyl acetate/methanol=100/0→85/15). The object fraction was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (97 mg) as pale-yellow powder crystals.
Reaction SMILES: C(OC([N:8]1[CH2:28][CH2:27][C:12]2=[C:13]([N:20]3[CH2:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=O)(C)(C)C.[ClH:29]>C(Cl)Cl.O1CCOCC1>[O:23]1[CH2:24][CH2:25][CH2:26][N:20]([C:13]2[N:14]3[C:18]([N:19]=[C:11]4[CH2:10][CH2:9][NH:8][CH2:28][CH2:27][C:12]=24)=[CH:17][CH:16]=[N:15]3)[CH2:21][CH2:22]1.[ClH:29]
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(N3CCCOCC3)c2CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: c1cc2nc3c(c(N4CCCOCC4)n2n1)CCNCC3
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 88 mg (0.23 mmol) 10-[1,4]oxazepan-4-yl-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in 3 mL DCM, was added 1.13 mL (4.5 mmol) HCl in dioxane (4 M), and the reaction was stirred at room temperature for 16 hours. The solvent was evaporated to give the desired product as a HCl salt.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8](C(=O)CCl)[C:7]=2[CH:6]=1)=[O:4].[ClH:23]>C(O)(=O)C>[Cl:23][CH2:2][C:3]([C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[CH:6]=1)=[O:4]
Reactant: O=C(CBr)c1ccc2c(c1)N(C(=O)CCl)c1ccccc1S2
Reactant: Cl
Solvent: CC(=O)O
Product: O=C(CCl)c1ccc2c(c1)Nc1ccccc1S2
Yield: 82 %

Procedure:
2-bromo-1-[10-(chloroacetyl)-10H-phenothiazin-2-yl)ethanone (2.2 g; 5.55 mmol; prepared according to a protocol described in J. Heterocyclic. Chem.(1978), 15, 175, followed by a Friedel-Crafts reaction) is dissolved hot in a mixture of acetic acid (20 ml) and 20% HCl (5.5 ml) and the mixture obtained is heated under reflux for 30 minutes. The reaction mixture is allowed to cool down, the precipitate is filtered, the mixture rinsed with acetic acid (5 ml) and dried under Vacuum, the solid obtained is purified by crystallization from toluene in order to produce a brown product with a yield of 82%. Melting point: 190-191° C. (value in the literature: 197-198° C.).
Reaction SMILES: [CH-:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li+].[CH3:11]OS(OC)(=O)=O.O>C(OCC)C>[CH3:11][C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]=1
Reactant: c1ccc2[cH-]ccc2c1
Reactant: COS(=O)(=O)OC
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC1=CCc2ccccc21
Yield: 94.6 %

Procedure:
Lithium indenide (9.60 g, 0.0786 moles) in diethylether (100 mL) was added dropwise to a solution of dimethylsulfate (9.91 g, 0.0786 moles) in diethylether (125 mL) over a period of 15 minutes. After the addition was complete, H2O (150 mL) was added to the reaction. The organic layer was then separated and washed with H2O (2×100 mL). Drying over MgSO4 followed by filtration and solvent removal yielded the desired product as a yellow oil (9.68 g, 94.7 percent).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[NH2:12][CH2:13][C:14]1([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:12][CH2:13][C:14]1([N:20]2[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:6]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CN1CCN(C2(CN)CCCCC2)CC1
Solvent: O
Solvent: c1ccccc1
Product: CN1CCN(C2(CNC(=O)c3ccc(Cl)c(Cl)c3)CCCCC2)CC1
Yield: 49.3 %

Procedure:
A solution of 3,4-Dichlorobenzoylchloride (1.05 g.,) in benzene (10 ml) was added dropwise over 40 mins. to a stirred solution of 1-[1-(Aminomethyl)cyclohexyl]-4-methyl piperazine (1.06 g.,) in benzene (15 ml). The mixture was heated under reflux for 1 hr. on a steambath and the solution was evaporated. The solid residue was dissolved in ethanol, acidified with ethereal HCl and evaporated to give a white solid. This solid was suspended in water made alkaline with 5NNaOH and extracted with chloroform (x2). The combined chloroform extracts were dried (anhyd.Na 2 SO4) and evaporated. The solid residue was dissolved in hot petroleum ether (80°-100°) decolourised with charcoal and crystallised from petroleum ether (80°-100° ) to give 1-[1-(3,4 Dichlorobenzamido methyl) cyclohexyl] -4-methyl piperazine (0.95 g; 49%) m.p. 143° -146°.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([CH3:9])[CH:8]=1.[N:11]([O-])=[O:12].[Na+]>C(O)C.O>[CH3:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([CH3:9])[C:8]=1[N:11]=[O:12]
Reactant: O=N[O-]
Reactant: Cc1cc(C)cc(O)c1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(O)cc(C)c1N=O
Temperature: 0 °C
Yield: 71.6 %

Procedure:
750 ml of concentrated HCl are added to a solution of 3,5-dimethyl phenol (80.6 g) in 750 ml of 95% ethyl alcohol. The mixture is cooled to 0° C. in an ice/methanol bath. While maintaining the temperature of the reaction mixture below 5° C., a solution of NaNO2 (69.0 g) in 150 ml of H2O is added dropwise to the reaction mixture. The mixture is stirred at 0° C. for more than an hour and then poured into 9 liters of water. The aqueous mixture is filtered to give a yellow solid which is recrystallized from hot methanol and filtered to give 71.45 grams of a yellow solid, M.P. 180°-181° C. (dec).