Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19](SC)[N:20]([CH3:23])[C:21](=[O:22])[C:16]=4[C:15]([CH3:26])=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(O)(=O)C>COCCOC.C(O)C.[Ni]>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[CH:19][N:20]([CH3:23])[C:21](=[O:22])[C:16]=4[C:15]([CH3:26])=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CSc1nc2c(c(C)cn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(=O)n1C
Agent: [Ni]
Solvent: COCCOC
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cn(Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c2ncn(C)c(=O)c12
Temperature: 40 °C
Yield: 84.9 %

Procedure:
In a mixture of DME (120 ml) and ethanol (12 ml) was dissolved 7-[4-(4-chlorobenzoyl)benzyl]-3,5-dimethyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (800 mg) followed by addition of acetic acid (672 mg), and the mixture was warmed to 40° C. Then, Raney nickel was added until disappearance of the starting compound had been verified by TLC. The catalyst was then filtered off and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution in that order, and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was allowed to stand, whereupon crystals separated out. This crystal crop was harvested by filtration, rinsed with ethanol and hexane, and dried to provide the title compound (608 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:24]([C:26]4[CH:31]=[C:30]([O:32][CH3:33])[N:29]=[C:28](Cl)[CH:27]=4)=[O:25])=[N:19][C:18]=3[C:17]([O:35][CH3:36])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.C(N(CC)CC)C>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:24]([C:26]4[CH:27]=[CH:28][N:29]=[C:30]([O:32][CH3:33])[CH:31]=4)=[O:25])=[N:19][C:18]=3[C:17]([O:35][CH3:36])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(C(=O)Nc2nc3c(OC)ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)c3s2)cc(Cl)n1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)Nc2nc3c(OC)ccc(C4CCN(C(=O)OC(C)(C)C)CC4)c3s2)ccn1
Reaction time: 6 h
Yield: 30.2 %

Procedure:
To a solution of 0.39 g (0.73 mMol) of 4-{2-[(2-chloro-6-methoxy-pyridine-4-carbonyl)-amino]-4-methoxy-benzothiazol-7-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester in 16.0 ml of methanol and 16.0 ml THF 100 mg of Pd/C (10%) and 0.15 ml triethyl amine were added. The reaction mixture was hydrogenated at 60° C. for 6 h, then filtered and evaporated to dryness in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane 1:1) to yield 0.110 g (30%) 4-{4-methoxy-2-[(2-methoxy-pyridine-4-carbonyl)-amino]-benzothiazol-7-yl}-piperidine-1-carboxylic acid tert-butyl ester as a white foam. ES-MS m/e (%): 499 ([M+H]+, 100).
Reaction SMILES: Cl[CH2:2][CH2:3][NH2:4].[CH3:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[N:15]=[C:16]=[S:17]>>[CH3:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[N:15]=[C:16]1[N:4]([CH:11]2[CH2:10][CH2:9][CH2:8][CH:7]=[CH:6]2)[CH2:3][CH2:2][S:17]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: NCCCl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCCN1C1C=CCCC1

Procedure:
Cyclohex-2-en-1-one was reduced according to Method B2b, Step 1 to afford cyclohex-2-en-1-ol. The alcohol was converted to the 3-bromo-1-cyclohexene according to Method B2b, Step 2. The halide was converted to N-(cyclohex-2-en-1-yl)-N-(2-hydroxyethyl)amine according to Method B2b, Step 3. The alcohol was reacted with SOCl2 according to Method B7a to afford N-(cyclohex-2-en-1-yl)-N-(2-chloroethyl)ammmonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to method C1a to afford 2-(2-methyl -4-nitrophenylimino)-3-(cyclohex-2-en-1-yl)-1,3-thiazolidine.
Reaction SMILES: CC(NC(C)C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][P:21](=[O:28])([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])=[CH:16][CH:15]=1.FC(F)(F)S([Cl:34])(=O)=O.P(=O)([O-])[O-].[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([P:21](=[O:28])([O:22][CH2:23][CH3:24])[O:25][CH2:26][CH3:27])[Cl:34])=[CH:18][CH:19]=1
Reactant: CCOP(=O)(Cc1ccc(Cl)cc1)OCC
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: O=[PH]([O-])[O-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: CCOP(=O)(OCC)C(Cl)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 52.1 %

Procedure:
Under a nitrogen atmosphere a stirred solution of 6.7 grams (0.067 mole) of di(1-methylethyl)amine in 50 mL of tetrahydrofuran was cooled to -78° C., and 29 mL (0.0725 mole) of n-butyllithium (2.5M in hexanes) was added. Upon completion of addition the reaction mixture was stirred at -78° C. for 15 minutes. The reaction mixture was warmed to 0° C. where it stirred for 30 minutes, and then 15.1 grams (0.0575 mole) of diethyl (4-chlorophenyl)methylphosphonate was added. The reaction mixture was cooled to -78° C. In a second reaction vessel under a nitrogen atmosphere, a rapidly stirred solution of 11.4 grams (0.068 mole) of trifluoromethanesulfonyl chloride in 60 mL of tetrahydrofuran was cooled to -78° C., and the cold phosphonate solution prepared above was added. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it stirred for 16 hours. The reaction mixture was stirred with aqueous ammonium chloride solution to quench any further reaction. The organic layer was taken up in diethyl ether and was washed first with an aqueous ammonium chloride solution and then with an aqueous sodium chloride solution. The organic layer was dried with magnesium sulfate and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 10% ethyl acetate in hexane. The appropriate fractions were combined and concentrated under reduced pressure to yield 8.9 grams of diethyl (4-chlorophenyl)chloromethylphosphonate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][NH:11]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>C1C=CC=CC=1>[C:15]([N:14]1[CH2:13][CH2:12][NH:11][C:10]1=[N:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])(=[O:17])[CH3:16]
Reactant: Clc1ccc(N=C2NCCN2)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: CC(=O)N1CCNC1=Nc1ccc(Cl)cc1Cl
Reaction time: 72 h

Procedure:
A solution of 2.3 g 2-(2,4-dichlorophenylimino)imidazolidine and 1.1 g acetic anhydride in 50 ml dry benzene was allowed to stand at room temperature for three days. The white crystalline solid was filtered off and washed with benzene to give the novel compound 1-acetyl-2-(2,4-dichlorophenylimino)imidazolidine, melting point 168°-169° C.
Reaction SMILES: BrBr.[OH-:3].[Na+].[Cl:5][C:6]1[C:11]([CH2:12][CH3:13])=[C:10]([F:14])[CH:9]=[CH:8][C:7]=1[C:15](=[O:17])C.O>O1CCOCC1>[Cl:5][C:6]1[C:11]([CH2:12][CH3:13])=[C:10]([F:14])[CH:9]=[CH:8][C:7]=1[C:15]([OH:17])=[O:3]
Reactant: CCc1c(F)ccc(C(C)=O)c1Cl
Reactant: [OH-]
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1c(F)ccc(C(=O)O)c1Cl
Temperature: 10 °C
Yield: 88.2 %

Procedure:
Bromine (8.94 g) was added to an aqueous solution (35.6 mL) of sodium hydroxide (7.61 g) with stirring at 10° C., and a solution (37.4 mL) of 1-(2-chloro-3-ethyl-4-fluorophenyl)ethanone (3.74 g) in dioxane was added under ice-cooling (sodium chloride-ice bath). The mixture was warmed to room temperature and, after stirring for 1 hr, poured into water and partitioned with chloroform. The aqueous layer was adjusted to pH=3 with concentrated hydrochloric acid, and extracted with ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound as colorless crystals (yield: 3.33 g).
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][C:27]([C:33]#[N:34])=[C:26]2[NH:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[C:38]([F:43])[CH:37]=1>C1COCC1.CN(C=O)C.O>[C:33]([C:27]1[CH:28]=[N:29][C:30]2[C:25]([C:26]=1[NH:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[C:38]([F:43])[CH:37]=1)=[CH:24][C:23]([NH:22][C:1](=[O:6])[C:2]#[C:3][CH3:4])=[CH:32][CH:31]=2)#[N:34]
Reactant: CC#CC(=O)O
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(F)c(F)c1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(F)c(F)c3)c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 60.2 %

Procedure:
Dissolved 425 mg (5.06 mmol) 2-butynoic acid in 40 ml THF and chilled to 0° C. under N2. Added 556 μl (5.06 mmol) N-methylmorpholine and 658 μl (5.06 mmol) isobutyl chloroformate and stirred for 10 minutes. Added dropwise a solution of 1.00 g (3.37 mmol) 6-amino-4-[(3,4-difluorophenyl)amino]-3-quinolinecarbonitrile in 2.0 ml hot DMF and 20 ml THF. Removed ice bath at 15 minutes and stirred at 25° C. overnight. Stripped solvent, slurried residue with water, and collected solids. Boiled in ethyl acetate, collected solids, and dried in vacuo, giving 735 mg of yellow solid: mass spectrum (electrospray m/e): M+H=363.3
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[OH:14])[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[CH3:2].C(OCC)(=O)C.C(O)C>C(O)(=O)C>[NH2:10][C:9]1[CH:8]=[CH:7][C:6]([CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[OH:14])=[CH:5][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CCOc1cc(C(O)c2ccccn2)ccc1[N+](=O)[O-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOc1cc(C(O)c2ccccn2)ccc1N
Reaction time: 8 h
Yield: 15.3 %

Procedure:
To a solution of (3-ethoxy-4-nitrophenyl)(2-pyridyl)methanol (2.5 g) in acetic acid (50 ml), reduced iron (7.5 g) was added to the mixture and the mixture was stirred overnight. Ethyl acetate and ethanol were added to the mixture, and the unnecessary substances were filtered off. The filtrate was concentrated under reduced pressure, the residue was diluted with ethyl acetate and neutralized with an aqueous solution of saturated sodium bicarbonate. The organic layer was separated and washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2) and recrystallized from hexane-ethyl acetate, to give (4-amino-3-ethoxyphenyl)(2-pyridyl)methanol (340 mg) as crystals.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:5]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[CH:27][CH:26]=2)=[CH:6][C:7]2[N:11]=[C:10]([O:12][C:13]3[CH:14]=[CH:15][C:16]([CH3:23])=[C:17]([CH:22]=3)[C:18]([O:20]C)=[O:19])[NH:9][C:8]=2[CH:24]=1>CO>[Cl:3][C:4]1[C:5]([C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[CH:29][CH:30]=2)=[CH:6][C:7]2[N:11]=[C:10]([O:12][C:13]3[CH:14]=[CH:15][C:16]([CH3:23])=[C:17]([CH:22]=3)[C:18]([OH:20])=[O:19])[NH:9][C:8]=2[CH:24]=1
Reactant: COC(=O)c1cc(Oc2nc3cc(-c4ccc(-c5cccc(F)c5)cc4)c(Cl)cc3[nH]2)ccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(Oc2nc3cc(-c4ccc(-c5cccc(F)c5)cc4)c(Cl)cc3[nH]2)cc1C(=O)O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
NaOH (5M in water) (0.12 mL, 0.600 mmol) was added to a solution of methyl 5-{[6-chloro-5-(3′-fluorobiphenyl-4-yl)-1H-benzimidazol-2-yl]oxy}-2-methylbenzoate (8.5 mg, 0.017 mmol) in MeOH (1 mL). The reaction was stirred at 50° C. for 2 h. Volatiles were removed. The residue was partitioned between EtOAc and water. The aqueous phase was acidified to pH=1 with 2 N aqueous HCl and extracted with ethyl acetate (3×30 mL). Combined organics were dried (MgSO4), filtered and concentrated to obtain the desired product. LC-MS: calculated for C27H18ClFN2O3 472.10, observed m/e 473.2 (M+H)+ (Rt: 2.28 min). 1 H NMR (500 MHz, CD3OD): δ7.90 (d, 1H), 7.70 (d, 2H), 7.40-7.55 (m, 9H), 7.05 (t, 1H), 2.61 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][C:14]1[N:15]2[C:19](=[C:20]([C:26]([O:28][CH3:29])=[O:27])[C:21]=1C(OC)=O)[CH2:18][C:17]([CH3:31])([CH3:30])[CH2:16]2.O.NN>CCO>[CH3:31][C:17]1([CH3:30])[CH2:18][C:19]2[N:15]([C:14]3[CH2:13][CH2:12][NH:3][C:2](=[O:1])[C:21]=3[C:20]=2[C:26]([O:28][CH3:29])=[O:27])[CH2:16]1
Reactant: COC(=O)c1c(C(=O)OC)c2n(c1CCN1C(=O)c3ccccc3C1=O)CC(C)(C)C2
Agent: NN
Solvent: O
Solvent: CCO
Product: COC(=O)c1c2c(n3c1CC(C)(C)C3)CCNC2=O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of 137k (15.0 g, 35.4 mmol) in EtOH (100 mL) was added hydrazine hydrate (3.5 g, 70.8 mmol). See FIG. 2. The mixture was stirred at 90° C. for 2 h. After cooling the reaction to RT, the resultant precipitate was filtered and washed with ethanol. The filtrate was concentrated to give crude methyl 7,7-dimethyl-1-oxo-2,3,4,6,7,8-hexahydro-1H-pyrido[3,4-b]pyrrolizine-9-carboxylate 137l as a yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([NH:5][C:6](=[O:8])[CH:7]=1)=[O:4].C([O-])(=O)C.[Na+].[CH2:14]([SH:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CO>[CH2:14]([S:20][C:2]1[C:3]([NH:5][C:6](=[O:8])[CH:7]=1)=[O:4])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=C1C=C(Br)C(=O)N1
Reactant: CCCCCCS
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCSC1=CC(=O)NC1=O
Yield: 86 %

Procedure:
To bromomaleimide (300 mg, 1.69 mmol) and sodium acetate (138 mg, 1.69 mmol) in methanol (60 mL) was added hexanethiol (356 μL, 2.50 mmol). After 5 minutes solvent removed in vacuo and purification by flash chromatography (10% ethyl acetate in petroleum ether) afforded 2,3 dihexanethiosuccinimide as a bright yellow paste (13 mg, 0.04 mmol) in 2% and hexylsulfanylmaleimide as a cream powder (alkene 310 mg, 1.46 mmol) in 86% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C:18]4[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.N[C@H](C(O)=O)CCSC.CS(O)(=O)=O.[OH-].[Na+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)cc1
Agent: CS(=O)(=O)O
Agent: CSCC[C@H](N)C(=O)O
Agent: [Na+]
Solvent: O
Product: Oc1ccc(Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.6 %

Procedure:
A mixture of 1-(4-Fluoro-phenyl)-5-(4-methoxy-phenoxy)-1H-indazole (0.3 grams, mmol), methionine (0.40 grams, mmol) and 3 mL of methanesulfonic acid was shaken for 24 hours at room temperature. The mixture was treated with a solution of 1.8 grams of sodium hydroxide in 20 mL of water with cooling in an ice bath, and the aqueous phase was extracted 3 times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo, affording 0.20 grams of 4-[1-(4-Fluoro-phenyl)-1H-indazol-5-yloxy]-phenol as a colorless solid. MS: 321.7 [M+H]+
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[NH:23][CH:22]([CH2:24][C:25]([O:27]C)=[O:26])[C:21](=[O:29])[N:20]([CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:19][C:18]=2[CH:38]=1)=[O:13].[Li+].[OH-].C1COCC1.C(O)(C(F)(F)F)=O>O>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[NH:23][CH:22]([CH2:24][C:25]([OH:27])=[O:26])[C:21](=[O:29])[N:20]([CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:19][C:18]=2[CH:38]=1)=[O:13]
Reactant: COC(=O)CC1Nc2ccc(C(=O)NCc3nc4ccccc4[nH]3)cc2CN(CCc2ccccc2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1Nc2ccc(C(=O)NCc3nc4ccccc4[nH]3)cc2CN(CCc2ccccc2)C1=O
Temperature: 42.5 °C
Reaction time: 0.33 h
Yield: 85.2 %

Procedure:
A mixture of methyl (±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (413.1 mg, 0.81 mmol), 1.0 N LiOH (0.97 mL, 0.97 mmol), THF (4 mL), and H2O (3 mL) was stirred at 40-45° C. for 20 min, and the resulting solution was stirred at RT for 17 h. Acidification with TFA (0.19 mL, 2.4 mmol) and concentration left an off-white solid. Recrystallization from CH3CN/H2O gave the title compound (343.2 mg, 69%) as a colorless powder: HPLC (PRP-1®, 30% CH3CN/H2O-0.1% TFA) K'=1.5; 1H NMR (400 MHz, CD3OD) δ 7.68-7.75 (m, 2H), 7.60 (dd, J=8.6, 2.2 Hz, 1H), 7.51-7.58 (m, 2H), 7.49 (d, J=2.2 Hz, 1H), 7.07-7.22 (m, 5H), 6.61 (d, J=8.6 Hz, 1H), 5.46 (d, J=16.8 Hz, 1H), 5.18 (dd, J=9.0, 5.1 Hz, 1H), 4.95 (s, 2H), 3.81 (d, J=16.8 Hz, 1H), 3.61-3.78 (m, 2H), 2.94 (dd, J=16.8, 9.0 Hz, 1H), 2.71-2.83 (m, 2H), 2.65 (dd, J=16.8, 5.1 Hz, 1H); MS (ES) m/e 498.4 (M+H)+. Anal. Calcd for C28H27N5O4.CF3CO2H.0.25 H2O: C, 58.49; H, 4.66; N, 11.37. Found: C, 58.52; H, 4.47; N, 11.04.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.B.O1CCCC1.FC(F)(F)C(O)=O>C(=O)([O-])[O-].[Na+].[Na+]>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: Cn1ccc2c([N+](=O)[O-])cccc21
Agent: B
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCc2c1cccc2[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51.3 %

Procedure:
To a stirred solution of 1-methyl-4-nitro-1H-indole (3.8 g, Organic Process Research and Development 2001 5 (6) 604) and borane-tetrahydrofuran complex (1M in tetrahydrofuran, 86.3 ml) at 0° C. under an atmosphere of nitrogen was added, dropwise, trifluoroacetic acid (88 ml). The resulting mixture was allowed to warm to room temperature and stirred at room temperature for 90 min. The mixture was cautiously added to 2M sodium carbonate solution (750 ml) over 20 min and then stirred for 30 min. The mixture was extracted with ethyl acetate (2×300 ml), the combined organic extracts were dried over sodium sulphate and the solvent was removed in vacuo. Purification by column chromatography on silica gel, eluting with hexane:ethyl acetate (9:1) gave the title compound as a red solid (1.97 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[C:9]2[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C.[CH3:26][CH:27]([CH3:36])[CH2:28][C:29](=O)[C:30](OCC)=[O:31].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[C:9]2[CH:10]=[C:11]3[C:12](=[CH:13][CH:14]=2)[NH:15][C:30](=[O:31])[C:29]([CH2:28][CH:27]([CH3:36])[CH3:26])=[N:16]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)CC(C)C
Reactant: Nc1ccc(C(c2cccc(Cl)c2)n2ccnc2)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Cc1nc2cc(C(c3cccc(Cl)c3)n3ccnc3)ccc2[nH]c1=O
Reaction time: 4 h
Yield: 12.6 %

Procedure:
To a stirred and cooled (0° C.) solution of 9.1 parts of 4-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-1,2-benzenediamine in 80 parts of acetic acid and 20 parts of water were added portionwise 5.8 parts of ethyl 4-methyl-2-oxopentanoate. Upon completion, stirring was continued for 4 hours at room temperature. The reaction mixture was poured into 100 parts of water and the whole was neutralized with a sodium hydroxide solution 3N. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 1,1'-oxybisethane. The product was filtered off (the filtrate was set aside) and dried, yielding 1.5 parts (12.6%) of 6-[(3-chlorophenyl) (1H-imidazol-1-yl)methyl]-3-(2-methylpropyl)-2(1H)-quinoxalinone; mp. 209.7° C. (comp. 178)
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][CH2:14]S(C)(=O)=O)[CH2:5]1)(=[O:3])[CH3:2].[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:25][NH:26]2)=[CH:22][CH:21]=1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][CH2:14][N:32]2[CH2:33][CH2:34][CH:29]([C:24]3[C:23]4[C:27](=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=4)[NH:26][CH:25]=3)[CH2:30][CH2:31]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Clc1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: CC(=O)N1CC(CCS(C)(=O)=O)c2ccccc21
Product: CC(=O)N1CC(CCN2CCC(c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
From 19a and 6-chloro-3-(piperidin-4-yl)-1H-indole (EP Patent publication No 465398-A1). Mp 188-90° C. 1H NMR (DMSO-d6) d 1.70-1.90 (m, 3H), 1.95-2.20 (m, 5H), 2.25 (s, 3H), 2.40 -2.55 (m, 2H), 2.80 (tt, 1H), 3.00-3.10 (m, 2H), 3.40-3.55 (m, 1H), 3.75 (dd, 1H), 4.20 (t, 1H), 6.95 (d, 1H), 7.05 (ddd, 1H), 7.25 (dt, 1H), 7.35 (d, 1H), 7.55 (d, 1H), 8.00 (s, 1H), 8.25 (d, 1H). MS m/z (%): 422 (MH+, 100%), 249 (15%), 146 (19%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:21]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([O-:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([O-:34])=[O:33]
Reactant: O=C(O)/C=C/C(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CC(C)O
Product: O=C([O-])/C=C/C(=O)[O-]
Temperature: 25 °C

Procedure:
Donepezil (3.79 g, dissolved in 70 ml of ethyl acetate) is slowly added to a solution of fumaric acid (0.58 g) in 2-propanol (35 ml) with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound. Melting point: 173.1° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:17][S:18]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:17][S:18]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][S:4][CH2:3][CH2:2]2)=[O:27])=[CH:24][CH:23]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: NCCN1CCSCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(C(=O)NCCN2CCSCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 150 ml of methylene chloride under nitrogen atmosphere add 3.1g (14.3 mmole) of 4-thiomorpholinethanamine and 4.42 g (43.6 mmole) of triethylamine. Stir the mixture at ambient temperature for 1 hour, then cool the mixture to -10° C. To the cooled mixture add slowly 3.67 g (15.1 mmole) of 4-[(methylsulfonyl)amino]benzoyl chloride, keeping the temperature below 5° C. When the addition is complete, allow the reaction mixture to stir at ambient temperature. Monitor the progress of the reaction by thin layer chromatography on silica gel (acetonitrile:ammonium hydroxide, 9:1). Upon completion of the reaction, remove the solvent in vacuo. To the resulting solid add 50 ml of water. To the mixture add 50% sodium hydroxide until pH of 14 is reached. Wash the aqueous layer with 3×50 ml of diethyl ether. Add concentrated hydrochloric acid until a white precipitate forms (pH=8.5). Filter the solid and recrystallize from methanol/ethanol to yield the title compound.