Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([NH2:18])=[C:13]([CH3:19])[CH:12]=1)[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[C:4]([CH3:10])[CH:3]=1.[CH2:20]([C:22]([CH3:24])=O)[CH3:21]>[Pt].C1(C)C=CC=CC=1>[CH:20]([NH:18][C:14]1[C:15]([CH3:17])=[CH:16][C:11]([CH2:1][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:1]([CH2:2][CH3:3])[CH3:11])=[C:4]([CH3:10])[CH:3]=2)=[CH:12][C:13]=1[CH3:19])([CH2:22][CH3:24])[CH3:21]
Reactant: CCC(C)=O
Reactant: Cc1cc(Cc2cc(C)c(N)c(C)c2)cc(C)c1N
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CCC(C)Nc1c(C)cc(Cc2cc(C)c(NC(C)CC)c(C)c2)cc1C
Temperature: 22 °C
Reaction time: 4.5 h
Yield: 96 %

Procedure:
4,4′-Methylenebis(2,6-dimethylbenzeneamine) (1.25 g), methyl ethyl ketone (15 g), Pt(S)/C (0.10 g), and toluene (40.0 g) were charged into reactor. The reactor was purged 3 times with 110 psig (8.60×105 Pa) of H2 at 22° C. The reaction mixture was then stirred at 22° C. under 110 psig of H2 for 4.5 hours. GC (conditions: 100° C./5 minutes/10° C.-minute/270° C.) showed 35% conversion of 4,4′-methylenebis(2,6-dimethylbenzeneamine). The reaction mixture was then stirred for 4 hours at 60° C., after which GC showed 79.5% conversion of 4,4′-methylenebis(2,6-dimethylbenzeneamine). The reaction mixture was then stirred for 11 hours at 130° C., after which GC showed 100% conversion of 4,4′-methylenebis(2,6-dimethylbenzeneamine), and a 96% yield of N,N′-di-sec-butyl-4,4′-methylenebis(2,6-dimethylbenzeneamine); the remaining 4% was determined to be N-sec-butyl-4,4′-methylenebis(2,6-dimethylbenzeneamine). The product was observed to be water-white in color, and the structure of the product was confirmed by GC-MS.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:11])([CH3:10])[CH3:9].C([Li])CCC.[CH2:17]=[O:18]>C1COCC1>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:17][OH:18])([CH3:11])([CH3:10])[CH3:9]
Reactant: C=O
Reactant: CC(C)(C)c1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1CO
Temperature: 78 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a solution of 1-bromo-2-tert-butylbenzene (2.88 g, 13.51 mmol) in anhydrous THF (45 mL) 2,2′-dipyridyl (ca 10 mg) was added under a nitrogen atmosphere. The mixture was cooled down minus 78° C., and a solution of n-butyllithium (2.5 M in hexanes, 5.94 mL, 14.86 mmol) was added dropwise via syringe within the period of ten minutes. Upon addition, the mixture was stirred for 30 minutes, then warmed up to minus 30° C., and a flow of formaldehyde (generated from 1.91 g of paraformaldehyde by heating at over 160° C.) was passed through the solution until the deep red color disappeared completely. The mixture was quenched with saturated ammonium chloride solution (5 mL), then poured into a mixture of dichloromethane (100 mL) and water (50 mL). The organic phase was separated and the aqueous phase was extracted with dichloromethane (20 mL) twice. The combined organic phase was dried over anhydrous Na2SO4, concentrated in vacuo, and purified by silica gel chromatography to yield 2-tert-butylbenzyl alcohol (1.67 g, 75%) as an oil. 1H NMR (400 MHz, CDCl3): δ 7.50 (m, 1 H, Ph-H), 7.41 (m, 1 H, Ph-H), 7.24 (m, 2 H, Ph-H), 4.93 (d, J=4.8 Hz, 2 H, CH2OH), 1.54 (br, 1 H, CH2OH), 1.43 (s, 1 H, C(CH3)3).
Reaction SMILES: [C:1]([C:3]1[C:4](=O)[NH:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1)#[N:2].P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:4]1[C:3]([C:1]#[N:2])=[CH:8][N:7]=[C:6]([S:9][CH3:10])[N:5]=1
Reactant: CSc1ncc(C#N)c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CSc1ncc(C#N)c(Cl)n1
Yield: 40 %

Procedure:
Phosphorus oxychloride (150 mL) was added to 5-cyano-3,4-dihydro-2-methylthiopyrimidin-4-one (30.0 g, 0.159 mmol) obtained in Step 1, and the mixture was heated under reflux for 7 hours. The reaction mixture was left to stand to cool, and then phosphorus oxychloride was evaporated under reduced pressure. The residue was poured into ice water (about 1,000 mL), and the precipitated light yellow solid was collected by filtration and washed with water. The resulting solid was dried under reduced pressure to give 4-chloro-5-cyano-2-methylthiopyrimidine (11.9 g, yield 40%).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:6][O:7][C:8]1[CH:16]=[C:15]([CH:17]=[C:18]([CH3:20])[CH3:19])[CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11]>C1C=CC=CC=1.CN(C)C=O.[Cu].[Zn].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:6][O:7][C:8]1[CH:16]=[C:15]([CH:17]=[C:18]([CH3:20])[CH3:19])[CH:14]=[CH:13][C:9]=1[C:10](=[O:11])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: COc1cc(C=C(C)C)ccc1C(=O)Cl
Reactant: CCCCI
Agent: [Cu]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Zn]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCCCC(=O)c1ccc(C=C(C)C)cc1OC
Temperature: 60 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
A mixture of 1-iodobutane (185 mg) and zinc-copper couple (101 mg) in benzene (3 ml) and N,N-dimethylformamide (0.2 ml) was stirred at 60° C. for 2 hours. To the mixture, a solution of tetrakis(triphenylphosphine)palladium (31 mg) and 2-methoxy-4-(2-methyl-1-propenyl)benzoyl chloride (prepared from 138 mg of 2-methoxy-4-(2-methyl-1propenyl)benzoic acid and 0.07 ml of oxalyl chloride) in benzene (2 ml) was added, and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and the organic solution was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column eluting with a mixture of hexane and ethyl acetate (9:1) to give 2'-methoxy-4'-(2-methyl-1-propenyl)valerophenone (91 mg) 10 as an oil.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:7]=1[O:14][CH3:15]>>[F:5][C:6]1[C:7]([O:14][CH3:15])=[C:8]([O:12][CH3:13])[CH:9]=[CH:10][C:11]=1[N+:1]([O-:4])=[O:2].[F:5][C:6]1[CH:11]=[C:10]([N+:1]([O-:3])=[O:2])[CH:9]=[C:8]([O:12][CH3:13])[C:7]=1[O:14][CH3:15]
Reactant: O=[N+]([O-])O
Reactant: COc1cccc(F)c1OC
Product: COc1cc([N+](=O)[O-])cc(F)c1OC
Product: COc1ccc([N+](=O)[O-])c(F)c1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28 %
Yield: 49 %

Procedure:
To a solution of nitric acid (853 ml, 1.91E+04 mmol) stirred at 0° C. was added dropwise 1-fluoro-2,3-dimethoxybenzene (149 g, 954 mmol). The mixture was stirred at the same temperature for 15 min, and then was allowed to warm up to RT for 15 min. The orange solution was poured into ice and the resultant solid was filtered, washed with water and dried. LCMS showed that the pale yellow solid was the mixture of two products (ratio 1/1.8). The crude material was purified by reverse phase automatic C18 column chromatography (Combiflash RF, 120 g column), eluting with Acetonitrile/Water (0-90%) over 35 min to afford 2-fluoro-3,4-dimethoxy-1-nitrobenzene (53 g, 263 mmol, 28% yield) and 1-fluoro-2,3-dimethoxy-5-nitrobenzene (94 g, 467 mmol, 49% yield) as white solids. LCMS: (M+H)+: 202.1.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](O)=[O:23])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1.C(Cl)(=O)C(Cl)=O.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:23])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1
Reactant: C1COCCN1
Reactant: COCCc1nc2cnc3ccccc3c2n1CCCCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Product: COCCc1nc2cnc3ccccc3c2n1CCCCC(=O)N1CCOCC1
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
5-[2-(2-Methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]pentanoic acid (5.5 g, 17 mmol) was treated according to a modification of the method described in Part F of Example 6. The reaction with oxalyl chloride (2.63 mL, 30.2 mmol) was carried out at ambient temperature and was complete in 30 minutes. The reaction with morpholine (4.40 mL, 50.4 mmol) was complete after 30 minutes. Following the work-up procedure, 6.5 g of 2-(2-methoxyethyl)-1-(5-morpholin-4-yl-5-oxopentyl)-1H-imidazo[4,5-c]quinoline were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].Cl.Cl.Cl.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[OH2:10].[ClH:1].[ClH:31].[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:21]2[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][CH2:15][NH:14][C:9]([NH:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[O:10])[CH2:23][CH2:22]2)=[CH:26][CH:27]=1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=C=Nc1ccccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O
Product: O=C(NCCCN1CCN(Cc2ccc(Cl)cc2)CC1)Nc1ccccc1Cl
Yield: 102.7 %

Procedure:
The procedure described in Example 29 was followed, using 2-chlorophenyl isocyanate (1.54 g; 10 mmole), 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (3.77 g; 10 mmole), methylene chloride (50 ml) and triethylamine (4.3 ml; 31 mmole). Recrystallization from methanol provided the title compound (2.63 g; 53% yield) as colorless crystals, m.p. 222°-224° C.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([NH:13][C@H:14]1[C@@:23](C(=O)C2C=CC=CC=2)([OH:24])[C@:22](C(=O)C2C=CC=CC=2)([OH:33])[C@@H:21]([CH2:42]O)[O:20][C@@H:15]1[O:16][CH2:17][CH:18]=[CH2:19])(=[O:12])[CH3:11]>COCCOCCOC.C[O-].[Na+].CO>[C:10]([NH:13][C@H:14]1[C@@H:23]([OH:24])[C@H:22]([OH:33])[C@@H:21]([CH2:42][F:7])[O:20][C@@H:15]1[O:16][CH2:17][CH:18]=[CH2:19])(=[O:12])[CH3:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: C=CCO[C@H]1O[C@H](CO)[C@](O)(C(=O)c2ccccc2)[C@@](O)(C(=O)c2ccccc2)[C@@H]1NC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: COCCOCCOC
Product: C=CCO[C@H]1O[C@H](CF)[C@@H](O)[C@H](O)[C@@H]1NC(C)=O
Temperature: 40 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a stirred solution of (diethylamino)sulfur trifluoride (0.5 mL) in dry diglyme (2mL) was added a solution of allyl 2-acetamido-3,4-di-benzoyl-2-deoxy-α-D-mannopyranoside, prepared as described above, (100 mg) in dry diglyme (3 mL) at room temperature, and the reaction mixture was stirred for one hour at room temperature and three hours at 40° C. After the starting material was consumed, the reaction mixture was poured onto ice-water and extracted with ethyl acetate. The extract was dried, concentrated, and the residue was applied to silica gel chromatography. After the impurity was eluted with hexane, the product was eluted with ether to give the fluorinated product in 89 percent yield. The product was then dissolved in 5 mL of 1N sodium methoxide in methanol to remove benzoyl group. After 20 minutes, Dowex 50W X-8[H+ ] was added to neutralize the reaction mixture. The resin was filtered and the filtrate was concentrated to give allyl 2-acetamido-2,6-dideoxy-6-fluoro-α-D-mannopyranoside in 99 percent yield. The product (50 mg), 1.2 equivalents of palladium (II) acetate, and 2.5 eq of sodium acetate in 95 percent acetic acid (5 mL) were stirred at 50° C. for 18 hours, and the solvent was removed under vacuum. The residue was applied to silica gel chromatography, eluted with ethyl acetate/methanol (2/1) to obtain 2-acetamido-2,6-di-deoxy-6-fluoro-α-D-mannopyranoside in 73 percent yield.
Reaction SMILES: [Cl:1][C:2]1[C:7](NC)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:10]([NH:13]C(C)C)(C)C.[Li].[C:18]1([CH2:24][O:25][CH2:26][CH:27]2[CH2:29][O:28]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[C:7]([CH2:10][NH:13][CH2:29][CH:27]([OH:28])[CH2:26][O:25][CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CNc1cccnc1Cl
Reactant: c1ccc(COCC2CO2)cc1
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(CNCc1cccnc1Cl)COCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
To a solution of intermediate (28) (0.031 mol) in THF (50 ml) under nitrogen flow at −78° C., lithium diisopropylamine (0.062 mol, 2 M) was slowly added. The reaction mixture was allowed to warm to 0° C. and was stirred for 1 hour. After cooling again to −78° C., a solution of [(phenylmethoxy)methyl]-oxirane (0.034 mol) in THF (40 ml) was added and the mixture was allowed to warm to room temperature and was stirred for 16 hours. A saturated NH4Cl-solution was added and the mixture was extracted with ethyl acetate. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by short open column chromatography over silica gel (eluent: hexane/ethyl acetate 50/50). The product fractions were collected and the solvent was evaporated, yielding 7.18 g of 1-[(2-chloro-3-pyridinyl)methylamino]-3-(phenylmethoxy)-2-propanol (intermediate 29).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-])=[O:5].Cl.C(N=C=NCCCN(C)C)C.[N:22]1([CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>ClCCl>[C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O:32][CH2:31][CH2:30][CH2:29][CH2:28][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:5]
Reactant: OCCCCN1CCOCC1
Reactant: COC(=O)/C=C/C(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)/C=C/C(=O)OCCCCN1CCOCC1

Procedure:
Monomethyl fumarate (MMF) was reacted with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC) (1.2 eq) in dichloromethane (DCM) at ca. 0° C. 4-Morpholin-4-yl-butan-1-ol (1 eq) and 4-N,N-dimethylaminopyridine (DMAP) (catalytic amount) were added to the activated carboxylic acid. After the completion of the reaction, followed by the work-up of the reaction mixture, the title compound was isolated as a viscous-oil.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[C:23]([NH:27][C:28]1[N:29]=[C:30]([N:37]2[CH2:41][CH2:40][C:39]([F:43])([F:42])[CH2:38]2)[C:31]2[N:36]=[N:35][NH:34][C:32]=2[N:33]=1)([CH3:26])([CH3:25])[CH3:24].[Cl:44][C:45]1[C:46]([CH2:51]Cl)=[N:47][CH:48]=[CH:49][CH:50]=1>>[C:23]([NH:27][C:28]1[N:29]=[C:30]([N:37]2[CH2:41][CH2:40][C:39]([F:42])([F:43])[CH2:38]2)[C:31]2[C:32](=[N:34][N:35]([CH2:51][C:46]3[C:45]([Cl:44])=[CH:50][CH:49]=[CH:48][N:47]=3)[N:36]=2)[N:33]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)Nc1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: ClCc1ncccc1Cl
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: CC(C)(C)Nc1nc(N2CCC(F)(F)C2)c2nn(Cc3ncccc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from tert-Butyl-[7-(3,3-difluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-amine and 3-chloro-2-(chloromethyl)pyridine. MS (m/e): 423.3 (MH+).
Reaction SMILES: CN(C=O)C.[C:6]([Cl:11])(=O)[C:7](Cl)=O.[N:12]1[C:17]2[CH:18]=[CH:19][S:20][C:16]=2C(=O)N[CH:13]=1.O>C(Cl)Cl>[Cl:11][C:6]1[CH:7]=[CH:13][N:12]=[C:17]2[CH:18]=[CH:19][S:20][C:16]=12
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=c1[nH]cnc2ccsc12
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: Clc1ccnc2ccsc12
Yield: 100 %

Procedure:
To a solution of DMF (13.2 mL, 170 mmol) in DCM (100 mL) at 0° C. was added oxalyl chloride (22 mL, 252 mmol) in DCM (100 mL) very slowly over 1 hour. To the resulting white gel solution was added the 3H-thieno[3,2-d]pyrimidin-4-one (12 g, 79 mmol). The mixture was refluxed for 4 hours. After cooling, the mixture was purred into water (500 mL) and extracted with DCM (3×250 mL). Then the organic phase was dried over magnesium sulfate, filtered and concentrated to afford 7-chloro-thieno[3,2-b]pyridine as white solid (13.4 g, 99%). 1H NMR (CDCl3, 400 Hz) δ 9.00 (s, 1H), 8.06 (d, J=5.6 Hz, 1H), 7.61 (d, J=5.6 Hz, 1H). MS (ESI+) [M+H]+ 170
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH2:13][CH:12](O)[O:11][C:10]=2[CH:16]=1)=[O:5])[CH3:2].[C:17](=[O:20])([O-])[O-].[Cs+].[Cs+].C(Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[I-].[Na+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([O:20][CH2:17][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:9]2[O:14][CH2:13][CH2:12][O:11][C:10]=2[CH:16]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)OC(O)CO2
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccccc1
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc2c(c(OCc3ccccc3)c1)OCCO2

Procedure:
The reaction mixture containing 900 ml of acetone, 17.4 g of hydroxy-1,4-benzodioxane-7-carboxylic acid ethyl ester, 37.9 g of caesium carbonate, 11 ml of benzyl bromide and 7.7 g of sodium iodide is stirred under reflux for 3 hours and then concentrated by evaporation. The residue is partitioned between diethyl ether and water. The organic phases are dried over sodium sulfate and concentrated by evaporation. The title compound is obtained from the residue by FC (900 g of silica gel, hexane/ethyl acetate=1:1): Rf (hexane/ethyl acetate=2:1)=0.36.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([NH:16]C)=[O:15])=O)=[CH:5][CH:4]=1.[NH2:22]N>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:12]3[C:13](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:14](=[O:15])[NH:16][N:22]=2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: CNC(=O)c1ccccc1C(=O)Cc1ccc(OC)cc1
Solvent: CCO
Product: COc1ccc(Cc2n[nH]c(=O)c3ccccc23)cc1

Procedure:
To 2-(2-(4-methoxyphenyl)acetyl)-N-methylbenzamide (1.76 g, 6.20 mmol) in EtOH (20 mL) was added hydrazine (3.50 ml, 112 mmol). A water condenser was attached and the mixture was heated to reflux under a nitrogen atmosphere for 5 days. After concentration, the reaction was diluted with EtOAc and extracted with water. The organics were dried over sodium sulfate, filtered and concentrated. The crude was purified by washing the resulting solid with diethyl ether and filtering to yield 4-(4-methoxybenzyl)phthalazin-1(2H)-one as a white solid. MS m/z=267[M+1]+. Calc'd for C16H14N2O2: 266.30.
Reaction SMILES: C([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C@:10]([CH2:16]C)([C:12]([O:14][CH3:15])=[O:13])[CH2:9][C:8]=2[CH:18]=1)(=O)C.[OH-:19].[K+].B(Br)(Br)Br.C[Si](C=[N+]=[N-])(C)C.C([OH:34])C>ClCCl.C1C=CC=CC=1.CO>[CH3:9][C:10]1([C:12]([O:14][CH3:15])=[O:13])[O:11][C:7]2[CH:8]=[C:18]([OH:34])[CH:4]=[CH:5][C:6]=2[O:19][CH2:16]1
Reactant: [OH-]
Reactant: CC[C@@]1(C(=O)OC)Cc2cc(C(C)=O)ccc2O1
Reactant: CCO
Agent: BrB(Br)Br
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [K+]
Solvent: CO
Solvent: c1ccccc1
Solvent: ClCCl
Product: COC(=O)C1(C)COc2ccc(O)cc2O1

Procedure:
The product from Step 5 (0.6 g, 2.9 mmol) was treated with 2 N KOH in ethanol under reflux for 4 h. Removal of ethanol and acidification of the residue with 2 N HCl gave the crude acid, which was dissolved in dichloromethane (mL) and treated with boron tribromide (1 M in hexane, mL, mmol) at 0 C for 1 h. The reaction was quenched with water and extracted with dichloromethane. The combined extracts were washed with brine and dried over MgSO4. Removal of solvents gave a residue which was taken up in 7:1 benzene/methanol and treated with excess trimethylsilyldiazo methane (1 m in hexane). Removal of solvents and purification of the residue by chromatography on silica gel afforded 0.48 (75% yield) of the title compound as an oil.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[S:14][CH:15]=[CH:16][C:17]=1[C:18]#[N:19].O.[OH-].[Li+]>CS(C)=O>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:12][C:13]2[S:14][CH:15]=[CH:16][C:17]=2[C:18]#[N:19])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: N#Cc1ccsc1N
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccsc1Nc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 44.9 %

Procedure:
Combine 2,4-difluoro-1-nitro-benzene (5.24 g, 32.94 mmol), 2-aminothiophene-3-carbonitrile (4.09 g, 32.94 mmol), and DMSO (30.0 ml). Add lithium hydroxide monohydrate (2.76 g, 65.88 mmol) all at once and then stir the mixture at 55° for 22 hours. Cool the mixture to ambient temperature and then pour it onto ice chips. Extract with ethyl acetate and then wash (brine), dry (sodium sulfate), and evaporate the organic to residue. Purify the residue on silica gel using hexanes/dichloromethane (35:65) to give 3.89 g (45%) of the title compound as a red solid: mass spectrum (ion spray): m/z=262.0 (M−1).
Reaction SMILES: C[O-].[Na+].[Na].[CH2:5]([O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[N+:25]=[N-:26]>CO.O>[N:24](/[C:27](=[CH:17]\[C:16]1[CH:19]=[CH:20][C:13]([O:12][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[C:14]([N+:21]([O-:23])=[O:22])[CH:15]=1)/[C:28]([O:30][CH3:31])=[O:29])=[N+:25]=[N-:26]
Reactant: O=Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Reactant: COC(=O)CN=[N+]=[N-]
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=O)/C(=C/c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 5 h
Yield: 58.7 %

Procedure:
Under argon, to a sodium methoxide solution (prepared from 2.5 g (108.7 mmol) of sodium and 70 ml of methanol) a mixture of 6.1 g (23.7 mmol) of 4-benzyloxy-3-nitrobenzaldehyde and 11.2 g (97.3 mmol) of methyl azidoacetate in 100 ml of methanol is added at 0° C. The mixture is stirred at 0° C. for 5 h, then diluted with 350 ml of water, the precipitated crystals were filtered off, washed with water and dried to yield 4.93 g (59%) of the title compound. Mp.: 95-96° C. (water).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][NH:8]C(=O)OC(C)(C)C)=[CH:5][C:4]=1[NH:18][C:19]1[N:23]([CH3:24])[C:22]2[CH:25]=[C:26]([N:30]3[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([F:39])([F:38])[F:37])[CH2:31]3)[C:27]([Cl:29])=[CH:28][C:21]=2[N:20]=1>O1CCOCC1.O.C([O-])([O-])=O.[K+].[K+]>[Cl:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][NH2:8])=[CH:5][C:4]=1[NH:18][C:19]1[N:23]([CH3:24])[C:22]2[CH:25]=[C:26]([N:30]3[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([F:38])([F:37])[F:39])[CH2:31]3)[C:27]([Cl:29])=[CH:28][C:21]=2[N:20]=1
Reactant: Cn1c(Nc2cc(CNC(=O)OC(C)(C)C)ccc2Cl)nc2cc(Cl)c(N3CCCC(C(F)(F)F)C3)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1c(Nc2cc(CN)ccc2Cl)nc2cc(Cl)c(N3CCCC(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4 M HCl in dioxane (20 mL) was added to tert-butyl N-{4-chloro-3-[5-chloro-1-methyl-6-(3-(trifluoromethyl)piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino]benzyl}-carbamate (700 mg, 1.2 mmol) in dioxane (20 mL). The reaction mixture was stirred at rt for 2 h then diluted with water and aq. K2CO3-solution and stirred for 1 h at rt. The mixture was concentrated, filtered and the filtercake was washed with water and dried to give the sub-title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[CH3:9][C:10]1[N:11]=[CH:12][NH:13][C:14]=1[CH2:15][S:16][CH2:17][CH2:18][NH2:19].[CH3:20][N:21]=[C:22]=[S:23]>O>[CH3:20][NH:21][C:22]([NH:19][CH2:18][CH2:17][S:16][CH2:15][C:14]1[NH:13][CH:12]=[N:11][C:10]=1[CH3:9])=[S:23]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CN=C=S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CNC(=S)NCCSCc1[nH]cnc1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
i. Potassium carbonate (7.75 g.) was added to a solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrochloride (14.6 g.) in water (120 ml.). The solution was stirred at room temperature for 15 minutes and methyl isothiocyanate (5.15 g.) was added. After heating under reflux for 30 minutes, the solution was slowly cooled to 5°. The product (13.1 g.) was collected and recrystallised from water to give N-methyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]thiourea, m.p. 150°-152°.