Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH2:9])[N:5]=[CH:4][N:3]=1.[S:10](Cl)(Cl)=O>C(Cl)(Cl)Cl.CO>[NH2:9][C:6]1[C:7]2[C:2](=[N:1][S:10][N:8]=2)[N:3]=[CH:4][N:5]=1
Reactant: Nc1ncnc(N)c1N
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1ncnc2nsnc12

Procedure:
A flask was charged with 19.78 g. (0.15 mole) of 4,5,6-triaminopyrimidine and 163.0 g. (137 mole) of thionyl chloride and the mixture stirred at reflux for 18 hours. The dark orange reaction mixture was evaporated to dryness on the rotary evaporator and to the residue was added 500 ml. water and 40 ml. methanol. The resulting solution was adjusted to a pH of 7.5-8.0 with saturated sodium bicarbonate solution and heated to reflux. The hot mixture was filtered and the filtrate cooled to 0°-5° C. in an ice-bath. The solid was collected by filtration, washed twice with 50 ml. ice water and twice with 50 ml. ether. The resulting tan product was dried in vacuo at 70° C. overnight to afford 18.2 g. (79%) of product. M.p. 247°-249° C.; tlc on silica gel in chloroform-methanol (8:1) showed one spot at Rf = 0.4.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][S:10][CH3:11])=[CH:4][N:3]=1.[N:12]#[C:13][NH2:14].IC1C=CC=C(CC([O-])=O)C=1CC([O-])=O.S(=O)(O)[O-].[Na+]>O>[Cl:8][C:7]1[CH:6]=[C:5]([CH2:9][S:10]([CH3:11])=[N:14][C:13]#[N:12])[CH:4]=[N:3][C:2]=1[Cl:1]
Reactant: CSCc1cnc(Cl)c(Cl)c1
Reactant: N#CN
Agent: O=C([O-])Cc1cccc(I)c1CC(=O)[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: CS(Cc1cnc(Cl)c(Cl)c1)=NC#N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2,3-dichloro-5-methylthiomethylpyridine (3.5 g, 16.8 mmol) and cyanamide (1.43 g, 34 mmol) cooled in an ice-water bath was added iodobenzenediacetate (6.76 g, 21 mmol) in one portion. The resulting mixture was stirred at 0° C. for 30 min and then continued at room temperature for 1 h. A solution of sodium bisulfite (2 g) in water (50 mL) was added and the organic phase separated. The aqueous phase was extracted with dichloromethane (2×50 mL). The combined organic phase was dried over MgSO4 and the solvent evaporated to give a dark red oily residue which was triturated with boiling ether (2×40 mL) with the ether being discarded each time. After standing at room temperature overnight, the residue solidified, which was triturated with hot ethyl acetate (25 mL). Upon cooling down, the off-white solid product was collected by filtration and dried. Concentration of the filtrate and repeating the trituration process gave additional product. The total yield for the product [1-(5,6-dichloropyridin-3-yl)methyl](methyl)-λ4-sulfanylidenecyanamide was 2.45 g (58.8%). LC-MS: calcd for C8H7Cl2N3S [M]+ 247. Found 247.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][C:24]2=O)[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].Cl.[NH2:30][OH:31]>N1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][C:24]2=[N:30][OH:31])[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: NO
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2=O)C(=O)Nc2cnccn2)cc1Cl
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2=NO)C(=O)Nc2cnccn2)cc1Cl
Temperature: 25 °C
Yield: 5.6 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(2-oxo-cyclopentyl)-N-pyrazin-2-yl-propionamide (99.3 mg, 0.23 mmol) in pyridine (0.69 mL) and methanol (0.69 mL) at 25° C. was treated with hydroxylamine hydrochloride (24.5 mg, 0.35 mmol). The reaction mixture was heated under reflux for 12 h. At this time, the reaction was cooled to 25° C. and was concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (75 mL) and was washed with a 1N aqueous sodium hydroxide solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 75/25 ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(2-hydroxyimino-cyclopentyl)-N-pyrazin-2-yl-propionamide (5.6 mg, 5.4%) as a white wax: (ES)−-HRMS m/e calcd for C19H21ClN4O4S (M−H)− 435.0899, found 435.0902.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[C:10]([N+:15]([O-])=O)[CH:9]=2)=[CH:4][CH:3]=1.FC1C=CC(COC2C=CC([N+]([O-])=O)=C([N+]([O-])=O)C=2)=CC=1>CO.[Ni]>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([NH2:15])[C:11]([NH2:12])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(OCc2ccc(F)cc2)cc1[N+](=O)[O-]
Agent: [Ni]
Agent: O=[N+]([O-])c1ccc(OCc2ccc(F)cc2)cc1[N+](=O)[O-]
Solvent: CO
Product: Nc1ccc(OCc2ccc(F)cc2)cc1N
Reaction time: 5 h

Procedure:
10 g of 4-(4-fluoro-benzyloxy)-2-nitro-aniline or 4-(4-Fluoro-benzyloxy)-1,2-dinitrobenzene was dissolved in 800 ml of methanol and 2 g of Raney Nickel was added. The resulting mixture was hydrogenated at room temperature under regular pressure for 5 hours. The reaction mixture was filtered with celite and washed with methanol. The filtrate was evaporated in vacuo to dryness to give the brown product, which gradually become black, in a quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[OH:12].[C:13](O)(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>O>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:13](=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:7]2[OH:12]
Reactant: Oc1cccc2c(Cl)cccc12
Reactant: CCCCCCCCCCCC(=O)O
Solvent: O
Product: CCCCCCCCCCCC(=O)c1ccc2c(Cl)cccc2c1O
Reaction time: 6 h

Procedure:
A mixture of 16.6 parts of 5-chloro-1-naphthalenol [Erdmann and Kirchoff, Liebig's Ann., 247, 372 (1888)] 19.2 parts of dodecanoic acid and 132 parts of boron trifluoride ether complex (48% BF3) was stirred under nitrogen on a steam bath for 6 hours. Water (114 parts) was added and ether distilled off by further heating. The resulting mixture was cooled in ice and a tan solid was filtered and recrystallized from ethanol to give 18 parts of yellow 1-(5-chloro-1-hydroxynaphthalen-2-yl)-1-dodecanone, m.p. 86°-87° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH2:17][N:18]4[CH2:23][CH2:22][CH:21]([NH:24][C:25](=[O:34])/[CH:26]=[CH:27]/[C:28]5[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=5)[CH2:20][CH2:19]4)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.[ClH:35]>C(O)C.[Pd].CCOCC.C(Cl)(Cl)Cl>[ClH:1].[ClH:35].[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH2:17][N:18]4[CH2:23][CH2:22][CH:21]([NH:24][C:25](=[O:34])[CH2:26][CH2:27][C:28]5[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=5)[CH2:20][CH2:19]4)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: O=C(/C=C/c1cccnc1)NC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=C(CCc1cccnc1)NC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Reaction time: 18 h
Yield: 52 %

Procedure:
To a stirred solution of N-(1-[2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl]-4-piperidyl)-trans-3-(3-pyridyl)propenamide (170 mg, 0.36 mmol) in ethanol (5 mL) was added 10% palladium on carbon (17 mg). This mixture was hydrogenated at 1 atmospheric pressure for 18 h. The reaction was filtered through diatomaceous earth. The filtrate as concentrated and the resulting residue was chromatographed over silica gel (eluant: 95:5 methylene chloride:methanol) to give a white foam. This material was dissolved in a cold (ice bath) solution of ether:chloroform (3:1, v/v, 15 mL) and treated with gaseous hydrochloric acid to afford the title compound as a white solid (100 mg, 52%), mp 220.0°-3.0° C.; (MS(CI): 472 (M+H); NNR (300 MHz,DMSO-d6): 1.65-2.06(m, 4H), 2.46(t, 1.70H, J=7.5 Hz), 2.59(t, 0.3H, J=7.5 Hz), 2.73(m, 2H), 2.87-3.03(m, 2H), 3.17-3.66(m, 3H), 3.78(br m, 0.85H), 3.96(m, 0.15H), 4.18-4.40(m, 2H), 4.48(s, 1H), 6.95-7.10(m, 3H), 7.27-7.42(m, 3H), 7.48(s, 1H), 7.59-7.71(m, 1H), 8.02(d, 1H, J=7.5 Hz), 8.11(d, 1H, J=7.2 Hz), 8.35(br s, - 0.15H), 8.54-8.65(m, 2H), 8.68(br s, - 0.85H), 9.70(br s, 0.15H), 9.96-10.08(br s, 0.85H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[CH:4][N:3]=1.[CH2:15]([OH:19])[C:16]#[C:17][CH3:18].[H-].[Na+].O>CN(C)C=O>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:19][CH2:15][C:16]#[C:17][CH3:18])[N:3]=[CH:4][N:5]=1
Reactant: Fc1ccccc1-c1cc(Cl)ncn1
Reactant: CC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1cc(-c2ccccc2F)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
In 5 ml of N,N-dimethylformamide were dissolved 207 mg of 4-chloro-6-(2-fluorophenyl)pyrimidine and 83 mg of 2-butyn-1-ol, to which 48 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 8 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 160 mg of 4-(2-fluorophenyl)-6-(2-butynyloxy)pyrimidine (the present compound (55)).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12].[NH2:18][C:19]1[CH:31]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH:18][C:19]1[CH:31]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Reactant: O=C(Cl)c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)c1ccccc1F
Reaction time: 2 h

Procedure:
0.059 mL of triethylamine and 0.037 mL of 2-fluorobenzoyl chloride were added to 3.0 mL of methylene chloride solution containing 60 mg of tert-butyl 2-amino-4-phenoxybenzoate at room temperature sequentially and stirred at the same temperature for 2 hours. 0.48 g of aminomethylated polystyrene was added to the reaction mixture and stirred at room temperature overnight. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 2-(2-fluorobenzamido)-4-phenoxybenzoate.
Reaction SMILES: [Li].[CH3:2][N:3]([CH3:7])[CH2:4][C:5]#[CH:6].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1>C(N)CN.O1CCCC1>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])([C:6]#[C:5][CH2:4][N:3]([CH3:7])[CH3:2])[CH3:16])=[CH:11][CH:10]=1
Reactant: C#CCN(C)C
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [Li]
Solvent: C1CCOC1
Solvent: NCCN
Product: CN(C)CC#CC(C)(O)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
In 500 ml of ethylene diamine there is dissolved 13.88 g of lithium wire. After the disappearance of the blue color, the grey suspension obtained is dropwise treated, at 5° C., with 166.3 g of 3-dimethylamino-1-propyne. After 1 hour at room temperature, a solution of 50 g of p-bromoacetophenone in 250 ml of tetrahydrofuran is added. After 2 hours at room temperature, the mixture is poured onto ice and extracted with chloroform to give 62.9 g of crude, 2-(p-bromophenyl)-5-dimethylamino-3-pentyn-2-ol which is dissolved in 500 ml of acetone and treated with 18 ml of methyl iodide. After 18 hours at 5°, the solution is evaporated to dryness and the residue triturated with chloroform-ether to give 68 g of pure 2-(p-bromophenyl)-5-dimethylamino-3-pentyn-2-ol methiodide, mp 185°-190°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[CH:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[NH:11][C:12]1[C:21]2[CH:22]=[CH:23][N:24]=[C:25]([O:26]C)[C:20]=2[C:19]2[C:14](=[CH:15][CH:16]=[N:17][CH:18]=2)[N:13]=1.[Si]([N:32]=[N+:33]=[N-:34])(C)(C)C.C(Cl)(Cl)Cl.B(Br)(Br)Br>C(OCC)(=O)C>[Cl:10][C:4]1[CH:5]=[C:6]([C:8]2[N:32]=[N:33][NH:34][CH:9]=2)[CH:7]=[C:2]([Cl:1])[C:3]=1[NH:11][C:12]1[C:21]2[CH:22]=[CH:23][NH:24][C:25](=[O:26])[C:20]=2[C:19]2[C:14](=[CH:15][CH:16]=[N:17][CH:18]=2)[N:13]=1
Reactant: C#Cc1cc(Cl)c(Nc2nc3ccncc3c3c(OC)nccc23)c(Cl)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: O=c1[nH]ccc2c(Nc3c(Cl)cc(-c4c[nH]nn4)cc3Cl)nc3ccncc3c12
Temperature: 150 °C

Procedure:
N-(2,6-Dichloro-4-ethynylphenyl)-10-methoxypyrido[4,3-c]-1,6-naphthyridin-6-amine (66 mg, 0.167 mmol) and TMS-N3 (1.5 mL, 11.30 mmol) were combined and heated in a sealed tube to 150° C. for 16 h. Volatiles were evaporated under vacuum. To the residue was added chloroform (1 mL) and boron tribromide (1.2 mL, 1.2 mmol, 1M in dichloromethane) and the mixture was heated at 85° C. for 45 min in a sealed tube. After cooling to room temperature, the reaction was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, followed by brine. The organic layer was dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in THF/MeOH, filtered and purified by reverse phase HPLC to afford the title compound.
Reaction SMILES: CC1(C)S[C@@H]2[C@H:7]([NH:10][C:11]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=O)C(=O)N2[C@H]1C([O-])=O.[K+].C[C@@H](NC)[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3OC[C@@](O)(C)[C@H:44]([NH:50]C)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](N)CC1>>[N:50]1[CH:44]=[C:16]([CH:15]2[CH2:14][CH2:13][CH2:11][N:10]2[CH3:7])[CH:17]=[CH:18][CH:19]=1
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Reactant: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H]([C@@H](C)NC)CC[C@H]3N)[C@@H](N)C[C@H]2N)OC[C@]1(C)O
Agent: [K+]
Product: CN1CCCC1c1cccnc1

Procedure:
Penicillin & Gentamicin
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.CN(C(O[N:21]1N=N[C:23]2C=CC=[N:27][C:22]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(=NO)(N)C>CN(C=O)C>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:8][N:27]=[C:22]([CH3:23])[N:21]=2)=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(I)ccc1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CC(N)=NO
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(I)ccc1-c1nc(C)no1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 39 %

Procedure:
A mixture of 4-iodo-2-methoxy benzoic acid (83 mg, 0.3 mmol), HATU (114 mg, 0.3 mmol), DIEA (26 μL, 0.15 mmol), and HOBt (8 mg, 0.06 mmol) in DMF was stirred at room temperature for 5 minutes. Acetamide oxime (22 mg, 0.3 mmol) was added, and reaction was stirred for 30 minutes at room temperature. The reaction was then heated to 110° C. for 16 hours. Cooled to room temperature. Partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by HPLC to provide 37 mg (39%) of desired product. MS (ESI) m/e 317 (M+H)+, 1H NMR (300 MHz, DMSO-d6): □ 7.70 (d, J=8.14 Hz, 1H), 7.64 (d, J=1.36 Hz, 1H), 7.53 (dd, J=8.31-1.53 Hz, 1H), 3.94 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.Cl[C:17]1[N:22]=[C:21]([N:23]([CH3:43])[CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[C@H:33]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:32][CH2:31]3)[C:20]([CH3:44])=[CH:19][N:18]=1>CN(C=O)C>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][C:17]1[N:22]=[C:21]([N:23]([CH3:43])[CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[C@H:33]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:32][CH2:31]3)[C:20]([CH3:44])=[CH:19][N:18]=1
Reactant: COc1cccc(O)c1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nc(Cl)ncc3C)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nc(Oc4cccc(OC)c4)ncc3C)ccc21
Temperature: 80 °C
Reaction time: 48 h
Yield: 47 %

Procedure:
To a suspension of K2CO3 (132 mg, 0.96 mmol) in DMF (5 mL) was added 3-methoxyphenol (36 mg, 0.290 mmol), followed by the portionwise addition of ethyl ((1S)-5-{3-[(2-chloro-5-methyl-4-pyrimidinyl)(methyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate prepared in Example 342. The reaction mixture was stirred at 80° C. for 48 h, and then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to yield the title compound (56.5 mg, 47%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.29 (t, 3H), 1.71-1.83 (m, 1H), 2.02 (m, 2H), 2.28 (s, 3H), 2.35-2.47 (m, 2H), 2.75 (dd, 1H), 2.79-2.96 (m, 2H), 3.15 (s, 3H), 3.49-3.57 (m, 1H), 3.56-3.61 (m, 2H), 3.78 (s, 3H), 3.81 (t, 2H), 4.19 (q, 2H), 6.64 (dd, 1H), 6.69-6.78 (m, 3H), 7.05 (d, 1H), 7.21-7.27 (m, 2H), 7.80 (s, 1H); LC-MS: RT=2.85 min, (M+H)+ 506.3.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=[O:8])[NH:2]2.N1C=CC=CC=1.[C:15]1([CH2:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C(#N)C>[C:15]1([CH2:21][C:22]([C:1]23[CH2:7][CH:4]([CH:5]=[CH:6]2)[C:3](=[O:8])[NH:2]3)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1NC2C=CC1C2
Reactant: O=C(Cl)Cc1ccccc1
Solvent: c1ccncc1
Solvent: O
Solvent: CC#N
Product: O=C1NC2(C(=O)Cc3ccccc3)C=CC1C2
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 112.6 %

Procedure:
33.4 g of (±)-2-azabicyclo[2.2.1]hept-5-en-3-one were dissolved in acetonitrile (240 ml) and pyridine (48.3 ml) under nitrogen. At 12° C., 68.6 g of phenylacetyl chloride were added dropwise over the course of 30 minutes. The mixture was then stirred at room temperature for 3.5 hours. 240 ml of water were added to the mixture. The acetonitrile was evaporated off in vacuo, and the aqueous phase was extracted 3 times with ethyl acetate (150 ml). The combined org. phases were washed with 1N HCl (150 ml), saturated NaCl (150 ml) and water (150 ml), dried with magnesium sulphate and completely evaporated. The crude product was filtered through silica gel (hexane:ethyl acetate=1:1). 78.34 g of the crude product were obtained as a yellow oil.
Reaction SMILES: [ClH:1].[N+:2]([CH2:5][C:6]([C:8]1[N:9]=[CH:10][N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]=1[N+:13]([O-])=O)=[O:7])([O-])=O>C(O)C>[ClH:1].[ClH:1].[NH2:2][CH2:5][C:6]([C:8]1[N:9]=[CH:10][N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]=1[NH2:13])=[O:7]
Reactant: O=C(C[N+](=O)[O-])c1ncn(Cc2ccccc2)c1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: NCC(=O)c1ncn(Cc2ccccc2)c1N
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A stirred solution of 38 g. of stannous chloride dihydrate in 100 ml. of concentrated hydrochloric acid is treated portionwise with 10 g. of 2-nitro-1-[5-nitro-1-(phenylmethyl)-1H-imidazol-4-yl]ethanone. Ten ml. of ethanol are added to clarify the solution and the mixture is stirred at 60° C. for 3 hours. The solution is evaporated to near dryness and three 100 ml. portions of ethanol are added sequentially and evaporated from the residue. The residual syrup is stirred with 800 ml. of ether and the resulting solid is collected by filtration, washed with ether and dried at reduced pressure. This solid (a tin complex) is dissolved in 150 ml. of water and the tin is precipitated as the sulfide by bubbling hydrogen sulfide gas into the solution. The mixture is filtered and the filter cake washed with water. The filtrate and washings are combined and evaporated at reduced pressure. The residue is repeatedly evaporated with 100 ml. portions of ethanol. The final residual gum is triturated with 30 ml. of ethanol to give as a crystalline solid 2-amino-1-[5-amino-1-(phenylmethyl)-1H-imidazol-4-yl]ethanone dihydrochloride, which is collected by filtration, washed with ethanol and dried at reduced pressure; m.p. 155° C. (dec.).
Reaction SMILES: C[O:2][C:3]1[C:4]([O:13]C)=[CH:5][C:6]2[S:10][C:9]([CH3:11])=[N:8][C:7]=2[CH:12]=1>Br>[CH3:11][C:9]1[S:10][C:6]2[CH:5]=[C:4]([OH:13])[C:3]([OH:2])=[CH:12][C:7]=2[N:8]=1
Reactant: COc1cc2nc(C)sc2cc1OC
Agent: Br
Product: Cc1nc2cc(O)c(O)cc2s1

Procedure:
5,6-Dimethoxy-2-methyl-benzothiazole (3.9 g) was refluxed with 47% hydrobromic acid (40 ml) for four hours. The solid was filtered and dried under vacuum.
Reaction SMILES: N1([C:6]([C:8]2[S:12][C:11]([CH2:13][CH2:14][C:15]3[N:16]=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[S:18][CH:19]=3)=[CH:10][CH:9]=2)=[O:7])C=CN=C1.O.[BH4-].[Na+]>O1CCCC1>[OH:7][CH2:6][C:8]1[S:12][C:11]([CH2:13][CH2:14][C:15]2[N:16]=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[S:18][CH:19]=2)=[CH:10][CH:9]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(C(=O)n3ccnc3)s2)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCc2ccc(CO)s2)cs1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 87.6 %

Procedure:
A solution of N-(4-{2-[5-(1H-imidazol-1-ylcarbonyl)thiophen-2-yl]ethyl}-1,3-thiazol-2-yl)acetamide (220.0 mg, 0.635 mmol) in anhydrous tetrahydrofuran (17.6 ml) was cooled to 0° C., and water (4.4 ml) and sodium borohydride (240.2 mg, 6.350 mmol) were added. After stirring at 0° C. for 1.5 hr, the reaction mixture was concentrated to about 2 ml, and saturated aqueous ammonium chloride (20 ml) was added dropwise. This was extracted 3 times with ethyl acetate, and the combined organic layer was washed with aqueous ammonium chloride and saturated brine. The mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP 100 g, ethyl acetate:hexane=2:1) to give N-(4-{2-[5-(hydroxymethyl)thiophen-2-yl]ethyl}-1,3-thiazol-2-yl)acetamide (157.1 mg, 0.556 mmol, yield 87.6%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:28])[NH:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].[CH:31]([S:34](Cl)(=[O:36])=[O:35])([CH3:33])[CH3:32]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[CH2:18][N:19]([S:34]([CH:31]([CH3:33])[CH3:32])(=[O:36])=[O:35])[C:20](=[O:28])[N:21]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)C(C)C)C(=O)N3c3ccccc3)CC2)c1

Procedure:
In analogy to example 33, (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (example 33, step 1) was reacted with sodium hydride and isopropylsulfonyl chloride to give the title compound as an off-white solid. MS: 485.2 ([M+H]+)