Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]N)=[CH:5][CH:4]=1)#[N:2].C=O.C([O-])(=[O:15])C.[NH4+].O>C(O)(=O)C>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:15])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CC(=O)[O-]
Agent: C=O
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccc(C=O)cc1
Yield: 61.1 %

Procedure:
13.2 g of p-cyanobenzylamine, 12.0 g of paraformaldehyde, 46.0 g of ammonium acetate, 60 ml of water and 60 ml of acetic acid were mixed and reacted at 100° C. for 3 hours while stirring. The reaction solution was concentrated to a half amount in an evaporator and water in an amount equal to the amount of solvent distilled off was added to precipitate crystals. The crystals precipitated were collected by filtration, washed with water and dried to obtain 8.0 g (yield: 62%) of p-cyanobenzaldehyde. The purity was 99.5% or more.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([O:25][C:26]([F:29])([F:28])[F:27])[CH:23]=4)[N:18]([CH3:30])[N:17]=3)[N:14]=2)[N:9](COCC[Si](C)(C)C)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([O:25][C:26]([F:29])([F:27])[F:28])[CH:23]=4)[N:18]([CH3:30])[N:17]=3)[N:14]=2)[NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccc(OC(F)(F)F)cc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4ccc(OC(F)(F)F)cc34)nc12
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a slightly yellow clear solution of N-isopropyl-2-(1-methyl-5-(trifluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (113 mg, 206 μmol) in dichloromethane (5 mL) was added TFA (1.48 g, 1.00 mL, 13.0 mmol), the reaction mixture was stirred overnight then concentrated. The residue was re-dissolved in 5 mL of a solution of dichloromethane/MeOH/ammonium hydroxide (60:10:1) and stirred at 25° C. for 3 h, then evaporated to a light yellow solid, dissolved in dichloromethane (containing a few drops of MeOH) and purified by chromatography (40 g column, 50 μm from Analogix, 0 to 5% MeOH containing 10% ammonium hydroxide)/dichloromethane). The pure product was suspended in dichloromethane and cyclohexane added to promote solid formation, then the solid was separated by filtration and dried to give N-isopropyl-2-(1-methyl-5-(trifluoromethoxy)-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (78 mg, 186 μmol, 91%) as a white solid. MS (M+H)+=419; 1H NMR (DMSO-d6) δ: 12.86 (br. s., 1H), 9.12 (s, 1H), 8.42 (s, 1H), 8.34 (s, 1H), 7.88-7.97 (m, 2H), 7.56 (d, J=9.1 Hz, 1H), 4.14-4.36 (m, 4H), 1.30 (d, J=6.4 Hz, 6H).
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@H:13]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[O:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C@@H:6]1[NH2:20])(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[N:26]#[C:27]Br>CO>[C:1]([NH:4][C@H:5]1[C@H:13]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[O:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C@@H:6]1[NH:20][C:27]#[N:26])(=[O:3])[CH3:2]
Reactant: N#CBr
Reactant: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(C(=O)O)=C[C@@H]1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(C(=O)O)=C[C@@H]1NC#N
Reaction time: 3.5 h
Yield: 106.6 %

Procedure:
5-(Acetylamino)-4-amino-2,6-anhydro-3,4,5-trideoxy-D-glycero-D-galacto-non-2-enonic acid (3 g, 10.35 mmol) was suspended in methanol (37.5 ml) and sodium acetate (1.89 g, 23.1 mmol) was added, causing a "caking" of the suspension and making stirring difficult. To this at 21° C. with exclusion of moisture was added a solution of cyanogen bromide (1.14 g, 10.8 mmol) in methanol (150 ml), in a dropwise manner. Stirring gradually became easier, until a readily stirrable suspension was obtained. Addition was complete in 3.5 hr. The mixture was then stirred at 21° C. with exclusion of moisture for 44 hr. The small amount of remaining solid was filtered off and solvent evaporated in vacuo to an orange-brown foam. The foam was taken up in methanol (125 ml) and with rapid stirring at 21° C. was treated dropwise with propan-2-ol (130 ml). The precipitate was filtered off, washed with iPrOH:MeOH 3:2, and combined filtrate and washings evaporated to give the title compound as a pale yellow foam (3.48 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]([C:15]2[N:19]([CH3:20])[CH:18]=[N:17][CH:16]=2)=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[OH-].[Na+].Cl>C1COCC1.CO>[CH3:20][N:19]1[C:15]([C:14]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:16][N:17]=[CH:18]1
Reactant: COC(=O)c1cc2ccccc2cc1-c1cncn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cncc1-c1cc2ccccc2cc1C(=O)O
Reaction time: 20 h
Yield: 74.3 %

Procedure:
A solution of methyl-3-(1-methyl-imidazol-5-yl)-2-naphthoate (Preparation 14) (8.5 g, 32 mmol) in THF/MeOH (3/2, 120 mL) was treated with aqueous NaOH (1.0 N, 48 mL). After 20 hours at RT, it was neutralized with aqueous HCl (1.0 N, 20 mL). The solvent was evaporated in vacuo. The solid residue was treated with MeOH (5 mL), then evaporated again. The resulting crude material was purified by flash chromatography (5% MeOH/EtOAc) affording the title compound as a pale-yellow solid (6.0 g, 74%). 1H NMR(CDCl3): 8.34 (s, 1H), 7.95 (d, J=8.1, 1H), 7.90 (d, J=8.1, 1H), 7.72 (s, 1H), 7.53 (s, 1H), 7.52 (m, 1H), 7.50 (m, 1H), 6.83 (s, 1H), 3.16 (s, 3H). (ESI) m/z (M+H)+=253.10.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:15](=[O:16])[CH2:14][C:13](=[O:17])[NH:12][C:11]3[C:18]4[C:23]([CH:24]=[CH:25][C:10]2=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:5][CH:4]=1.C[C:27]1[C:37](C)=[CH:36][CH:35]=[CH:34][C:28]=1[CH2:29][S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[CH3:19][C:18]1[C:23]([CH3:22])=[CH:24][CH:25]=[CH:10][C:11]=1[C:28]1([CH2:29][S:30]([N:2]([C:3]2[CH:4]=[CH:5][C:6]([N:9]3[C:15](=[O:16])[CH2:14][C:13](=[O:17])[NH:12][C:11]4[C:18]5[C:23]([CH:24]=[CH:25][C:10]3=4)=[CH:22][CH:21]=[CH:20][CH:19]=5)=[CH:7][CH:8]=2)[CH3:1])(=[O:31])=[O:32])[CH:27]=[CH:37][CH:36]=[CH:35][CH2:34]1
Reactant: Cc1cccc(CS(=O)(=O)Cl)c1C
Reactant: CNc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Solvent: c1ccncc1
Product: Cc1cccc(C2(CS(=O)(=O)N(C)c3ccc(N4C(=O)CC(=O)Nc5c4ccc4ccccc54)cc3)C=CC=CC2)c1C
Yield: 55.9 %

Procedure:
5-[4-(Methylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (40 mg, 0.121 mmol) obtained in Example 198, (1), and 2,3-dimethylbenzylsulfonyl chloride (132 mg, 0.605 mmol) were treated by heating in pyridine (1.0 mL). After the disappearance of the starting materials was confirmed, the same treatment as that of Example 145 was performed to give the title compound (20 mg, yield 32%) as pale yellow crystals.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:21]=[C:20]([CH3:22])[C:19]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:28]CCCCC>CN(C)C=O>[CH2:26]([N:25]1[CH:28]=[CH:22][C:20]2[N:21]=[C:16]([N:13]3[CH2:14][CH2:15][N:10]([CH2:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:11][CH2:12]3)[N:17]=[CH:18][C:19]=2[C:23]1=[O:24])[CH3:27]
Reactant: CCCCCC
Reactant: CCNC(=O)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccc2nc(N3CCN(Cc4ccccc4)CC3)ncc2c1=O
Yield: 87 %

Procedure:
After washing 240 mg of sodium hydride (60% in oil, 6 mmol) with hexane, it was suspended in 3 ml of N,N-dimethylformamide (DMF). Thereafter, a DMF solution (10 ml) of 1.7 g (5 mmol) of 2-(4-benzylpiperazino)-N-ethyl-4-methylpyrimidine-5-carboxylic acid amide (Referential Example 5) was added and the reactants were reacted at 150° C. for 1.5 hours. After distilling off DMF under reduced pressure, 100 ml of water was added, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried with magnesium sulfate, and ethyl acetate was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain 1.5 g of the intended product as light yellowish crystals (yield: 87%).
Reaction SMILES: [Br-:1].[CH2:2]([N+:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH3:14])=[CH:6][CH:5]=1)[CH3:3].[CH3:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][N:22]1[C:34]2[CH:33]=[CH:32][C:31]([CH:35]=O)=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2.N1CCCCC1>C(O)C>[Br-:1].[CH2:2]([N+:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](/[CH:14]=[CH:35]/[C:31]2[CH:32]=[CH:33][C:34]3[N:22]([CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH3:15])[C:23]4[C:28]([C:29]=3[CH:30]=2)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:6][CH:5]=1)[CH3:3]
Reactant: COCCOCCn1c2ccccc2c2cc(C=O)ccc21
Reactant: CC[n+]1ccc(C)c2ccccc21
Agent: [Br-]
Solvent: CCO
Solvent: C1CCNCC1
Product: CC[n+]1ccc(/C=C/c2ccc3c(c2)c2ccccc2n3CCOCCOC)c2ccccc21
Temperature: 25 °C
Yield: 53 %

Procedure:
A solution mixture of 6 (0.20 g, 0.8 mmol), 3a (0.33 g, 1.1 mmol) and piperidine (0.1 mL) in ethanol (40 mL) was heated to reflux overnight. After cooling down to room temperature, the organic solvent was removed. The residue was purified by precipitation from methanol and ethyl acetate to afford SLE (0.22 g) in 53% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.34 (d, J=8.4 Hz, 1H), 9.15 (d, J=8.4 Hz, 1H), 8.86 (s, 1H), 8.54-8.51 (m, 2H), 8.44 (d, J=16 Hz, 1H), 8.36 (d, J=16 Hz, 1H), 8.28-8.23 (m, 2H), 8.12 (d, J=8.0 Hz, 1H), 8.05 (t, J=7.6 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H), 4.99 (tr, J=6.8 Hz, 2H), 4.63 (t, J=4.8 Hz, 2H), 3.84 (t, J=4.8 Hz, 2H), 3.48 (t, J=4.8 Hz, 2H), 3.31 (t, J=4.8 Hz, 2H), 3.11 (s, 3H), 1.59 (t, J=6.8 Hz, 3H). 13C NMR (400 MHz, DMSO-d6) δ 153.2, 146.7, 145.1, 142.2, 140.9, 137.7, 135.0, 128.9, 127.4, 126.8, 126.7, 126.5, 126.4, 122.8, 122.2, 121.8, 120.4, 119.9, 119.0, 116.2, 115.5, 110.4, 110.3, 71.3, 69.8, 68.9, 58.1, 51.9, 15.1. HRMS (MALDI-TOF) m/z Calcd for C30H31N2O2 451.2380. Found 451.2362 [M]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].Br[CH2:12][CH2:13][CH3:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:13][CH3:14])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: CCCBr
Reactant: COc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1ccc(Br)c(OC)c1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
1.50 g (7.39 mmol) 4-bromo-3-methoxy-phenol are added to 1.36 g (11.1 mmol) 1-bromopropane in 10 mL DMF. 2.04 g (14.8 mmol) K2CO3 are added and the mixture is stirred at 80° C. for 12 h. After that time, the mixture is diluted with water and extracted with DCM. The organic layer is dried over sodium sulphate and the solvent is removed in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[N:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=[O:19])[CH2:9]1.ClC1C=CC=C(C(OO)=[O:28])C=1.C(=O)([O-])O.[Na+].N([O-])=O.[Na+]>C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N+:15]([O-:28])=[N:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=[O:19])[CH2:9]1
Reactant: Cc1cnnc2c1C(=O)CC(c1ccccc1Cl)C2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: Cc1cn[n+]([O-])c2c1C(=O)CC(c1ccccc1Cl)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.3 %

Procedure:
In benzene (10 ml) was dissolved 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (1.54 g), and to the solution was added m-chloroperbenzoic acid (1.72 g). The mixture was stirred at room temperature for 1 hour, and to the mixture were added ethyl acetate (300 ml), saturated sodium hydrogen carbonate solution (300 ml) and sodium nitrite (500 mg). The mixture was shaken, and the separated upper layer was washed with water and concentrated under reduced pressure. The residue was purified with silica gel column chromatography to give 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one-1-oxide (478 mg) as pale yellow crystals.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([Cl-]C([O-])=O)[CH:2]=1.C([O:21]C1C=CC(CO)=CC=1)C1C=CC=CC=1.CN1CCOCC1>ClCCl>[N+:7]([C:6]1[CH:5]=[CH:4][C:3]([OH:21])=[CH:2][CH:1]=1)([O-:9])=[O:8]
Reactant: OCc1ccc(OCc2ccccc2)cc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(O)cc1

Procedure:
4-Nitrophenylchloroformate (260 g, 1.30 mmol) as a solution in 500 ml dichloromethane (DCM) is added to Wang resin (p-benzyloxybenzyl alcohol resin ex Calbiochem-Nova-biochem, 350 g, 0.60 mmol) suspended in 1000 ml DCM and N-methylmorpholine (196 ml, 1.79 mmol) and stirred at room temperature for 18 hours. The resin is filtered and washed successively using methanol, DCM and ether to give WANG PARA-NITROPHENOL RESIN. [IR. 1761.5 cm−1; Loading 1.20 mmol/g].
Reaction SMILES: C([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@@H:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH2:12][CH2:11][C@@H:10]1[NH:20][C:21]([C:23]1[N:24]=[CH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[C:28]([Cl:33])[CH:27]=2)=[O:22])=O)(C)(C)C.Cl.[CH3:35][N:36]1[CH2:41][CH2:40][C:39]2[N:42]=[C:43](C([O-])=O)[S:44][C:38]=2[CH2:37]1.[Li+]>C(O)C>[ClH:33].[Cl:33][C:28]1[CH:27]=[C:26]2[C:31]([CH:32]=[C:23]([C:21]([NH:20][C@H:10]3[CH2:11][CH2:12][C@H:13]([C:15](=[O:19])[N:16]([CH3:17])[CH3:18])[CH2:14][C@H:9]3[NH:8][C:6]([C:43]3[S:44][C:38]4[CH2:37][N:36]([CH3:35])[CH2:41][CH2:40][C:39]=4[N:42]=3)=[O:5])=[O:22])[N:24]=[CH:25]2)=[CH:30][CH:29]=1
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Reactant: CN(C)C(=O)[C@H]1CC[C@H](NC(=O)c2cc3ccc(Cl)cc3cn2)[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Li+]
Solvent: CCO
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)N(C)C)CC[C@@H]3NC(=O)c3cc4ccc(Cl)cc4cn3)sc2C1

Procedure:
(1S,2R,4S)—N2-(tert-Butoxycarbonyl)-N1-[(7-chloroisoquinolin-3-yl)carbonyl]-4-(N,N-dimethyl-carbamoyl)-1,2-cyclohexanediamine was treated with a saturated ethanol solution of hydrochloric acid and then condensed with lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in a similar manner to Example 118 to obtain the title compound.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[CH2:25]O)=[O:8])[CH2:5][CH2:4]1)#[N:2].[F:27]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.C(N(CC)CC)C>O1CCCC1>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[CH2:25][F:27])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2CO)CC1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2CF)CC1
Yield: 24.3 %

Procedure:
A mixture of (1R,2R,4S)-4-(2-Chloro-4-fluoro-benzenesulfonyl)-2-hydroxymethyl-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (41 mg), perfluoro-1-butanesulfonyl fluoride (62 mg), triethylamine (62 mg) and triethylamine.trishydrofluoride salt (33 mg) in tetrahydrofuran (1 mL) was stirred 24 h at room temperature. The mixture was then adsorbed unto silica and was purified by flash chromatography on silica gel with a gradient of cyclohexane:ethyl:acetate (3:1 to 1:1 v/v) as eluant to afford the title compound (10 mg, 24%) as a colorless solid. MS (EI): 403.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[CH:13][NH:12][C:11]=2[C:15]([NH2:17])=[O:16])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]=[CH:13][NH:12][C:11]=2[C:15]([NH2:17])=[O:16])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: NC(=O)c1[nH]cnc1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1[nH]cnc1-c1ccc(N)cc1
Yield: 97.8 %

Procedure:
To a suspension of 0.009 g (0.081 mmol) of 10% palladium-on-charcoal in 20 cm3 of methanol is added, at a temperature in the region of 20° C., 0.04 g (0.172 mmol) of 5-(4-nitrophenyl)-3H-imidazole-4-carboxamide. After hydrogenating for 3 hours in an autoclave under 3 bar of hydrogen, at a temperature in the region of 25° C., the reaction mixture is filtered. The catalyst is rinsed with twice 2 cm3 of methanol and the filtrate is then concentrated to dryness under reduced pressure (2.7 kPa) to give 0.034 g of 5-(4-aminophenyl)-3H-imidazole-4-carboxamide in the form of a brown solid; EI: m/z=202: M+; Cl: m/z=203: [M+H]+; ES+: m/z=203: [M+H]+; ES−: m/z=201: [M−H]−.
Reaction SMILES: C([O-])(O)=O.[Na+].[OH:6][CH2:7][CH2:8][N:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][C:13]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:14][CH:15]=2)[C:10]1=[O:25].[CH:26]1[C:38]2[CH:37]([CH2:39][O:40][C:41](Cl)=[O:42])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]=2[CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH:26]1[C:38]2[CH:37]([CH2:39][O:40][C:41]([N:22]3[CH2:23][CH2:24][N:19]([C:13]4[CH:12]=[C:11]5[C:16]([CH:17]=[CH:18][N:9]([CH2:8][CH2:7][OH:6])[C:10]5=[O:25])=[CH:15][CH:14]=4)[CH2:20][CH2:21]3)=[O:42])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]=2[CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: O=c1c2cc(N3CCNCC3)ccc2ccn1CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCN(c2ccc3ccn(CCO)c(=O)c3c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
To a solution of sat. aqueous NaHCO3 (80 mL), compound 8 (4.3 g, 15.7 mmol) in tetrahydrofuran was added chloroformic acid 9-fluorenylmethyl ester (1.5 eq.). The mixture was stirred for 2 h at room temperature, then concentrated. The residue was extracted with ethyl acetate, dried (sodium sulfate) and concentrated in vacuo to give 9 (4.6 g, yield 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:32]([F:35])([F:34])[F:33])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][C:28](=[O:30])[NH:27][CH2:26]4)=[O:24])=[C:19]([CH3:31])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CN(C)C=O.[H-].[Na+].FC(F)(F)S(O[CH2:49][C:50]([F:53])([F:52])[F:51])(=O)=O>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:32]([F:33])([F:34])[F:35])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][C:28](=[O:30])[N:27]([CH2:49][C:50]([F:53])([F:52])[F:51])[CH2:26]4)=[O:24])=[C:19]([CH3:31])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=O)N1CNC(=O)C1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=O)N1CC(=O)N(CC(F)(F)F)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylphenyl)carbonyl]imidazolidin-4-one (80 mg, 0.15 mmol, 1.00 equiv), N,N-dimethylformamide (5 mL). This was followed by the addition of NaH (60%) (12.3 mg, 0.51 mmol, 2.00 equiv) in several batches at 0° C. The resulting solution was stirred for 30 min at 0° C. To this was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (71 mg, 0.31 mmol, 2.00 equiv). The resulting solution was allowed to react, with stirring, for an additional 3 h at room temperature. The reaction was then quenched by the addition of 20 mL of water/ice. The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined. The mixture was dried over anhydrous sodium sulfate. This resulted in 14 mg (15%) of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylphenyl)carbonyl]-3-(2,2,2-trifluoroethyl)imidazolidin-4-one as a light yellow solid. (ES, m/z): [M+CH3CN]+ 643; 1H NMR (300 MHz, CDCl3): δ 7.82 (s, 1H), 7.76 (s, 1H), 7.697 (s, 1H), 7.58-7.61 (m, 2H), 7.28-7.34 (m, 1H), 5.196 (s, 1H), 4.911 (s, 1H), 4.646 (s, 1H), 4.03-4.18 (m, 2H), 3.998 (s, 1H), 3.70-3.76 (m, 1H), 2.399 (s, 3H).
Reaction SMILES: I.CO[C:4]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[CH:8][CH:7]=[CH:6][C:5]=1[CH:18]([CH3:22])[C:19]([OH:21])=[O:20].S([O-])(O)=O.[Na+]>C(OC(=O)C)(=O)C>[CH3:22][CH:18]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[O:20][C:19]1=[O:21]
Reactant: COc1c(Oc2ccccc2F)cccc1C(C)C(=O)O
Agent: I
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC1C(=O)Oc2c(Oc3ccccc3F)cccc21
Yield: 57.7 %

Procedure:
Hydriodic acid (55-58%, 30 ml) was added portionwise to a solution of 2-[2-methoxy-3-(2-fluorophenoxy)phenyl]propionic acid (3.8 g) in acetic anhydride (15 ml) with stirring under ice-cooling, and the mixture was refluxed under heating for 15 minutes. After cooling, the reaction mixture was poured into aqueous solution of sodium hydrogen sulfite and extracted with diethyl ether. The extract was washed with aqueous sodium hydrogen sulfite and water, dried and then evaporated. The residue was purified by column chromatography (silica gel, benzene) and crystallization from ethanol to give 3-methyl-7-(2-fluorophenoxy)-2,3-dihydrobenzofuran-2-one (1.95 g). mp 70°-71.5° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(Cl)nc2s1
Reactant: c1cn[nH]c1
Product: CCc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-ethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-ethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@@:8]2([CH3:19])[NH:13][C:12](=S)[C:11]([CH3:16])([CH3:15])[S:10](=[O:18])(=[O:17])[CH2:9]2)[CH:7]=1.[NH3:21]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:9][S:10](=[O:18])(=[O:17])[C:11]([CH3:16])([CH3:15])[C:12]([NH2:21])=[N:13]2)[CH:7]=1
Reactant: N
Reactant: CC1(C)C(=S)N[C@](C)(c2cc(Br)ccc2F)CS1(=O)=O
Product: CC1(C)C(N)=N[C@](C)(c2cc(Br)ccc2F)CS1(=O)=O
Temperature: 60 °C
Reaction time: 20 h
Yield: 81.6 %

Procedure:
A mixture of (R)-5-(5-bromo-2-fluoro-phenyl)-2,2,5-trimethyl-1,1-dioxo-1λ6-thiomorpholin-3-thione (1.28 g, 3.37 mmol, Eq: 1.00) and ammonia (7 N in MeOH) (38.5 ml, 269 mmol, Eq: 80) was stirred in a sealed tube for 20 hours at 60° C. Extracted with ethyl acetate/sat. NaHCO3-sol., dried the organic layer over Na2SO4, filtered and evaporated. The residue was chromatographed with ethyl acetate to give (R)-5-(5-bromo-2-fluoro-phenyl)-2,2,5-trimethyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (1 g, 2.75 mmol, 81.8% yield) as a white solid. MS (ISP): m/z=363.3 [M+H]+ and 365.3 [M+2+H]+.