Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2O)CCc2ccc(C#N)cc2)cc1
Reactant: BrCCCCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCCCCCCc2ccccc2)CCc2ccc(C#N)cc2)cc1

Procedure:
A solution of 200 mg (0.49 mmol) of methyl 4-[(3E)-2-[2-(4-cyanophenyl)ethyl]-4-(2-hydroxyphenyl)but-3-en-1-yl]benzoate in 25 ml of acetonitrile is mixed with 176 mg (0.73 mmol) of (6-bromohexyl)benzene and 101 mg (0.73 mmol) of potassium carbonate and then stirred under reflux for 12 h. After cooling, the potassium carbonate is filtered off and the filtrate is evaporated. 364 mg (0.48 mmol, 98% of theory, purity 76%) of a yellowish oil are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]#[N:8])=[C:5]([N+:9]([O-:11])=[O:10])[N:4]=[C:3]1[CH2:12][OH:13].[CH3:14][N:15]([CH3:19])[C:16](Cl)=[O:17]>N1C=CC=CC=1>[CH3:1][N:2]1[C:6]([C:7]#[N:8])=[C:5]([N+:9]([O-:11])=[O:10])[N:4]=[C:3]1[CH2:12][O:13][C:16](=[O:17])[N:15]([CH3:19])[CH3:14]
Reactant: CN(C)C(=O)Cl
Reactant: Cn1c(CO)nc([N+](=O)[O-])c1C#N
Solvent: c1ccncc1
Product: CN(C)C(=O)OCc1nc([N+](=O)[O-])c(C#N)n1C

Procedure:
1.8 G. (0.01 moles) of 1-methyl-2-hydroxymethyl-4-nitro-5-cyanoimidazole and 2.14 g. (0.12 moles) of dimethylcarbamoyl chloride are combined in 15 ml. of pyridine and heated at 100°C. for 24 hours. The reaction mixture is evaporated to dryness, treated with 50 ml. of water and extracted with methylene chloride. The combined methylene chloride extracts are washed with water, dried, evaporated to dryness and the residue triturated with ether. The solid material is filtered and crystallized from isopropanol affording 1-methyl-2-(N,N-dimethylcarbamoyloxymethyl)-4-nitro-5-cyanoimidazole, m.p. 85° to 88°C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][NH:10][N:9]=[C:8]2[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[S:31])=[CH:25][CH:24]=1.C(Cl)Cl>CCOCC>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([N:10]2[CH2:11][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][CH:13]=3)=[N:9]2)=[S:31])=[CH:25][CH:24]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: FC(F)(F)c1ccc(C2=NNCC2c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: FC(F)(F)c1ccc(C2=NN(C(=S)Nc3ccc(Cl)cc3)CC2c2ccccc2)cc1
Reaction time: 8 h
Yield: 62.2 %

Procedure:
A mixture of 0.7 g of the compound from Step B and 0.41 g of 4-chlorophenyl isothiocyanate were combined in a solvent mixture of 2 mL methylene chloride and 5 mL ether. After stirring overnight the precipitated solids were filtered and dried to afford 0.69 g of the title compound as a white solid, mp 208°-210° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([C:18](=[O:19])[NH:17][C:16](=[O:20])[NH:15]2)[C:7]1=[O:21].[H-].[Na+].Br[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:31](=[O:32])[O:30]1.Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([C:18](=[O:19])[NH:17][C:16](=[O:20])[N:15]2[CH:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:31](=[O:32])[O:30]2)[C:7]1=[O:21]
Reactant: O=C1OC(Br)c2ccccc21
Reactant: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1OC(N2C(=O)NC(=O)C23C(=O)N(Cc2ccc(Cl)c(Cl)c2)c2ccccc23)c2ccccc21
Reaction time: 0.5 h
Yield: 16.4 %

Procedure:
1'-(3,4-Dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (1.8 g.) was stirred in anhydrous N,N-dimethylformamide (50 ml.) under an atmosphere of nitrogen at 25° C. Sodium hydride (0.25 g; 50% w/v oil dispersion) was added, and the mixture stirred for 30 minutes. 3-Bromophthalide (1.15 g.) was then added. The mixture was stirred for 16 hours and then poured into water (150 ml.). The mixture was acidified (concentrated hydrochloric acid) and then extracted with ethyl acetate (150 ml.). The extract was washed with water (2×150 ml.), brine (150 ml.) and then dried (MgSO4). The dry solution was evaporated onto silica gel (10 g., Merck type 7734) which was then added to the top of a column of silica gel (150 g., Merck type 7734) made up in toluene. The column was eluted with an increasing concentration of ethyl acetate in toluene up to 25% v/v. The fractions containing the major product [Relative flow value: 0.5 on Merck SiO2TLC plates No. 5715; eluant: EtOAc/toluene, 1:1 v/v] were collected and evaporated to give an oil which crystallised on treatment with ethyl acetate/petrol 60-80 to give 1'-(3,4-dichlorobenzyl)-3-phthalidyl-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (0.4 g.), m.p. 154°-158° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]([CH2:20][CH3:21])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=2)[CH2:4][C@H:3]1[O:22][CH2:23][CH2:24][CH3:25].[Cl:26][C:27]1[N:28]=[C:29]([C:34](O)=[O:35])[NH:30][C:31]=1[CH2:32][CH3:33].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.ClCCl>[Cl:26][C:27]1[N:28]=[C:29]([C:34]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[O:9][C:10]([CH2:20][CH3:21])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=3)[CH2:4][C@H:3]2[O:22][CH2:23][CH2:24][CH3:25])=[O:35])[NH:30][C:31]=1[CH2:32][CH3:33]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](N)[C@H](OCCC)C2)oc1CC
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCCC)C2)oc1CC
Yield: 41.2 %

Procedure:
The same operation as in Example (106d) was performed using butyl cis(±)-2-(4-amino-3-propoxypiperidin-1-yl)-5-ethyl-1,3-oxazole-4-carboxylate obtained in Example (113h) (0.70 g, 2.0 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 0.2 g, 1 mmol), WSC hydrochloride (0.5 g, 2.5 mmol), HOBt (0.2 g, 1.5 mmol), dichloromethane (5 mL) and DMA (3 mL), to obtain 0.21 g of the title compound as a colorless amorphous solid (41%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]1[OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.[Pt]>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:18][CH:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:11][CH:10]1[OH:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1Cc2ccccc2CC1O
Agent: [Pt]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1CC2CCCCC2CC1O
Yield: 85.2 %

Procedure:
A solution of 3-tert-butoxycarbonylamino-1,2,3,4-tetra-hydro-2-naphthalenol (1.05 g) in acetic acid (100 ml) was hydrogenated over platinum oxyde (121 mg) under pressure (5.5.6 bars) at room temperature for 3 days. The catalyst was filtered and the solvent was evaporated under vacuum. The residue was purified by chromatography on silica gel [140 g, elution with ethyl acetate:cyclohexane, 2:8 (0.7 1) and 5:7 (1 1)]to afford the title compound as an oil (915 mg).
Reaction SMILES: [CH2:1]([N:4]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:29])C=1.S([O-])(O)=O.[Na+]>ClCCl>[CH2:14]([O:13][C:11]([N:4]([CH2:1][CH:2]1[O:29][CH2:3]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=CCN(C(=O)OCc1ccccc1)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N(CC1CO1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.7 %

Procedure:
Under nitrogen, to a solution of N-allyl-N-phenyl-benzyloxycarbonylamine (5.5 g) in dichloromethane (50 ml) was added m-chloroperbenzoic acid (3.9 g) at 5° C., and the mixture was stirred at room temperature for 3 days. The resulting mixture was poured into aqueous sodium hydrogensulfite and extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=10:1 to 5:1) to give 1-(N-benzyloxycarbonyl-N-phenylamino)-2,3-epoxypropane (2.2 g).
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:13]([CH:16]1[CH2:21][CH2:20][CH:19](Br)[CH2:18][CH2:17]1)[CH2:14][CH3:15]>C(O)C>[CH2:13]([CH:16]1[CH2:21][CH2:20][CH:19]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:18][CH2:17]1)[CH2:14][CH3:15]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCC1CCC(Br)CC1
Agent: [Na]
Solvent: CCO
Product: CCCC1CCC(C(C(=O)OCC)C(=O)OCC)CC1
Temperature: 25 °C
Yield: 43.2 %

Procedure:
31 g (1.35 mol) of sodium was dissolved in 660 cm3 of anhydrous ethanol, after which 216 g (1.35 mol) of diethyl malonate and then 180 g (0.88 mol) of 4-propylbromocyclohexane were added in single additions, and it was refluxed for 10 hours on a hot water bath. The reactant was cooled to room temperature, and after filtering the NaBr crystals that had formed, the ethanol in the filtrate was removed. Water was added to the residue, it was extracted with chloroform, and washed with water. The chloroform was removed, and the remaining oily substance was distilled under reduced pressure (b. p. 138° C./1.4 mmHg) to obtain 108 g (0.38 mol) of diethyl 4-propylcyclohexylmalonate (trans-cis form mixture).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[C:5]1([CH3:17])[CH:10]=[CH:9][C:8]([S:11](N=C=O)(=[O:13])=[O:12])=[CH:7][CH:6]=1>O1CCOCC1>[C:5]1([CH3:17])[CH:10]=[CH:9][C:8]([S:11]([NH:1][C:2]([NH2:4])=[S:3])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: NC(N)=S
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)NC(N)=S)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
In a 100 mL RBF equipped with a condenser, thermo-probe, sealed system nitrogen purge, pressure-equilibrated addition funnel and magnetic stirrer were placed thiourea (9.36 g, 0.12 mol) and dioxane (50 mL). The mixture was warmed to a temperature of 100° C. to encourage dissolution. The mixture was then cooled to a temperature of about 20° C., at which point para-toluenesulfonylisocyanate (25.0 g, 0.12 mol) was added slowly over a period of time of 1 hour. A milky-white suspension was observed to form. The temperature was maintained with an ice-water bath between 20° C. and 32° C. The reaction mixture was stirred overnight at room temperature before it was concentrated in vacuo at a temperature of 40° C. to yield a white solid that was further dried to constant weight in vacuo at a temperature of 50° C. and a pressure of <1 mTorr.
Reaction SMILES: [N:1]1([CH:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([NH2:18])[CH:16]=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([N:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])[C:23]([Cl:39])=[CH:22][N:21]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(O)(C)C>>[Cl:39][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([N:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])=[N:25][C:20]([NH:18][C:15]2[CH:16]=[CH:17][C:10]3[CH2:9][CH2:8][CH:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH2:13][CH2:12][C:11]=3[CH:14]=2)=[N:21][CH:22]=1
Reactant: Nc1ccc2c(c1)CCC(N1CCOCC1)CC2
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCC(N2CCOCC2)CC3)ncc1Cl
Yield: 8.4 %

Procedure:
7-Morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (18.0 mg, 0.0000731 mol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide (25.0 mg, 0.0000720 mol) and 10-Camphorsulfonic acid (17.0 mg, 0.0000732 mol) were dissolved in Isopropyl alcohol (3.0 mL, 0.039 mol) and the reaction was microwaved on 300 watts, 140° C. for 20 minutes. The mixture was then reduced under nitrogen. The crude residue was isolated and purified by Gilson prep HPLC to afford 3.35 mg (8%) of 2-[5-Chloro-2-(7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-N,N-dimethyl-benzenesulfonamide. LC/MS (ESI): 557.18. 1H NMR (400 MHz, DMSO, d6) δ 7.60 (d, 1H, J=8.59 Hz), 7.26 (s, 1H), 7.00 (d, 1H, J=8.09 Hz), 6.76 (t, 1H, J=7.58 Hz), 6.48 (t, 2H, J=7.57 Hz), 6.40 (d, 1H, J=8.34 Hz), 6.18 (d, 1H, J=8.09 Hz), 3.17 (d, 2H, J=13.39 Hz), 2.90 (m, 2H), 2.61 (t, 1H, J=12.89 Hz), 2.45 (m, 4H), 2.03 (m, 1H), 1.95 (m, 3H), 1.81 (s, 6H), 1.50 (m, 2H), 0.66 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2](/[CH:1]=[CH:14]/[N:15]([CH3:17])[CH3:16])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)/C=C/c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of 1-methyl-2-nitro-4-bromobenzene (17) (29.86 g, 138.2 mmol) in toluene (200 mL) was added dimethylformamide dimethylacetal (17.52 g, 138.2 mmol). The mixture was heated to reflux for 14 hours. After cooling to room temperature the mixture was concentrated under vacuum and the resulting oil was immediately used in the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([CH3:17])([CH2:14][CH:15]=C)[CH:12]=[O:13].[BH4-].[Na+].ClCCl.C[OH:24]>[Cl-].[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([CH3:17])([CH2:14][CH2:15][OH:24])[CH2:12][OH:13]
Reactant: CO
Reactant: C=CCC(C)(C=O)c1cc([N+](=O)[O-])ccc1F
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(CO)(CCO)c1cc([N+](=O)[O-])ccc1F
Temperature: -78 °C

Procedure:
2-(2-fluoro-5-nitrophenyl)-2-methylpent-4-enal(1 eq) was dissolved in dichloromethane:methanol (3:1) and cooled to −78° C. Ozone was then bubbled through the solution until a blue color was noticed. Air was then passed through the solution followed by the addition of sodium borohydride(5 eq). Resulting solution was allowed to warm to room temperature and diluted with brine, extracted with dichloromethane. Organics were dried with sodium sulfate and concentrated to afford 2-(2-fluoro-5-nitrophenyl)-2-methylbutane-1,4-diol. The product was used in the next step with no further characterization.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([NH:9][CH:10]2[CH:17]3[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:19][CH:11]2[CH2:12]4)[CH2:16]3)=[O:8])[CH2:3]1.CCN(C(C)C)C(C)C.Cl[C:30]([O:32][CH3:33])=[O:31].Cl>C(Cl)Cl>[CH:17]12[CH2:16][CH:15]3[CH2:14][CH:13]([CH2:12][CH:11]([CH2:19]3)[CH:10]1[NH:9][C:7]([N:4]1[CH2:5][CH2:6][C@@H:2]([NH:1][C:30](=[O:31])[O:32][CH3:33])[CH2:3]1)=[O:8])[CH2:18]2
Reactant: COC(=O)Cl
Reactant: N[C@@H]1CCN(C(=O)NC2C3CC4CC(C3)CC2C4)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N[C@@H]1CCN(C(=O)NC2C3CC4CC(C3)CC2C4)C1
Yield: 49.1 %

Procedure:
A vial equipped with a flea stir bar was charged with (R)-3-amino-N-(2-adamantyl)pyrrolidine-1-carboxamide (25 mg, 0.095 mmol), i-Pr2NEt (0.07 mL, 0.38 mmol) and CH2Cl2. The solution was stirred and methyl chloroformate (0.009 mL, 0.11 mmol) was added. The mixture was stirred overnight at rt and applied to a 10-mL ChemElut cartridge prewetted with 5% aq HCl (6 mL). The cartridge was eluted with ether (20 mL). The eluate was evaporated to dryness and the residue was purified by preparative HPLC to afford (R)-methyl 1-(2-adamantylcarbamoyl)pyrrolidin-3-ylcarbamate (15 mg, 49%). LC-MS Method 1, tR=1.5 min, m/z=322; 1H NMR (CDCl3) 1.60-2.00 (15H), 2.20 (m, 1H), 3.26 (m, 1H), 3.46 (m, 2H), 3.63 (m, 1H), 3.69 (s, 3H), 3.96 (s, 1H), 4.30 (1H), 4.60 (1H), 4.89 (d, 1H).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10][C:11]1[C:12](Cl)=[N:13][CH:14]=[C:15]([CH3:17])[CH:16]=1.O>CC(N(C)C)=O>[Br:10][C:11]1[C:12]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:13][CH:14]=[C:15]([CH3:17])[CH:16]=1
Reactant: Cc1cnc(Cl)c(Br)c1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cnc(Oc2ccccc2)c(Br)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
Sodium hydride dispersion in oil (˜70%, 0.68 g) was added in portions to a well stirred solution of phenol (1.33 g, 14 mmol) in DMA (100 mL). After stirring the mixture for 1 h at 50° C. 3-bromo-2-chloro-5-methyl-pyridine (2.68 g, 13 mmol) was added and stirring continued for 28 h at 100° C. The cooled mixture was poured into water and extracted with diethyl ether. Organic phases were pooled, dried with Na2SO4 and the solvent was evaporated. The residue was purified by column chromatography on silica (n-heptane/ethyl acetate 8:1) to yield 1.4 g of the title compound as a colorless oil, 1H NMR (CDCl3): δ=2.27 (s, 3H), 7.12 (d, 2H), 7.19 (t, 1H), 7.39 (t, 2H), 7.76 (s, 1H), 7.88 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18].C(O)(=O)C>C(O)C>[NH2:23][C:21]1[CH:20]=[CH:19][C:3]([CH2:4][N:5]2[C:9]3=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]3[N:7]=[C:6]2[CH3:18])=[C:2]([Cl:1])[CH:22]=1
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc([N+](=O)[O-])cc3Cl)c2n1
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(N)cc3Cl)c2n1
Yield: 94.1 %

Procedure:
Methyl 3-(2-chloro-4-nitrobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (705 mg) was suspended in ethanol (6 ml), and reduced iron (437 mg) and acetic acid (1.01 ml) were added. The mixture was refluxed under heating for 2 hr. Then, reduced iron (218 mg) and acetic acid (1.01 ml) were further added, and the mixture was refluxed under heating for 1 hr. The reaction mixture was filtered through Celite, the insoluble matter was washed with ethanol and the filtrate was concentrated under reduced pressure. To the concentrate were added a saturated aqueous sodium hydrogencarbonate solution and ethyl acetate to make the aqueous layer alkaline. At this stage, part of the objective compound was precipitated. The precipitate was collected by filtration and the filtrate was partitioned. The organic layer was washed successively with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The objective compound that precipitated during neutrlization was dissolved in a mixed solvent of methanol/chloroform (1/4), and the mixture was filtrated. Both filtrates were combined and concentrated under reduced pressure to give the objective compound (608 mg) as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30]C(=O)C(C)(C)C)[CH:24]=[CH:23][C:22]=3[CH2:21]2)=O)=[CH:4][CH:3]=1.Cl[CH:40]([CH3:49])[C:41]([N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)=O>>[CH3:19][O:18][C:16]1[CH:15]=[CH:14][C:13]([CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=3[CH2:21]2)=[C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:6][C:5]2[CH:37]=[CH:38][C:2]([O:1][CH:40]([CH3:49])[CH2:41][N:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)=[CH:3][CH:4]=2)[CH:17]=1
Reactant: CC(Cl)C(=O)N1CCCCC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCC(=O)c2ccc(O)cc2)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCCc2ccc(OC(C)CN3CCCCC3)cc2)c1
Yield: 29.8 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)propylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 2-chloro-1-piperidin-1-ylpropan-1-one (21 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (9.4 mg) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:19]1[CH:24]=[C:23]([N:25]2[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]([CH3:36])[C:26]2=[O:37])[C:22]([F:38])=[CH:21][C:20]=1[N+:39]([O-:41])=[O:40]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:19]2[CH:24]=[C:23]([N:25]3[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[N:27]([CH3:36])[C:26]3=[O:37])[C:22]([F:38])=[CH:21][C:20]=2[N+:39]([O-:41])=[O:40])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc(OCc4ccccc4)cc3)c([N+](=O)[O-])cc2F)c1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 44.1 %

Procedure:
A mixture of 1.71 g of 4-benzyloxyphenol and 4.0 ml of N,N-dimethylformamide was added dropwise into a mixture of 0.34 g of sodium hydride and 8.5 ml of N,N-dimethylformamide while cooling with ice, and the mixture was stirred for 20 minutes. A mixture of 3.0 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene (described later, produced in Intermediate Production Example 4) and 7.0 ml of N,N-dimethylformamide was added dropwise at the same temperature, and stirred for 1 hour. This reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed once with 1N hydrochloric acid and once with saturated saline and dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 2.0 g of 2-(4-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:16][C:15]3[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[C:13]=2[C:21]([O:23]CC)=[O:22])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[S:16][C:15]3[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[C:13]=2[C:21]([OH:23])=[O:22])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2)sc2c1CCCC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1c(NS(=O)(=O)c2ccc(F)cc2)sc2c1CCCC2
Temperature: 120 °C
Yield: 21.6 %

Procedure:
A solution of ethyl 2-(4-fluorobenzenesulphonylamino)-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylate (Intermediate 2, 0.12 g) and lithium hydroxide monohydrate (0.036 g) in a mixture of dioxane and water (2:1, 6 ml) was divided between two 2-5 ml microwave vials and the contents of each vial were stirred and heated in the microwave at 120° C. for 30 minutes. The two batches were combined, diluted with water and extracted with ethyl acetate. The aqueous phase was acidified to pH1 by addition of hydrochloric acid (1M) and the resultant suspension was extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of methanol and DCM (2.5%) to give a solid which was triturated with DCM. The resultant solid was collected by filtration to give 2-(4-fluorobenzenesulphonylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.024 g) as a light orange solid.