Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[C:5]1([C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:12][CH2:13][CH2:14][SH:15])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>ClCCl>[C:5]1([C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:12][CH2:13][CH2:14][S:15][C:3]([NH:2][CH3:1])=[O:4])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
Methylisocyanate (243 mg) was dissolved in anhydrous dichloromethane (5 ml). To the solution were added N-triphenylmethylcysteamine (3.19 g: 0.33 equimolar amount) while cooling with ice. The reaction solution was stirred at room temperature for 4 hours and was concentrated under reduced pressure. The residue was dissolved in chloroform (50 ml), and the chloroform solution was well washed with water and a saturated solution of sodium chloride. Anhydrous sodium sulate was used to dry the chloroform layer which was then concentrated under reduced pressure. The residue was purified by silica gel chromatography using a solvent system of hexane/ethyl acetate (5:1 v/v) to obtain the desired substance (297 mg) with a yield of 79%.
Reaction SMILES: CC([O-])(C)C.[K+].C([O:12][N:13]=O)CC(C)C.[CH2:15]1[CH2:25][C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1.Cl>C1COCC1>[C:23]1(=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][C:25]1=[N:13][OH:12]
Reactant: O=C1CCCc2ccccc21
Reactant: CC(C)CCON=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1C(=NO)CCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the mixture of t-BuOK (1.2 eq.) in THF at 0° C. was added a solution of isoamylnitrite (1.2 eq.) and α-tetralone (Aldrich) (1.0 eq.) in THF dropwise. The reaction mixture was warmed to RT and stirred at RT for 2 h. The reaction mixture was stripped to dryness, mixed with ice-cooled HCl (1M), extracted with EtOAc, washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified with flash chromatography (silica gel, 2:1 hexane/EtOAc) to give the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]1)[C:14](=[O:26])[N:13]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1)[C:12]2=[O:38])C1C=CC=CC=1>C(O)=O>[CH3:37][O:36][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][C:31]=1[O:34][CH3:35])[CH2:27][N:13]1[C:12](=[O:38])[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=2)[N:15]([CH:19]2[CH2:20][CH2:21][S:22](=[O:25])[CH2:23][CH2:24]2)[C:14]1=[O:26]
Reactant: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCS(=O)CC3)c2=O)cc1OC
Solvent: O=CO
Product: COc1ccc(Cn2c(=O)c3cc(O)ccc3n(C3CCS(=O)CC3)c2=O)cc1OC
Yield: 93.5 %

Procedure:
A mixture of 0.57 g of the compound of Step 17.1 and 10 ml of formic acid is irradiated in a microwave field for 3 minutes at 140° C. The reaction mixture is evaporated under reduced pressure. The residue is chromatographed on an RP18 column, eluting with an ACN/water mixture from (10/90, v/v) to (50/50, v/v) to give 0.443 g of the expected product in the form of a mixture of two isomers.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[CH:19]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1>>[CH:24]([C:20]1[CH:19]=[C:18]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:31]4[CH:32]=[N:27][CH:28]=[N:29][CH:30]=4)[CH:3]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:23]=[CH:22][N:21]=1)([CH3:25])[CH3:26]
Reactant: CC(C)c1cc(C2(c3cccc(Br)c3)N=C(N)c3ccccc32)ccn1
Reactant: OB(O)c1cncnc1
Product: CC(C)c1cc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3ccccc32)ccn1
Yield: 58 %

Procedure:
The title compound was synthesized from 1-(3-bromophenyl)-1-(2-isopropylpyridin-4-yl)-1H-isoindol-3-amine (Example 113) as described in Example 67 Scheme #10, D in 58% yield using pyrimidine-5-boronic acid. 1H NMR (DMSO-d6) δ 9.11 (s, 1 H), 8.93 (s, 2 H), 8.30 (d, J=5.30 Hz, 1 H), 7.90-7.82 (m, 1 H), 7.81-7.69 (m, 1 H), 7.65-7.53 (m, 2 H), 7.49-7.33 (m, 4 H), 7.17-7.11 (m, 1 H), 7.07 (dd, J=5.31, 1.77 Hz, 1 H), 6.86 (br s, 2 H), 2.97-2.75 (m, 1 H), 1.08 (d, J=6.82 Hz, 6 H); MS (ESI) m/z 406 [M+1]+.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]([C:25]([O:27][CH3:28])=[O:26])=[N:17]1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:30][OH:31]>N1C=CC=CC=1>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([N:16]2[C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]([C:25]([O:27][CH3:28])=[O:26])=[N:17]2)=[C:9]([C:1](=[N:30][OH:31])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:14]=1
Reactant: NO
Reactant: COC(=O)c1cc(C(=O)OC)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)c1cc(C(=O)OC)n(-c2ccc(Cl)cc2C(=NO)c2ccccc2)n1
Temperature: 25 °C

Procedure:
A mixture of 11.2 g. (28 mmol) of the final product of Example 3, 5.80 g. (84 mmol) of hydroxylamine hydrochloride and 180 ml. pyridine was heated to reflux for 6.5 hours. After cooling to room temperature, the reaction was concentrated in vacuo to remove the pyridine. The crude product, as isolated, was then chromatographed on silica gel, using 10% EtOAc in benzene as eluent, to give the final product. Recrystallization from EtOH/H2O gave an analytical sample as colorless prisms mp: 177°-179°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[C:24](I)[CH:23]=2)[C:10]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:2].C([Sn](CCCC)(CCCC)[C:46]1[N:47]=[CH:48][S:49][CH:50]=1)CCC>C1(C)C=CC=CC=1.CCOC(C)=O.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>[CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:46]3[N:47]=[CH:48][S:49][CH:50]=3)[CH:25]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:27]=2)[C:10]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3cscn3)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Temperature: 90 °C
Yield: 99.4 %

Procedure:
To a solution of 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-iodo-5-methanesulfonyl-phenoxy)-hexyl]-phenoxy}-butyric acid ethyl ester (300 mg, 0.436 mmol) in toluene (20 mL), 4-(tributylstannyl)thiazole (243 mg, 0.25 mL, 0.653 mmol) was added, followed by Pd(PPh3)4 (25 mg, 0.0217 mmol). The reaction mixture was heated at 90° C. overnight. The reaction was diluted with EtOAc (250 mL), washed with water (100 mL). The organic layer was washed with brine, dried over Na2SO4, concentration under reduced pressure gave an oil which was purified by column chromatography. The title compound was eluted with 50% EtOAc/Hexanes to provide title compound (280 mg, 99%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Br[CH2:15][CH2:16][CH2:17][OH:18].C([O-])([O-])=O.[K+].[K+].Cl>CN1C(=O)CCC1>[OH:18][CH2:17][CH2:16][CH2:15][O:12][C:9]1[CH:10]=[CH:11][C:6](/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:13])=[CH:7][CH:8]=1
Reactant: OCCCBr
Reactant: COC(=O)C=Cc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)/C=C/c1ccc(OCCCO)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 29.2 %

Procedure:
15 g (84.2 mmol) of 4-hydroxycinnamic acid methyl ester, 14 g (101 mmol) of 3-bromo-1-propanol, 23.4 g of K2CO3 are dissolved in 90 mL of NMP. The solution is heated up to 80° C. and stirred for 20 hours. Then, the reaction mixture is cooled down to room temperature and carefully acidified with 1N HCl solution. The solution is extracted with ethylacetate. The organic phase is dried over sodium sulfate, filtrated and concentrated under reduced pressure. Chromatography of the residue on silica gel using hexane:ethyl acetate 7:3 as eluent yielded 5.8 g of methyl (2E)-3-[4-(3-hydroxypropoxy)phenyl]prop-2-enoate as a white solid.
Reaction SMILES: [C:1]([CH:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([C:24](=[O:26])[CH3:25])C(OC)=O)C(OC)=O)(=[O:3])[CH3:2].[Cl-].[Na+].O>CS(C)=O>[CH3:2][C:1](=[O:3])[CH2:4][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:24](=[O:26])[CH3:25]
Reactant: COC(=O)C(CCCCCCCCCCC(C(C)=O)C(=O)OC)C(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)CCCCCCCCCCCCC(C)=O

Procedure:
0.37 g (1 mmol) of dimethyl 2,13-bisacetyl-1,14-tetradecanedioate were dissolved in 20 ml of DMSO and refluxed with 0.06 g (0.1 mmol) of sodium chloride and 0.04 g (2 mmol) of water for 3 h at 155 to 160° C. For work-up, the DMSO is firstly distilled off under reduced pressure, and the residue is distilled using a bulb tube. This gives 0.21 g of hexadecane-1,15-dione. Accordingly, the yield of 1,15-hexadecanedione is 82%, based on 1,9-decadiene.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[N:15]1([CH2:21][CH2:22][C:23]2[N:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]3=[C:25]([C:32](Cl)=[O:33])[N:24]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>C(Cl)Cl>[N:1]1([C:32]([C:25]2[N:24]=[C:23]([CH2:22][CH2:21][N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[N:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=23)=[O:33])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1nc(CCN2CCOCC2)n2ccccc12
Reactant: C1COCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1nc(CCN2CCOCC2)n2ccccc12)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
To a solution of morpholine (0.050 mL, 0.54 mmol) and triethylamine (0.16 mL, 1.14 mmol) in CH2Cl2 (10 mL) was added 3-(2-morpholin-4-yl-ethyl)-imidazo[1,5-a]pyridine-1-carbonyl chloride hydrochloride (150 mg, 0.45 mmol). The mixture was stirred at ambient temperature for 1 h then washed with sat. aq. NaHCO3 (20 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (85 mg, 55%). 1H NMR (DMSO-d6) δ 8.35 (1H), 8.05 (1H), 7.08 (1H), 6.85 (1H), 3.65 (4H), 4.05 (4H), 3.53 (4H), 3.18 (2H), 2.75 (2H), 2.45 (4H); m/z (M+H)=345.21.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([CH3:21])=[N:11][C:12]([O:16][CH2:17][C:18]([OH:20])=O)=[N:13][C:14]=1[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22]1([CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([NH:32][CH3:33])[CH2:28][CH2:27]2)[CH2:24][CH2:23]1.C(N(CC)CC)C.C([O-])(=O)C>C(#N)C>[CH:22]1([CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([N:32]([CH3:33])[C:18](=[O:20])[CH2:17][O:16][C:12]3[N:13]=[C:14]([CH3:15])[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[C:10]([CH3:21])[N:11]=3)[CH2:28][CH2:27]2)[CH2:23][CH2:24]1
Reactant: CNC1CCN(CC2CC2)CC1
Reactant: Cc1nc(OCC(=O)O)nc(C)c1NC(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc(OCC(=O)N(C)C2CCN(CC3CC3)CC2)nc(C)c1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
Compound 9 (100 mg), 1-(cyclopropylmethyl)-N-methylpiperidine-4-amine (56.6 mg) and triethylamine (234 μL) were suspended in acetonitrile (2 mL). While the suspension was cooled with ice, a 50% propane phosphonic acid anhydride ethyl, acetate solution (273 mg) was added portionwise. The equipment used to add the 50% propane phosphonic acid anhydride ethyl acetate solution was thoroughly washed with acetonitrile (0.5 mL) and was stirred at room temperature (20 to 30° C.) overnight. Subsequently, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by amino-coated silica gel (Fuji Sylysia Chemical Ltd.; NH-DM1020) column chromatography (methylene chloride:methanol=30:1) to give 79 mg (52% yield) of the desired product as a pale yellow amorphous.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.C1(P(C2C3CC4C(=CC=CC=4)OC=3C=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].[C:53](=[NH:66])([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[Cl:8][C:5]1[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:3][C:2]([N:66]=[C:53]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[CH:7][N:6]=1
Reactant: O=S(=O)(Nc1cc(Br)cnc1Cl)c1ccc(F)cc1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: O=S(=O)(Nc1cc(N=C(c2ccccc2)c2ccccc2)cnc1Cl)c1ccc(F)cc1
Temperature: 100 °C
Yield: 40.7 %

Procedure:
A mixture of N-(5-bromo-2-chloropyridin-3-yl)-4-fluorobenzenesulfonamide (Inogent, Inc.) (1.000 g, 2.74 mmol), palladium (II) acetate (Aldrich) (0.035 g, 0.156 mmol), (diphenylphosphino)xanthene (Acros) (0.176 g, 0.304 mmol), sodium tert-butoxide (Fluka) (0.620 g, 6.45 mmol), toluene (10 mL), and benzophenone imine (Aldrich) (0.459 mL, 2.74 mmol) was heated at 100° C. in a sealed tube for 6 h. The reaction mixture was partitioned between EtOAc and Tris HCl (1 M, pH 7). The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (120 g, 10% to 20% acetone in hexanes) to give the product as a yellow solid (0.520 g). m/z (ESI, +ve ion) 466.0 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 7.75 (d, J=7.45 Hz, 2H); 7.61 (d, J=2.05 Hz, 1H); 7.50-7.59 (m, 3H); 7.40-7.49 (m, 3H); 7.35 (br. s., 3H); 7.03-7.17 (m, 4H); 6.73 (br. s., 1H).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[C:9]([CH2:11][O:12][C:13]([C:15]2[N:16]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:17](=[O:32])[C:18]3[C:23]([C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:22][C:21]([Br:31])=[CH:20][CH:19]=3)=[O:14])[CH:8]=[CH:7][N:6]=1)([OH:4])=[O:3].S(=O)(=O)(O)O.[CH3:45]O>>[CH3:45][O:3][C:2]([C:5]1[CH:10]=[C:9]([CH2:11][O:12][C:13]([C:15]2[N:16]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:17](=[O:32])[C:18]3[C:23]([C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:22][C:21]([Br:31])=[CH:20][CH:19]=3)=[O:14])[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: CO
Reactant: O=C(O)c1cc(COC(=O)c2c(-c3ccccc3)c3cc(Br)ccc3c(=O)n2Cc2ccccc2)ccn1
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(COC(=O)c2c(-c3ccccc3)c3cc(Br)ccc3c(=O)n2Cc2ccccc2)ccn1

Procedure:
To a solution (3.0 ml) of 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid 2-carboxypyridin-4-ylmethyl ester hydrochloride (120 mg) in methanol was added conc. sulfuric acid (0.3 ml) at 0° C. with stirring, and the mixture was stirred at 50° C. for 48 hrs. After cooling the mixture, the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane/ethyl acetate=4/1-1/1) to give the title compound (73 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].C(O)(=O)C.[C:11]([NH:14][C:15]([NH2:17])=[S:16])(=N)[NH2:12]>C(O)C>[CH2:1]([NH:6][C:11]([NH:14][C:15]([NH2:17])=[S:16])=[NH:12])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: N=C(N)NC(N)=S
Reactant: CCCCCN
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCCNC(=N)NC(N)=S
Temperature: 85 °C

Procedure:
To a one liter, 3-necked round bottom flask which was equipped with a mechanical stirrer, thermometer, and reflux condenser were added absolute ethanol (180 ml.) and pentylamine (100.0 g., 1.15 mol). The amine solution was cooled in an ice bath while glacial acetic acid (68.9 g., 1.15 mol) was slowly added. Amidinothiourea (90.37 g., 0.76 mol) was added and then the mixture was heated to reflux (85° C.). After 24 hours at reflux, HPLC analysis of the reaction solution indicated that title product (72.6 area %) had formed and that residual amidinothiourea (8.5 area %) remained.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([N:12]=[CH:13][C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:20][CH2:21][O-:22].[Na+]>>[CH2:21]([O:22][C:2]1[C:3]2[N:4]([N:12]=[CH:13][C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:20]
Reactant: CCOC(=O)c1cnn2c1c(Cl)nc1ccccc12
Reactant: CC[O-]
Agent: [Na+]
Product: CCOC(=O)c1cnn2c1c(OCC)nc1ccccc12

Procedure:
5.5 g. of 4-chloropyrazolo[1,5-a]quinoxaline-3-carboxylic acid, ethyl ester is heated for two hours with 10 ml. of a 2 molar sodium ethylate solution. The hot reaction solution is filtered and, upon cooling, 4-ethoxypyrazolo[1,5-a]quinoxaline-3-carboxylic acid, ethyl ester crystallizes in the form of white needles. The product is recrystallized from ethanol to obtain 3.4 g. of white crystals, m.p. 88°-90°.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][OH:12]>[O-2].[Mn+2].C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12]
Reactant: OCc1ccccc1CCCCCCCBr
Agent: [Mn+2]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: O=Cc1ccccc1CCCCCCCBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To ethyl acetate (150 ml), cooled to 0° C., was added manganese oxide (15 g) followed by 2-(7-bromoheptyl) benzyl alcohol (3.39 g, 1.2 mmoles). The reaction mixture was permitted to warm to room temperature slowly, and stirred for 1 hour. The mixture was then cooled to 0° C. and stirred for 18 hours. Subsequently the mixture was filtered and evaporated to yield the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.Br[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[CH2:24]Br)[CH:17]=[CH:16][CH:15]=1.[H-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([C:8]2=[O:11])[CH2:24][C:22]2[C:23]4[C:18]([CH:19]=[CH:20][CH:21]=2)=[CH:17][CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: BrCc1cccc2cccc(CBr)c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1c2cc(Br)ccc2CC12Cc1cccc3cccc(c13)C2
Yield: 55.9 %

Procedure:
A mixture of 6-bromo-2,3-dihydro-1H-inden-1-one (400 mg, 1.9 mmol) and 1,8-bis(bromomethyl)naphthalene (596 mg, 1.9 mmol) in THF (20 mL) was added NaH (152 mg, 3.8 mmol) at room temperature, the mixture was heated under reflux for 2 h. The mixture was quenched with water, concentrated, then extracted with CH2Cl2, washed with brine, dried over Na2SO4 and concentrated to give 6-bromo-1′,3′-dihydrospiro[indene-2,2′-phenalen]-1(3H)-one (386 mg, 56%). 1H-NMR (CDCl3): 2.79 (d, 2H), 3.50 (d, 2H), 7.12 (m, 1H), 7.18 (m, 2H), 7.36 (m, 2H), 7.60 (m, 1H), 7.71 (m, 1H), 7.92 (m, 1H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([S:33]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=3)=[O:9])[NH:23][C:24]=2[C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[CH:18][CH:19]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2nc(Sc3cccc(OC)c3)[nH]c2-c2ccc(OC)cc2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3cccc(OC)c3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 4.19 g of 4,5-bis(4-methoxyphenyl)-2-(3-methoxyphenylthio)imidazole in 100 ml of dichloromethane. The solution is stirred for 3 hours at room temperature, washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with acetone/hexane, thus obtaining 3.96 g of 4,5-bis(4-methoxyphenyl)-2-(3-methoxyphenylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: [Si]([O:18][C:19]1[CH:20]=[C:21]([C@:26]([NH:45][C:46]([NH:48][CH2:49][C:50]([F:53])([F:52])[F:51])=[O:47])([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[C:36]([C:41]([F:44])([F:43])[F:42])[CH:35]=2)[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=[C:23]([F:25])[CH:24]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(Cl)Cl>[F:40][C:37]1[CH:38]=[CH:39][C:34]([C@@:26]([NH:45][C:46]([NH:48][CH2:49][C:50]([F:51])([F:52])[F:53])=[O:47])([C:21]2[CH:20]=[C:19]([OH:18])[CH:24]=[C:23]([F:25])[CH:22]=2)[CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:35][C:36]=1[C:41]([F:44])([F:42])[F:43]
Reactant: CC(C)(C)[Si](Oc1cc(F)cc([C@](Cc2ccccc2)(NC(=O)NCC(F)(F)F)c2ccc(F)c(C(F)(F)F)c2)c1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(NCC(F)(F)F)N[C@@](Cc1ccccc1)(c1cc(O)cc(F)c1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 78.9 %

Procedure:
To a solution of (R)-1-(1-(3-(tert-butyldiphenylsilyloxy)-5-fluorophenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)urea (85 mg, 0.11 mmol) in THF (1.5 mL) was added TBAF (1.0 M in THF, 0.12 mL, 0.12 mmol). The resulting mixture was stirred at room temperature for 45 min. The reaction was diluted with CH2Cl2 and washed with sat. NH4Cl, H2O and sat. NaCl, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash chromatography (silica gel, hexanes/EtOAc) to give (R)-1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-hydroxyphenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)urea (Example 254, 45 mg, yield 77%). LCMS: RT=2.0 min [M+H] 519.1 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 7.20-7.27 (3H, m), 7.09-7.18 (3H, m), 6.72 (1H, d, J=9.60 Hz), 6.66 (3H, d, J=7.07 Hz), 6.57 (1H, s), 3.73-3.78 (1H, m), 3.65-3.71 (1H, m), 3.63 (1H, d, J=8.59 Hz), 3.47-3.58 (1H, m).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[C:8]([O:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:9][C:10]([N+:16]([O-:18])=[O:17])=[C:11]([CH:15]=1)[C:12](O)=[O:13].C[N:30](C=O)C>>[CH3:5][O:6][C:7]1[C:8]([O:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:9][C:10]([N+:16]([O-:18])=[O:17])=[C:11]([CH:15]=1)[C:12]([NH2:30])=[O:13]
Reactant: CN(C)C=O
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OCCCN1CCOCC1
Solvent: O=S(Cl)Cl
Product: COc1cc(C(N)=O)c([N+](=O)[O-])cc1OCCCN1CCOCC1
Temperature: 50 °C

Procedure:
Thionyl chloride (15 ml) and DMF (0.05 ml) were added to 5-methoxy-4-(3-morpholinopropoxy)-2-nitrobenzoic acid (7.54 g). The mixture was heated at 50° C. for 1 hour, the excess thionyl chloride was removed by evaporation and by azeotroping with toluene (x2). The resulting solid was suspended in THF (200 ml) and ammonia was bubbled through the mixture for 30 minutes. The precipitate was removed by filtration and washed with THF. After concentration of the filtrate by evaporation, the product crystallised and was collected by filtration to give 5-methoxy-4-(3-morpholinopropoxy)-2-nitrobenzamide (5.25 g) as light yellow crystals which were used without further purification.