Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8](=[O:38])[N:9]=[C:10]([S:36][CH3:37])[C:11]([C:25]1[CH:30]=[C:29]([O:31][CH2:32][CH3:33])[CH:28]=[C:27]([OH:34])[C:26]=1[F:35])=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][CH2:47][O:48][CH:49]1[CH2:54][CH2:53][CH2:52][CH2:51][O:50]1>O>[CH3:6][O:7][C:8](=[O:38])[N:9]=[C:10]([S:36][CH3:37])[C:11]([C:25]1[CH:30]=[C:29]([O:31][CH2:32][CH3:33])[CH:28]=[C:27]([O:34][CH2:46][CH2:47][O:48][CH:49]2[CH2:54][CH2:53][CH2:52][CH2:51][O:50]2)[C:26]=1[F:35])=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: BrCCOC1CCCCO1
Reactant: CCOc1cc(O)c(F)c(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(OCCOC2CCCCO2)c(F)c(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To 2 ml of a DMF solution containing 75 mg of {2-(5-ethoxy-2-fluoro-3-hydroxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester, 100 mg of potassium carbonate and 0.1 ml of 2-(2-bromoethoxy)tetrahydro-2H-pyran were added. The resulting mixture was stirred at room temperature for 10 hours, and then water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed with water and then dried through PRESEP™. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give {2-{5-ethoxy-2-fluoro-3-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (51 mg) as a yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH2:4][S:5](=[O:62])[C@@H:6]2[CH:26]([NH:27][C:28](=[O:60])/[C:29](=[N:55]\[O:56][CH:57]([CH3:59])[CH3:58])/[C:30]3[N:31]=[C:32]([NH:35][C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[S:33][CH:34]=3)[C:25](=[O:61])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[I-].[Na+].Br.[OH:66][C:67]1[CH:68]=[C:69]2[C:73](=[CH:74][C:75]=1[OH:76])[CH2:72][NH:71][CH2:70]2.C(N(CC)CC)C>CC(C)=O>[OH:66][C:67]1[CH:68]=[C:69]2[C:73](=[CH:74][C:75]=1[OH:76])[CH2:72][N:71]([CH2:2][C:3]1[CH2:4][S:5](=[O:62])[C@@H:6]3[CH:26]([NH:27][C:28](=[O:60])/[C:29](=[N:55]\[O:56][CH:57]([CH3:59])[CH3:58])/[C:30]4[N:31]=[C:32]([NH:35][C:36]([C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)[C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[S:33][CH:34]=4)[C:25](=[O:61])[N:7]3[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH2:70]2
Reactant: Oc1cc2c(cc1O)CNC2
Reactant: CC(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Br
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CN3Cc4cc(O)c(O)cc4C3)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
2.0 g (2.26 mmol) of Benzhydryl 3-chloromethyl-7-[(Z)-2-isopropoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate 1-oxide was dissolved in 40 ml of acetone, and 750 mg (5 mmol) of sodium iodide was added thereto under cooling with ice. The mixture was stirred for 30 minutes. The reaction solution was concentrated under reduced pressure. To the residue, ethyl acetate and water were added. The organic layer was washed with a sodium metabisulfite aqueous solution and with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The oily residue was dissolved in 10 ml of N,N-dimethylformamide, and 790 mg (3.4 mmol) of 5,6-dihydroxyisoindoline hydrobromide was added thereto, then 0.47 ml (3.38 mmol) of triethylamine was dropwise added at room temperature. The reaction solution was stirred at the same temperature for 2 hours, and then N,N-dimethylformamide was distilled off under reduced pressure. To the residue, chloroform and water were added. The organic layer was washed with water and with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flush column chromatography (5% methanol-chloroform) to obtain 1.74 g (yield: 78%) of the above-identified compound.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[N:18]=[CH:19][C:20](=[O:26])[NH:21]4)[CH:10]=2)=[CH:5][CH:4]=1.[C:29]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH3:29][N:21]1[C:22]2[C:17](=[C:16]([O:15][C:11]3[CH:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:27])([F:1])[F:28])=[CH:4][CH:5]=4)[N:14]=[CH:13][N:12]=3)[CH:25]=[CH:24][CH:23]=2)[N:18]=[CH:19][C:20]1=[O:26]
Reactant: O=c1cnc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(=O)cnc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc21

Procedure:
The title compound was prepared analogous to the methods used in Example 42 using 5-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-1H-quinoxalin-2-one, (Example 34(b)), (0.10 g, 0.26 mmol), K2CO3 (0.043 g, 0.31 mmol, Aldrich) and iodomethane (0.019 mL, 0.31 mmol, Aldrich) in DMF (1 mL). Purification by flash chromatography (0→5% 2M NH3 in MeOH/CH2Cl2) afforded the title compound as a white amorphous solid. Mp: 258° C. MS (ESI, pos. ion) m/z: 399 (M+1)
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[S:17]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)(=[O:19])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36]Cl>>[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:9]1[S:17]([N:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)(=[O:18])=[O:19]
Reactant: O=S(=O)(c1[nH]c2ccccc2c1C(c1ccccc1)c1ccccc1)N1CCCCC1
Reactant: CN(C)CCCl
Agent: Cl
Product: CN(C)CCn1c(S(=O)(=O)N2CCCCC2)c(C(c2ccccc2)c2ccccc2)c2ccccc21
Yield: 75.3 %

Procedure:
Substantially the same procedure as in Example 243 was repeated using Compound 263 (1.0 g, 2.25 mmol) obtained in Example 264 and 2-dimethylaminoethylchloride hydrochloride (360 mg, 2.47 mmol) to give 0.85 g (yield: 75%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:9][NH:10][CH2:11][CH2:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1.Cl[CH2:28][C:29]([NH:31][C:32]([NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:33])=[O:30]>>[OH:1][C:2]1[C:7]2[C:8]3[CH2:9][N:10]([CH2:28][C:29]([NH:31][C:32]([NH:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:33])=[O:30])[CH2:11][CH2:12][C:13]=3[C:14]([CH3:16])([CH3:17])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Reactant: O=C(CCl)NC(=O)Nc1ccccc1
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)NC(=O)Nc2ccccc2)CC1

Procedure:
The above-titled compound was prepared by reacting 10-hydroxy-5,5-dimethyl-8-(1,2-dimethylheptyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine with N-chloroacetyl-N'-phenylurea according to the method of Example 1; m.p. 159°-161°.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:8][CH:9]=1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>C(Cl)Cl>[F:13][C:10]([F:11])([F:12])[C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[O:3][CH2:18][CH2:17][CH2:16][CH2:15][Br:14]
Reactant: BrCCCCBr
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: FC(F)(F)c1cccc(OCCCCBr)c1
Reaction time: 5 h
Yield: 80.8 %

Procedure:
267 ml of 1.6 N sodium hydroxide solution are added dropwise with stirring at 100° C. within 90 minutes to a mixture of 69.3 g of 3-hydroxybenzotrifluoride and 119 g of 1,4-dibromobutane. The mixture is stirred at this temperature for a further 5 hours and is then allowed to cool. 200 ml of methylene chloride are added, the organic phase is separated off, washed with dilute sodium hydroxide solution, dried over sodium sulfate and concentrated. The residue is distilled in vacuo. 102.6 g of 4-(3-trifluoromethylphenoxy)butyl bromide of b.p. 143° to 144° C. (13 mm Hg=1730 Pa) are obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([NH:9][NH2:10])[CH:6]=[CH:5][C:4]=1[OH:11].[CH3:12][CH:13]([C:17](=O)[CH3:18])[C:14](=O)[CH3:15]>C(O)C>[Cl:2][C:3]1[CH:8]=[C:7]([N:9]2[C:17]([CH3:18])=[C:13]([CH3:12])[C:14]([CH3:15])=[N:10]2)[CH:6]=[CH:5][C:4]=1[OH:11]
Reactant: CC(=O)C(C)C(C)=O
Reactant: NNc1ccc(O)c(Cl)c1
Agent: Cl
Solvent: CCO
Product: Cc1nn(-c2ccc(O)c(Cl)c2)c(C)c1C

Procedure:
A mixture of 2-chloro-4-hydrazinophenol hydrochloride salt 3.0 g, 3-methyl-2,4-pentanedione, ethanol 100 ml was stirred with heating under reflux for twelve hours. The solvent was distilled off and thereto was added ethyl acetate 200 ml, and the resulting mixture was stirred for one hour. The precipitates was filtered and was washed with hexane, and was then dried under reduced pressure to give 2-chloro-4-(3,4,5-trimethyl-pyrazol-1-yl)-phenol 3.3 g.
Reaction SMILES: I.[CH3:2][N:3]1[C:7]([NH:8][C:9](=N)SC)=[CH:6][C:5]([CH3:13])=[N:4]1.[CH3:14][NH:15][CH2:16][CH2:17][NH2:18]>C(Cl)Cl>[CH3:14][N:15]1[CH2:16][CH2:17][N:18]=[C:9]1[NH:8][C:7]1[N:3]([CH3:2])[N:4]=[C:5]([CH3:13])[CH:6]=1
Reactant: CNCCN
Reactant: CSC(=N)Nc1cc(C)nn1C
Agent: I
Solvent: ClCCl
Product: Cc1cc(NC2=NCCN2C)n(C)n1

Procedure:
N(1,3-Dimethyl-5-pyrazolyl)-5-methyl isothiourea hydroiodide (Example XXV) (20.0 g) and 11.5 g. -N-methyl ethylenediamine were heated to 120° for 30 minutes and to 160° for 1 hour. After cooling, methylene chloride was added and the solid which formed was filtered and discarded. The methylene chloride solution was shaken with 15% KOH solution, dried over potassium carbonate, concentrated and the residue crystallized from acetonitrile to get 10.16 g. product, mp. 128°-130°.
Reaction SMILES: [C:1]1([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[C:24](Cl)[N:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[C:24]([NH:18][CH:16]([C:8]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH3:17])[N:23]=[CH:22][N:21]=1
Reactant: C[C@H](N)c1nc2cccnc2n1-c1ccccc1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(Nc1ncnc(N)c1C#N)c1nc2cccnc2n1-c1ccccc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 65.8 %

Procedure:
A mixture of (S)-1-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)ethylamine (0.194 g, 0.81 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (0.176 g, 1.14 mmol) and DIPEA (0.26 mL, 1.47 mol) in IPA (2 mL) was stirred at 90° C. in a sealed tube for 16 h. The resulting mixture was concentrated in vacuo and the residue purified by chromatography (SiO2, 0-10% MeOH in EtOAc) to give 302 as a white solid (0.190 g, 66%). LCMS (method K): Rt 3.01 min, [M+H]+ 357. 1H NMR (DMSO-d6): δ 8.25 (1H, dd, J=4.76, 1.48 Hz), 8.12 (1H, dd, J=7.98, 1.48 Hz), 7.87 (1H, s), 7.72 (1H, d, J=7.21 Hz), 7.53-7.52 (4H, m), 7.32 (1H, dd, J=7.99, 4.77 Hz), 7.19 (2H, s), 5.51 (1H, m, J=6.98 Hz), 1.52 (3H, d, J=6.84 Hz)
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=[CH:29][C:30]#[N:31])[CH:23]=1>>[C:16]1([C:14]2[N:15]=[C:11]3[CH:10]=[C:28]([C:24]4[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=4)[CH:29]=[C:30]([NH2:31])[N:12]3[N:13]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N#CC=Cc1cccnc1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccccc2)n1)c1ccccc1
Product: Nc1cc(-c2cccnc2)cc2nc(-c3ccccc3)nn12

Procedure:
The title compound, mp. 201-203° C., MS m/e (%): 288 (M+H+, 100), was prepared in accordance with the general method of example 22 from 3-benzenesulfonylmethyl-5-phenyl-1H-[1,2,4]triazole and 3-pyridin-3-yl-acrylonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:12][C:13](=O)[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].O=P(Cl)(Cl)[Cl:29].CN(C)C1C=CC=CC=1>>[Cl:29][C:13]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:10]=[C:11]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:12]=1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2Cl)nc(-c2ccccc2)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)c1c(Cl)nc(-c2ccccc2)nc1-c1ccc(Cl)cc1Cl
Reaction time: 4 h
Yield: 97 %

Procedure:
To a stirred solution of ethyl 4-(2,4-dichlorophenyl)-6-oxo-2-phenyl-1,6-dihydropyrimidine-5-carboxylate (372 mg, 0.91 mmol) in doixane (6 mL) was added POCl3 (0.4 mL, 4.55 mmol) and N,N-dimethylaniline (11.5 μL, 0.09 mmol). After 4 hrs at 70° C., the reaction was concentrated under reduced pressure and diluted with EtOAc (100 mL). The organic layer was extracted with saturated NaHCO3 solution (2×60 mL), brine (50 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The crude reaction product was purified by flash chromatography (silica gel, 30% EtOAc/hexane) to give ethyl 4-chloro-6-(2,4-dichlorophenyl)-2-phenylpyrimidine-5-carboxylate (360 mg, 97% for 3 steps) as a clear oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:10]1.C[O:25][C:26](=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Br)[CH:28]=1>>[O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:33][C:29]3[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=3)[C:26]([OH:35])=[O:25])[CH2:20][CH2:19]2)=[CH:10]1
Reactant: c1ccc2c(c1)c(C1CCNCC1)cn2CCC1COCCO1
Reactant: COC(=O)c1cccc(CBr)c1
Product: O=C(O)c1cccc(CN2CCC(c3cn(CCC4COCCO4)c4ccccc34)CC2)c1

Procedure:
This compound was prepared following the procedure described in example 71 (part C) starting with 0.06 g (0.19 mmol) of 1-(2-[1,4]dioxan-2-yl-ethyl)-3-piperidin-4-yl-1H-indole and 0.060 g (0.26 mmol) of 3-bromomethyl-benzoic acid methyl ester. After standard purification, 0.037 g (75% of yield) were obtained.
Reaction SMILES: [C:1]([C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=2[Cl:23])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[H][H]>N.CO.[Ni]>[NH2:2][CH2:1][C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=2[Cl:23])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccc(Cl)c2Cl)CC1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CN)(c2cccc(Cl)c2Cl)CC1

Procedure:
Tert-butyl 4-cyano-4-(2,3-dichlorophenyl)piperidine-1-carboxylate (2.30 g, 6.47 mmol) was dissolved in 75 ml of a 7M solution of NH3 in MeOH. Raney Nickel (˜2 g aq. suspension) was added and the mixture shaken on a PARR apparatus under 60 psi of hydrogen for 4 days. The catalyst was removed by filtration through a layer of Celite and the crude reaction mixture concentrated. The crude product (1.90 g yellow oil) was used in the next reaction (amide bond formation) “as is”.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.COC1C=CC(COC(C2C(C)=C([Br:56])C3C(=CC=CC=3)C=2O)C(OCC)=O)=CC=1>>[Br:56][C:6]1[C:5]2[C:10](=[CH:11][CH:2]=[CH:3][CH:4]=2)[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:7]=1[CH3:30]
Reactant: CCOC(=O)C(OCc1ccc(OC)cc1)c1c(C)c(Br)c2ccccc2c1O
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)c(Br)c2ccccc2c1-c1ccc(Cl)cc1

Procedure:
Ethyl 2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (125) was prepared in a similar manner as ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate of Example 67 except using ethyl 2-(4-methoxybenzyloxy)-2-(4-bromo-1-hydroxy-3-methylnaphthalen-2-yl)acetate. 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J=8.6 Hz, 1H), 7.57-7.42 (m, 4H), 7.36-7.24 (m, 3H), 5.16 (s, 1H), 4.24-4.09 (m, 2H), 2.75 (s, 3H), 1.23 (t, J=7.1 Hz, 3H), 1.00 (s, 9H).
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:11][CH2:10]1)C)(C)(C)C.[ClH:27]>O1CCOCC1.CCOCC>[ClH:27].[CH2:23]([N:20]([CH2:21][CH3:22])[C:19](=[O:25])[CH2:18][CH2:17][CH2:16][CH2:15][C@H:12]1[CH2:11][CH2:10][C@H:9]([NH:7][CH3:6])[CH2:14][CH2:13]1)[CH3:24]
Reactant: CCN(CC)C(=O)CCCC[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCN(CC)C(=O)CCCC[C@H]1CC[C@H](NC)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 0.99 g (2.7 mmol) trans-[4-(4-Diethylcarbamoyl-butyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester in 5 ml dioxane were added 7 ml 4M HCl in dioxane at 0° C. The solution was stirred at RT for 2 h, diluted with ether, and the precipitated solid was isolated. 0.83 g (quant.) trans-5-(4-Methylamino-cyclohexyl)-pentanoic acid diethylamide.hydrochloride were isolated as white solid, mp. 122° C., MS: 269 (MH+).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.BrC[C:14]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1)=O>>[F:22][C:20]1[CH:21]=[C:16]([C:14]2[C:6]3=[C:5]([OH:11])[CH:4]=[C:3]([OH:2])[CH:8]=[C:7]3[O:9][CH:10]=2)[CH:17]=[C:18]([F:23])[CH:19]=1
Reactant: O=C(CBr)c1cc(F)cc(F)c1
Reactant: COc1cc(O)cc(OC)c1
Product: Oc1cc(O)c2c(-c3cc(F)cc(F)c3)coc2c1
Yield: 50 %

Procedure:
This compound was prepared using Method B from 3,5-dimethoxyphenol and 2-bromo-1-(3,5-difluorophenyl)ethanone: Yield 50% following procedures B.2, B.3 and B.5; m.p. 149-151° C.; IR 3373, 1629, 1507, 1359, 1255, 1157, 1123, 1031 cm−1; 1H-NMR (500 MHz, δ ppm, DMSO-d6) 10.08 (s, 1H), 9.45 (s, 1H), 8.02 (s, 1H), 7.49 (d, J=7.7 Hz, 2H), 7.13 (t, J=9.4 Hz, 1H), 6.43 (s, 1H), 6.28 (s, 1H); 13C-NMR (75 MHz, δ ppm, CD3OD) 164.3 (dd, J=244.8 Hz, 13.4 Hz), 160.4, 158.1, 153.5, 141.7, 137.8 (t, J=10.7 Hz), 122.6, 112.8 (dd, J=8.1 Hz, 17.6 Hz), 108.4, 102.6 (t, J=25.9 Hz), 99.4, 91.0.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][N:14]=[C:13]([N:18]3[CH:22]=[C:21]([CH2:23][O:24][CH3:25])[N:20]=[CH:19]3)[CH:12]=[C:7]12.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:32](I)([CH3:34])[CH3:33]>C1COCC1.CN(C=O)C>[CH:32]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][N:14]=[C:13]([N:18]3[CH:22]=[C:21]([CH2:23][O:24][CH3:25])[N:20]=[CH:19]3)[CH:12]=[C:7]12)([CH3:34])[CH3:33]
Reactant: COCc1cn(C2=NCC(=O)N3CCc4c(O)cccc4C3=C2)cn1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCc1cn(C2=NCC(=O)N3CCc4c(OC(C)C)cccc4C3=C2)cn1
Temperature: 25 °C
Reaction time: 17 h
Yield: 48 %

Procedure:
Example 142. To a stirred suspension of 9-hydroxy-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (50 mg, 0.148 mmol) and cesium carbonate (120 mg, 0.369 mmol) in THF (1 mL) and DMF (0.35 mL), isopropyl iodide (55 mg, 0.325 mmol) was added. The mixture was stirred at rt for 17 h and poured onto H2O. The mixture was extracted with DCM and the combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by by SFC (column: PPU 5 μm, 250×30 mm, 60A, Princeton; eluent: 5% MeOH/CO2 isocratic run for 20 min; flow 100 mL/min; UV detection at 220 nm). The residue was crystallized from diethyl ether and gave the title compound as white crystals (27 mg). UPLC-MS: MS 381.2 (M+H+); UPLC rt 0.98 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (d, J=6.11 Hz, 6 H), 2.80 (t, J=6.11 Hz, 2 H), 3.23 (s, 3 H), 3.82 (br. s., 2 H), 4.22 (br. s., 2 H), 4.27 (s, 2 H), 4.64 (dt, J=12.04, 6.08 Hz, 1 H), 7.14 (d, J=8.07 Hz, 1 H), 7.22 (s, 1 H), 7.31 (t, J=8.19 Hz, 1 H), 7.63 (s, 1 H), 7.66 (d, J=7.82 Hz, 1 H), 8.20 (s, 1 H).
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[Na+].[C:13]1([S:19]([O-:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1OCCOCCOCCOCCOCCOC1>CC#N>[C:13]1([S:19]([CH2:2][C:3]2[O:4][C:5]3[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=3[N:7]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1nc2ccccc2o1
Reactant: O=S([O-])c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CC#N
Product: O=S(=O)(Cc1nc2ccccc2o1)c1ccccc1
Reaction time: 8 h
Yield: 68.9 %

Procedure:
To 9.1 g (0.043 mol) of 2-bromomethyl-benzooxazole in CH3CN (300 mL) were added 7.39 g (0.045 mol, 1.05 eq) of benzenesulfinic acid sodium salt and 2.27 g (8.6 mmol, 0.2 eq) of 18-crown-6. Stirring was continued overnight, solvent evaporated and a column chromatography afforded 8.1 g (70%) of 2-benzenesulfonylmethyl-benzooxazole as a white solid, MS: 274 (H+). (Y. Nagao, S. Yamada, E. Fujita, Tet. Lett., 1983, 24, 2291)
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:9])=[CH:5][C:6]=1[CH2:7][NH2:8].[N-:10]=[N+:11]=[N-].[Na+]>CN(C=O)C>[N:8]([CH2:7][C:6]1[CH:5]=[C:4]([Cl:9])[S:3][C:2]=1[Cl:1])=[N+:10]=[N-:11]
Reactant: [N-]=[N+]=[N-]
Reactant: NCc1cc(Cl)sc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cc(Cl)sc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
C-(2,5-dichloro-thiophen-3-yl)-methylamine: To 103A (250 mg, 1.016 mmol) in DMF (4 mL) was added sodium azide (661 mg, 10.16 mmol) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated yielding 3-azidomethyl-2,5-dichloro-thiophene (135 mg). To a solution of this intermediate (135 mg, 0.519 mmol) in methanol (5 mL) was added 10% palladium on carbon. The reaction mixture was stirred at rt under a hydrogen balloon for 1 h. The mixture was filtered and the catalyst was washed with MeOH. The combined filtrate was concentrated and the resulting residue was dissolved in 0.25 N HCl (2 mL) and washed with EtOAc (10 mL). The aqueous layer was basified with 1N NaOH and extracted with EtOAc (5×10 mL). The combined organic layers were washed with brine, dried with Na2SO4, filtered and concentrated yielding 103B (41 mg). LCMS m/z 182.1 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:12][CH:13]2[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15][CH2:14]2)[C:3]1=[O:21].[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32](O)=[O:33])=[CH:26]2>>[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32]([NH:1][CH:2]1[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]([CH2:12][CH:13]3[CH2:14][O:15][C:16]([CH3:19])([CH3:20])[O:17][CH2:18]3)[C:3]1=[O:21])=[O:33])=[CH:26]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CC1(C)OCC(CN2C(=O)C(N)Cc3ccccc32)CO1
Product: CC1(C)OCC(CN2C(=O)C(NC(=O)c3cc4cc(Cl)ccc4[nH]3)Cc3ccccc32)CO1
Yield: 85 %

Procedure:
Following a standard amide coupling procedure analogous to Example 1, using 3-amino-1-[(2,2-dimethyl-1,3-dioxan-5-yl)methyl]-3,4-dihydroquinolin-2(1H)-one (Method 4) as the amine and 5-chloroindole-2-carboxylic acid as the acid afforded the title compound (85%) as a white solid.