Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](I)[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[Cl:11].[NH2:12][C@@H:13]([CH3:17])[C:14]([OH:16])=[O:15].C1(NN=CC2C=CC=CC=2O)C=CC=CC=1.O>CN(C=O)C.[Cu]I.CCOCC>[Br:1][C:2]1[C:3]([Cl:11])=[CH:4][C:5]([O:9][CH3:10])=[C:6]([NH:12][C@@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=1
Reactant: C[C@H](N)C(=O)O
Reactant: COc1cc(Cl)c(Br)cc1I
Agent: [Cu]I
Agent: Oc1ccccc1C=NNc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1cc(Cl)c(Br)cc1N[C@@H](C)C(=O)O
Temperature: 80 °C
Reaction time: 16 h
Yield: 63.8 %

Procedure:
A mixture of 1-bromo-2-chloro-5-iodo-4-methoxybenzene (3 g, 8.64 mmol), (S)-2-aminopropanoic acid (769 mg, 8.64 mmol), CuI (164 mg, 0.864 mmol), 2-hydroxybenzaldehyde phenylhydrazone (366 mg, 1.73 mmol), K3PO4.3H2O (4.6 g, 17.28 mmol) in DMF (10 mL) was stirred under argon at 80° C. for 16 h. The mixture was allowed to cool to RT, H2O and Et2O were added to the solution. The resulting solution was partitioned into two phases, the aqueous phase was separated, and the organic layer was extracted with 5% NaOH. The combined aqueous phase was acidified to pH 4 with 20% HCl, and then extracted with Et2O. The resulting organic layer was dried over MgSO4 and concentrated in vacuo to afford the desired product (1.7 g, 64% yield). ESI-MS m/z: 306.1[M+H]−
Reaction SMILES: [CH2:1]([C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14]O)[C@@H:11]([OH:12])[CH2:10]1)[CH2:2][CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:39]=[N+:40]=[N-:41].[Na+].C(Br)(Br)(Br)Br>CN(C)C=O.CO>[N:39]([CH2:14][C@H:13]1[O:16][C@@H:9]([N:8]2[CH:17]=[C:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:19])[NH:6][C:7]2=[O:18])[CH2:10][C@@H:11]1[OH:12])=[N+:40]=[N-:41]
Reactant: CCCc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: [N-]=[N+]=[N-]
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CO
Product: CCCc1cn([C@H]2C[C@H](O)[C@@H](CN=[N+]=[N-])O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.8 %

Procedure:
0.57 g of 2'-deoxy-5-n-propyluridine, 0.6 g of triphenylphosphine and 0.69 g of sodium azide were stirred in 20 ml of dry dimethylformamide. 0.77 g of carbon tetrabromide was added over a period of 5 minutes. The mixture was stirred at room temperature for 72 hours, 20 ml of methanol were added and the mixture was stirred for a further 0.5 hour. The mixture was evaporated and the residue was stirred with a mixture of 25 ml of dichloromethane/ methanol (8:2). An insoluble solid was removed by filtration and the filtrate was chromatographed on 200 g of silica gel in the same solvent mixture to give 0.41 g of 5'-azido-2',5'-dideoxy-5-n-propyluridine of melting point 177°-179° C. (decomposition).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:14](O)=[O:15].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH2:31]/[CH:32]=[CH:33]/[CH2:34][NH2:35])[CH2:27][CH2:26]1.Cl>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:26][CH2:27][N:28]([CH2:31]/[CH:32]=[CH:33]/[CH2:34][NH:35][C:14]([C:2]2[CH:1]=[CH:13][C:12]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH2:5][C:4]=3[CH:3]=2)=[O:15])[CH2:29][CH2:30]1
Reactant: COc1ccccc1N1CCN(C/C=C/CN)CC1
Reactant: O=C(O)c1ccc2c(c1)Cc1ccccc1-2
Agent: Cl
Product: COc1ccccc1N1CCN(C/C=C/CNC(=O)c2ccc3c(c2)Cc2ccccc2-3)CC1
Yield: 61 %

Procedure:
Prepared from 9H-fluorene-2-carboxylic acid and 4-(4-(2-methoxyphenyl)-piperazin-1-yl)-trans-but-2-enyl amine according to the general procedure. Yield: 61%. Mp. (hydrochloride): 224-226° C. 1H NMR (400 MHz, CDCl3): d 2.68 (s, 4H), 3.09-3.10 (m, 6H), 3.86 (s, 3H), 3.94 (s, 2H), 4.13 (m, 2H), 5.81-5.83 (m, 2H), 6.32 (t, J 5.4, 1H), 6.85 (dd, J 8.2, 1.2, 1H), 6.89-6.96 (m, 2H), 7.00 (m, 1H), 7.35 (td, J 7.3, 1.3, 1H), 7.40 (td, J 7.4, 1.6, 1H), 7.57 (d, J 7.4, 1H), 7.78-7.83 (m, 3H), 7.99 (s, 1H). 13C NMR (101 MHz, CDCl3): d 37.4, 42.0, 51.0, 53.8, 55.8, 60.8, 111.6, 118.7, 120.2, 121.0, 121.4, 123.4, 124.3, 125.7, 126.2, 127.5, 128.1, 129.3, 130.4, 133.1, 141.1, 141.7, 143.9, 144.5, 145.4, 152.7, 168.0. Anal. (C29H31N3O2.3HCl) C, H, N.
Reaction SMILES: [ClH:1].[CH2:2]([C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1)[CH2:3][CH2:4][C:5]#[CH:6].[N:13]([CH2:16][CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[N+:14]=[N-:15]>>[ClH:1].[C:19]1([CH:18]=[CH:17][CH2:16][N:13]2[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][C:7]3[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=3)[N:15]=[N:14]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: [N-]=[N+]=NCC=Cc1ccccc1
Reactant: C#CCCCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(CCCc2cn(CC=Cc3ccccc3)nn2)c[nH]1
Yield: 38.4 %

Procedure:
4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (0.115 g, 0.620 mmol) was reacted with (3-azido-propenyl)-benzene (0.119 g, 0.748 mmol) following the general procedure for click reactions outlined above to produce 4-{3-[1-(3-Phenyl-allyl)-1H-[1,2,3]triazol-4-yl]-propyl}-1Himidazol-2-ylamine hydrochloride (0.082 g, 43%) as a pale yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.34-7.24 (m, 6H), δ 6.67 (d, 1H), δ 6.34 (q, 1H), δ 6.25 (s, 1H), δ 5.08 (d, 2H), δ 2.72 (t, 2H), δ 2.47 (t, 2H), δ 1.91 (m, 2H) ppm; 13C (75 MHz, CD3OD) 149.1, 137.9, 133.5, 129.5, 128.9, 128.7, 128.3, 128.2, 127.7, 126.8, 54.8, 48.9, 31.3, 29.6, 27.5 ppm; HRMS (ESI) calcd for C17H21N6 (M+) 308.1822. found 308.1821.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[C:6]([NH:8][C:9]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:29][C:10]=1[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[N:15]=1)=[O:12])=[O:7].[SH:42][C:43]1[CH:44]=[C:45]([CH:49]=[CH:50][CH:51]=1)[C:46]([OH:48])=[O:47].C(N(CC)C(C)C)(C)C>O1CCCC1.[I-].[K+]>[N:33]1([C:30]2[CH:31]=[CH:32][C:9]([NH:8][C:6]([C:5]3[CH:4]=[C:3]([CH:41]=[CH:40][CH:39]=3)[CH2:2][S:42][C:43]3[CH:44]=[C:45]([CH:49]=[CH:50][CH:51]=3)[C:46]([OH:48])=[O:47])=[O:7])=[C:10]([C:11](=[O:12])[NH:13][C:14]3[CH:18]=[CH:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[N:15]=3)[CH:29]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=C(Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1)c1cccc(CCl)c1
Reactant: O=C(O)c1cccc(S)c1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1cccc(SCc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3C(=O)Nc3ccn(-c4cccc(C(F)(F)F)c4)n3)c2)c1
Temperature: 40 °C
Reaction time: 24 h
Yield: 63.3 %

Procedure:
Into a 250-mL round bottom flask, was placed a solution of 2-(3-(chloromethyl)benzamido)-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide 21a (1.6 g, 2.56 mmol, 1.00 equiv) in tetrahydrofuran (100 mL), 3-mercaptobenzoic acid (390 mg, 2.53 mmol, 0.99 equiv), potassium iodide (21.2 mg, 0.13 mmol, 0.05 equiv), and N,N-diisopropylethylamine (660 mg, 5.12 mmol, 2.00 equiv). The resulting solution was stirred for 24 h at 40° C. in an oil bath. The reaction progress was monitored by TLC/LCMS. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 20 mL of H2O, extracted with 3×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×20 mL of hydrochloric acid (1 mol/L) and 3×20 mL of brine. The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20-1:1). This resulted in 1.12 g (63%) of product as a yellow to green solid. 1H-NMR (400 MHz, CDCl3, ppm): δ 11.68 (s, 1H), 9.75 (s, 1H), 8.60-8.56 (d, J=9.2 Hz, 1H), 8.00 (s, 1H), 7.91 (s, 3H), 7.88-7.81 (m, 2H), 7.80-7.79 (d, J=2.1 Hz, 1H), 7.66-7.65 (d, J=2.4 Hz, 4H), 7.53-7.38 (m, 2H), 7.33-7.25 (m, 1H), 7.10-7.08 (m, 1H), 4.20 (s, 2H), 3.17 (s, 4H), 1.69-1.54 (m, 6H). MS (ES, m/z): 700 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[N:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH:28]4[CH2:30][CH2:29]4)=[CH:26][C:25]([CH:31]4[CH2:33][CH2:32]4)=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1>>[CH:28]1([C:27]2[C:22]([N:19]3[CH2:18][CH2:17][N:16]([C:14]([C:11]4[CH:10]=[CH:9][C:8]([N:1]5[CH2:5][CH2:4][CH2:3][C:2]5=[O:6])=[N:13][CH:12]=4)=[O:15])[CH2:21][CH2:20]3)=[N:23][CH:24]=[C:25]([CH:31]3[CH2:33][CH2:32]3)[CH:26]=2)[CH2:29][CH2:30]1
Reactant: O=C1CCCN1
Reactant: O=C(c1ccc(Br)nc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: O=C(c1ccc(N2CCCC2=O)nc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 48.7 %

Procedure:
Using pyrrolidin-2-one (94 mg) and (6-bromopyridin-3-yl)[4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (427 mg) described in Preparation Example 143 and by the reaction and treatment in the same manner as in Example 1, the title compound (210 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH3:17])[C:12]3=[N:18][CH:19]=[C:20]([C:21]#[N:22])[N:11]3[N:10]=2)=[CH:6][C:5]([C:23]#[N:24])=[CH:4][C:3]=1[N:25]1[CH2:30][CH2:29][C@@H:28]([NH:31][C:32](=[O:35])[O:33][CH3:34])[C@H:27]([OH:36])[CH2:26]1.CC(OC([NH:44][C@H:45]([C:67](O)=[O:68])[CH2:46][CH2:47][CH2:48][N:49]=[C:50]([NH:59]C(OC(C)(C)C)=O)[NH:51]C(OC(C)(C)C)=O)=O)(C)C.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[ClH:1].[ClH:1].[ClH:1].[NH2:44][C@@H:45]([CH2:46][CH2:47][CH2:48][NH:49][C:50]([NH2:59])=[NH:51])[C:67]([O:36][C@H:27]1[C@H:28]([NH:31][C:32]([O:33][CH3:34])=[O:35])[CH2:29][CH2:30][N:25]([C:3]2[CH:4]=[C:5]([C:23]#[N:24])[CH:6]=[C:7]([NH:8][C:9]3[N:14]=[C:13]([NH:15][CH2:16][CH3:17])[C:12]4=[N:18][CH:19]=[C:20]([C:21]#[N:22])[N:11]4[N:10]=3)[C:2]=2[Cl:1])[CH2:26]1)=[O:68]
Reactant: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Reactant: CC(C)(C)OC(=O)NC(=NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)NC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](OC(=O)[C@@H](N)CCCNC(=N)N)C3)c2Cl)nn2c(C#N)cnc12
Product: Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (Example 328) methyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate (50 mg, 0.098 mmol), BOC-ARG(BOC)2-OH (96 mg, 0.202 mmol), DMAP (2.391 mg, 0.020 mmol) and DCC (60.6 mg, 0.294 mmol) were dissolved in DCM (5 mL) under nitrogen. The reaction mixture was stirred at room temperature 12 hr; the LCMS showed complete conversion. The solvent was removed and the material was diluted with acetone and filtered (removes 1,3-dicyclohexylurea).
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH:9]([CH3:12])[C:8](=[O:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[C:2]1[C:11]2[O:10][CH:9]([CH3:12])[C:8](=[O:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(B(O)O)c(C)c1
Reactant: CC1Oc2c(Br)cccc2NC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2cccc3c2OC(C)C(=O)N3)c(C)c1
Yield: 90.5 %

Procedure:
To a solution of 8-bromo-2-methyl-2H-1,4-benzoxazin-3(4H)-one (1.20 g, 4.96 mmol) in 1,2-dimethoxyethane (50 ml) were added 2,4-dimethylphenylboronic acid (818 mg, 5.45 mmol), tetrakis(triphenylphosphine)palladium(0) (286 mg, 0.245 mmol) and 2M sodium carbonate solution (4.96 ml, 9.92 mmol). The mixture was refluxed for 16 h and diluted with water. The aqueous solution was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography eluting with 20% ethyl acetate/n-hexane to afford 1.20 g (91%) of the title compound.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].[H-].[Na+].Cl[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][N:9]=1>C1COCC1>[Cl:14][C:13]1[C:8]([S:4][CH2:1][CH2:2][CH3:3])=[N:9][CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=1
Reactant: CCCS
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCSc1ncc(C(F)(F)F)cc1Cl
Temperature: 27.5 °C
Reaction time: 10 h
Yield: 99.3 %

Procedure:
23.8 g (0.313 mol) of 1-propanethiol were added in the course of minutes to a mixture of 7.9 g (0.313 mol) of 95% pure sodium hydride in 200 ml of THF while flushing with nitrogen and stirring, a temperature of 25-30° C. being maintained by means of cooling. After the mixture had been stirred for 1 hour, 54 g (0.25 mol) of 2,3-dichloro-5-trifluoromethylpyridine in 50 ml THF were added at 25-30° C. in the course of 20 minutes with stirring, and stirring was continued for 10 hours at 23° C. The reaction mixture was concentrated in vacuo, taken up in methylene chloride, extracted with 0.5 N sodium hydroxide solution, dried over magnesium sulfate and concentrated, yielding 63.5 g (99.4%) of the title compound of n23D=1.5120.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]3[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]([CH3:21])([CH3:20])[CH:9]=2)=[N:6][CH:7]=1.[CH3:22][N:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28].N([O-])=O.[Na+].[ClH:33]>O>[Cl:33][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]3[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]([CH3:21])([CH3:20])[CH:9]=2)=[N:6][CH:7]=1.[OH:28][C:24]1[CH:25]=[CH:26][C:27]([C:8]2[C:13]3[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]([CH3:21])([CH3:20])[CH:9]=2)=[N:23][CH:22]=1
Reactant: Cl
Reactant: CC1(C)C=C(c2ccc(N)cn2)c2cc(C#N)ccc2O1
Reactant: CN1CCCC1=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC1(C)C=C(c2ccc(Cl)cn2)c2cc(C#N)ccc2O1
Product: CC1(C)C=C(c2ccc(O)cn2)c2cc(C#N)ccc2O1
Temperature: -5 °C

Procedure:
1.62 g of 4-(5-amino-2-pyridyl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile were suspended in 12 ml of concentrated hydrochloric acid, 30 g of ice and 18 ml of N-methylpyrrolidone. The mixture was cooled to -5° C. and 0.44 g of sodium nitrite in 5 ml of water was added dropwise while maintaining the temperature below 0° C. After completion of the addition the mixture was allowed to warm to room temperature and was then heated at 40° C. for 1 hour. The mixture was extracted with ethyl acetate and the extract was evaporated. The residue was taken up in diethyl ether and water and the separated organic phase was washed with water, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:1) and ethyl acetate for the elution to give 270 mg of 4-(5-chloro-2-pyridyl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile and 254 mg of 4 -(5-hydroxy-2-pyridyl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile.
Reaction SMILES: C([O:8][C:9]1[CH:42]=[C:41]([CH3:43])[C:12]([CH2:13][CH:14]([C:24]([NH:26][C@@H:27]([C:29]([N-:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:30])[CH3:28])=[O:25])[N:15]([C:17](OC(C)(C)C)=O)C)=[C:11]([CH3:44])[CH:10]=1)C1C=CC=CC=1.CO.[ClH:47]>O1CCOCC1>[ClH:47].[CH3:17][NH:15][CH:14]([C:24]([NH:26][C@@H:27]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:30])[CH3:28])=[O:25])[CH2:13][CH:12]1[C:11]([CH3:44])=[CH:10][C:9]([OH:8])=[CH:42][C:41]1([CH3:43])[CH2:44][C:11]1[CH:12]=[CH:41][CH:42]=[CH:9][CH:10]=1
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1CC(C(=O)N[C@H](C)C(=O)[N-]CCCc1ccccc1)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CNC(CC1C(C)=CC(O)=CC1(C)Cc1ccccc1)C(=O)N[C@H](C)C(=O)NCCCc1ccccc1

Procedure:
O-Benzyl-N-methyl-BOC-2,6-dimethyl (DL)-tyrosyl-(D)-alanylphenylpropylamide was treated with methanol (1.5 ml) and 6.8N HCl in dioxane (1 ml) for 24 hr. The mixture was evaporated in a stream of nitrogen, and dissolved in aqueous methanol. The solution was filtered through Whatman 50 filter paper, reduced in volume in a nitrogen stream, and lyophilized. The product is
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[C:4](CC#N)=[CH:3]1.[OH-:15].[K+].[CH2:17]([OH:19])[CH3:18]>O>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:18][C:17]([OH:15])=[O:19])=[CH:3]1
Reactant: [OH-]
Reactant: Cc1cccc2c1c(CC#N)cn2C
Reactant: CCO
Agent: [K+]
Solvent: O
Product: Cc1cccc2c1c(CC(=O)O)cn2C
Temperature: 25 °C

Procedure:
(1,4-Dimethyl-1H-indol-3-yl)-acetonitrile (6.0 g, 33 mmol) is suspended in ethanol (150 mL) and then potassium hydroxide (10.6 g, 162 mmol) in water (150 mL) is added to the solution. The reaction is stirred and then heated to reflux for 16 hours. the reaction is then cooled to room temperature and diluted with water. The aqueous layer is washed with DCM (3×150 mL) and then the water layer is cooled to zero and acidified with the addition of 12N HCl. The resulting suspension is extracted with DCM (3×100 mL) and the organic layers are combined, filtered and evaporated in vacuo. The resulting product is used without further purification (3.9 g, 20 mmol, 60%) LC/MS (M++1): 204.7.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1>CN(C)C=O>[Si:15]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)CCc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Reaction time: 14 h

Procedure:
To a solution of ethyl 3-(4-hydroxyphenyl)propionate (940 mg, 4.84 mmol) in anhydrous dimethylformamide (9.4 mL) were added t-butyldimethylsilyl chloride (1.0 g, 6.6 mmol) and imidazole (490 mg, 1.5 mmol) at room temperature, and the mixture was left standing at the same temperature for 14 h. The reaction mixture was directly concentrated, and subjected to silica gel column chromatography (hexane-ethyl acetate 25:1→20:1) to give 1.49 g (quantitative) of the title compound as a solid.
Reaction SMILES: [CH:1]1([CH2:7][C:8](Cl)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:11](=[CH2:13])=[N-:12]>CCOCC>[N+:11](=[CH:13][C:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9])=[N-:12]
Reactant: C=[N+]=[N-]
Reactant: O=C(Cl)CC1CCCCC1
Solvent: CCOCC
Product: [N-]=[N+]=CC(=O)CC1CCCCC1

Procedure:
A solution of 19.8 g of cyclohexylacetyl chloride (b.p. 98° - 100°/23 mm Hg) in 150 ml of dry ether is slowly added at 0°-5° with cooling in an ice-water bath to a vigorously stirred solution of 11 g of diazomethane in 500 ml of ether. The excess diazomethane and ether is distilled off under reduced pressure and cyclohexylmethyl diazomethyl ketone is obtained as residue; infra-red absorption spectrum (in methylene chloride): characteristic bands at 3.45μ, 3.52μ, 4.75μ and 6.12μ; the product is processed without any further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c2)cc1

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) and 4-methoxyphenylboronic acid according to the general procedure B. Obtained as a yellow solid (637 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([O:14]CC)=O)[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:14])[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Reactant: C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)N2CCCCC2)C1
Temperature: 120 °C

Procedure:
A mixture of ethyl 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate (200 mg) and piperidine (2 ml) was heated at 120° C. for 8 h to obtain 5 mg of 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(piperidin-1-yl)ethanone as TFA salt after purification on silica gel (230-400 mesh) chromatography eluting with methanol-dichloromethane gradient followed by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@@H:12]([C:14](=[O:21])[CH2:15][C:16](OCC)=[O:17])[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])=[CH:4][C:3]=1[F:26].[OH-].[Na+].[NH2:29]O.Cl>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@@H:12]([C:14]3[O:21][NH:29][C:16](=[O:17])[CH:15]=3)[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])=[CH:4][C:3]=1[F:26]
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(Cl)c(F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(Cl)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 57.8 %

Procedure:
Cis-methyl 2-(4-chloro-3-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.731 g, 4.49 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (1.181 mL, 4.49 mmol) dissolved in water (2 mL) was added and the reaction stirred at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.247 mL, 4.49 mmol) was added dropwise and stirring continued for 3 h. The mixture was then transferred to a prewarmed 80° C. solution of 6 M hydrogen chloride (23.18 mL, 139.09 mmol) and stirring was continued at 80° C. for 20 min. The solvent was evaporated and DCM (200 mL) and water (200 mL) were added. The phases were shaken, separated and the organic phase dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 10-60% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(4-chloro-3-fluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)-piperidine-1-carboxylate (0.921 g, 57.9%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) δ 1.79-1.87 (m, 1H), 2.06-2.15 (m, 1H), 2.19-2.28 (m, 1H), 2.30-2.37 (m, 1H), 3.00-3.09 (m, 1H), 3.31-3.40 (m, 1H), 3.66 (s, 3H), 4.07-4.16 (m, 1H), 5.00-5.07 (m, 1H), 5.56 (s, 1H), 6.87-6.91 (m, 1H), 6.95 (dd, 1H), 7.29 (t, 1H). MS m/z 355 (M+H)+