Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][C@H:26]5[CH2:28][O:27]5)=[CH:20][CH:19]=4)[N:15]=[C:14]3[CH2:29][O:30][CH2:31][CH3:32])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:35]([NH2:37])[CH3:36]>CO>[Cl:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][C@H:26]([OH:27])[CH2:28][NH:37][CH2:35][CH3:36])=[CH:20][CH:19]=4)[N:15]=[C:14]3[CH2:29][O:30][CH2:31][CH3:32])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCOCc1nc(-c2ccc(OC[C@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CCN
Solvent: CO
Product: CCNC[C@@H](O)COc1ccc(-c2cn(-c3ccc(Oc4ccc(Cl)cc4)cc3)c(COCC)n2)cc1

Procedure:
A solution of 1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-4-[4-((R)-1-oxiranylmethoxy)-phenyl]-1H-imidazole (50 mg, 0.11 mmol, from intermediate B2) in 4 mL of ethylamine in MeOH (2M) was stirred at 60° C. overnight in a teflon-capped vial. Upon completion (determined by LC/MS), the reaction was dried in vacuo and purified by silica gel flash column chromatography using a gradient of EtOAc to 4% ammonia/MeOH (2.0M) in EtOAc as an eluent to afford (R)-1-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenoxy)-3-ethylamino-propan-2-ol.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4ccccc4)cc32)N=C1N
Temperature: 120 °C
Yield: 7.8 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and phenylboronic acid (16 mg, 0.1 mmol). The mixture was heated under microwave at 120° C. for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and then by preparative HPLC to give pure 2′-amino-1′-methyl-2,6-diphenylspiro-[chroman-4,4′-imidazol]-5′(1′H)-one (1.55 mg, 5%). 1H-NMR (MeOD): 2.42 (m, 1H), 2.61 (m, 1H), 3.27 (s, 3H), 5.83 (d, 1H), 7.10 (d, 1H), 7.29 (m, 1H), 7.40 (m, 5H), 7.59 (m, 5H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1)=[O:39].[C:47]1([N:53]=[C:54]=[O:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][CH2:43][N:42]([C:54]([NH:53][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:55])[CH2:41]1)=[O:39]
Reactant: O=C=Nc1ccccc1
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCCNC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCCN(C(=O)Nc2ccccc2)C1
Yield: 42 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-3-carboxamide bis(trifluoroacetate) and phenyl isocyanate as starting materials in 42% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.43 (s, 1H), 9.40 (s, 1H), 9.38 (s, 1H), 8.59 (s, 1H), 8.14 (s, 1H), 8.00 (s, 1H), 7.72 (s, 1H), 7.44 (d, 2H), 7.21 (m, 3H), 7.04 (m, 2H), 6.90 (m, 2H), 4.22 (d, 1H), 4.10 (d, 1H), 2.90 (m, 6H), 2.63 (m, 1H), 2.03 (m, 1H), 1.72 (m, 2H), 1.47 (m, 1H). LCMS for C31H31ClN7O2 (M+H)+: m/z=568.2.
Reaction SMILES: [C-:1]#[N:2].[K+].[OH:4][CH2:5][C:6]([CH2:11][OH:12])([CH2:9][OH:10])[CH2:7]Br>C(#N)C>[OH:4][CH2:5][C:6]([CH2:11][OH:12])([CH2:9][OH:10])[CH2:7][C:1]#[N:2]
Reactant: OCC(CO)(CO)CBr
Reactant: [C-]#N
Agent: [K+]
Solvent: CC#N
Product: N#CCC(CO)(CO)CO
Yield: 78 %

Procedure:
0.07 mol of KCN is added to 0.055 mol of 2,2-bis(hydroxymethyl)-3-hydroxypropyl bromide and the mixture is dissolved in 50 ml of acetonitrile and refluxed for 5 h, with stirring. After the solution has cooled, the solid is filtered off with suction and the mother liquor is concentrated. The residue is dissolved in chloroform, the residual KBr is separated off and the solvent is distilled off after drying. The desired nitrile is separated from the residue as a pale yellowish oil by column chromatography. Yield: 78%.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](O)=[O:16]>>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:16]
Reactant: O=C(O)CCCCCBr
Reactant: OCc1ccccc1
Product: O=C(CCCCCBr)OCc1ccccc1
Yield: 85 %

Procedure:
From benzyl alcohol and 6-bromocaproic acid. Yield: 85% (oil).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C:13]1([CH3:40])[CH:18]([C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20])[N:17]2[C:27](=[O:39])[CH:28]([NH:29][C:30](=[O:38])[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:16]2[S:15][CH2:14]1>C(Cl)(Cl)Cl>[Br:12][C:13]1([CH3:40])[CH:18]([C:19]([O:21][CH2:22][C:23]([Cl:24])([Cl:25])[Cl:26])=[O:20])[N:17]2[C:27](=[O:39])[CH:28]([NH:29][C:30](=[O:38])[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:16]2[S:15](=[O:9])[CH2:14]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(Br)CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC1(Br)CS(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Yield: 88.3 %

Procedure:
A solution of m-chloroperbenzoic acid (0.445 g) in chloroform (5 ml) was added to a solution of 2,2,2-trichloroethyl 3-bromo-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate (1.21 g) under stirring at -5° to -10° C., and the mixture was stirred for an hour at the same temperature. After the reaction, the reaction mixture was washed with 5% sodium bicarbonate aqueous solution and with water in turn and then dried. After the solvent was distilled off, the residue was crystallized by adding ether. Thus obtained crystals were recrystallized from ethanol to give 2,2,2-trichloroethyl 3-bromo-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate-1-oxide (1.10 g), mp 159° to 161° C.
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][C@H:6]([CH3:30])[C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH:27]3[CH2:29][CH2:28]3)=[O:26])=[CH:21][CH:20]=2)[CH2:11][CH2:10]1)=[O:8].[CH3:31][C:32]([CH3:34])=O>>[CH:27]1([C:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:11][CH2:10][N:9]([C:7](=[O:8])[C@H:6]([NH:5][CH:32]([CH3:34])[CH3:31])[CH3:30])[CH2:14][CH2:13]3)=[CH:24][CH:23]=2)=[O:26])[CH2:29][CH2:28]1
Reactant: C[C@@H](N)C(=O)N1CCN(CCCOc2ccc(C(=O)C3CC3)cc2)CC1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)N[C@H](C)C(=O)N1CCN(CCCOc2ccc(C(=O)C3CC3)cc2)CC1
Reaction time: 8 h
Yield: 25 %

Procedure:
Sodium cyanoborohydride (75 mg, 1.2 mmol) was added to a room temperature solution of Example 138 (401 mg, 1 mmol) in acetone (10 mL). After stirring overnight, the reaction mixture was concentrated, and the concentrate was taken up in dichloromethane and washed with water, and brine, dried (Na2SO4), filtered, concentrated and purified by silica gel column chromatography using dichloromethane:methanol (9:1) as the eluant. The product was obtained in 25% yield.
Reaction SMILES: [O:1]1[C:5]([CH2:6][C:7]([OH:9])=O)=[CH:4][N:3]=[CH:2]1.[CH2:10]([C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]2[CH:31]=[C:30]3[C:26]([C:27]([CH2:35][CH3:36])=[N:28][N:29]3[CH:32]([CH3:34])[CH3:33])=[CH:25][CH:24]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C@H:17]1[CH2:18][N:19]([C:23]2[CH:31]=[C:30]3[C:26]([C:27]([CH2:35][CH3:36])=[N:28][N:29]3[CH:32]([CH3:33])[CH3:34])=[CH:25][CH:24]=2)[CH2:20][CH2:21][N:22]1[C:7](=[O:9])[CH2:6][C:5]1[O:1][CH:2]=[N:3][CH:4]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)Cc1cnco1
Reactant: CCc1nn(C(C)C)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc12
Product: CCc1nn(C(C)C)c2cc(N3CCN(C(=O)Cc4cnco4)[C@@H](Cc4ccccc4)C3)ccc12
Yield: 34 %

Procedure:
Prepared by the method outlined for Example 189 using 2-(oxazol-5-yl)acetic acid and 6-((S)-3-benzyl-piperazin-1-yl)-1-isopropyl-3-ethyl-1H-indazole as starting materials. Product was obtained as a light brown solid (34%). LC/MS (Method B) 3.77 min, [M+1]+ 472.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[C:13]3[CH3:20])=[CH:4][N:3]=1.[N+:21]([O-])([OH:23])=[O:22].[OH-].[NH4+]>S(=O)(=O)(O)O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=2)[N:16]=[CH:15][CH:14]=[C:13]3[CH3:20])=[CH:4][N:3]=1
Reactant: Cc1ccnc2ccc(Cc3cnc(N)nc3N)cc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1ccnc2c([N+](=O)[O-])cc(Cc3cnc(N)nc3N)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
The product of Example 11 (0.53 g, 2 mmol) was dissolved in 7 ml of concentrated sulfuric acid, and chilled to 0°. Then 0.3 ml (6.4 mmol) of fuming nitric acid (d=1.5) in 0.5 ml of concentrated sulfuric acid was added dropwise to the solution. The reaction was stirred at 0°-5° for 30 minutes, then at 25° for 1 hour. It was then poured onto 50 ml of ice and neutralised to pH 9 with concentrated ammonium hydroxide. The precipitate which formed was filtered and dried, and then purified on a silica gel column which was eluted with methylene chloride:methanol/12:1, giving 0.33 g (53%) of the title compound, which melted at 256°-258° after recrystallisation from beta methoxyethanol:water/2:1. NMR (Me2SO-d6) δ 2.72 (s, 3, Me), 3.90 (s, 2, CH2), 5.77 (br s, 2, NH2), 6.24 (br s, 2, NH2), 7.55 (d, 1, pyridine-beta H, J=4.1), 7.71 (s, 1, pyrimidine-H6), 8.05 (d, 1, ArH5, J=1.8), 8.28 (d, 1, ArH7, J=1.6), 8.81 (d, 1, pyridine-alpha H, J=4.4). Anal. Calcd. for C15H14N6O2 0.5H2O: C, 56.42; H, 4.73; N, 26.32. Found: C, 56.34; H, 4.82; N, 26.21.
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH:19]2[CH2:22][CH2:21][CH2:20]2)=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[F:12])[N:8]([C:14](=[O:16])[CH3:15])[C@@H:7]([CH3:17])[CH2:6][CH2:5]2.C[C@H]1CCC2C(=CC=C([C:38]3[CH:39]=[N:40][N:41]([CH:43]4[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]4)[CH:42]=3)C=2OCCC)N1C(=O)C>>[CH:19]1([O:18][C:3]2[C:2]([C:38]3[CH:39]=[N:40][N:41]([CH:43]4[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]4)[CH:42]=3)=[C:11]([F:12])[C:10]([F:13])=[C:9]3[C:4]=2[CH2:5][CH2:6][C@H:7]([CH3:17])[N:8]3[C:14](=[O:16])[CH3:15])[CH2:22][CH2:21][CH2:20]1
Reactant: CC(=O)N1c2c(F)c(F)c(Br)c(OC3CCC3)c2CC[C@@H]1C
Reactant: CCCOc1c(-c2cnn(C3CCNCC3)c2)ccc2c1CC[C@H](C)N2C(C)=O
Product: CC(=O)N1c2c(F)c(F)c(-c3cnn(C4CCNCC4)c3)c(OC3CCC3)c2CC[C@@H]1C

Procedure:
(S)-1-(5-cyclobutoxy-7,8-difluoro-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone was synthesized from (S)-1-(6-bromo-5-cyclobutoxy-7,8-difluoro-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone according to the procedures described above in Steps 2 and 3 of the synthesis of (S)-1-(2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (Example 4-1). 1H NMR (300 MHz, CD3OD) δ ppm 1.12-1.28 (m, 4H), 1.30-1.41 (m, 1H), 1.56-1.68 (m, 1H), 1.98-2.20 (m, 11H), 2.32-2.49 (m, 2H), 2.75-2.88 (m, 2H), 2.99-3.10 (m, 1H), 3.21-3.25 (m, 2H), 4.17-4.20 (m, 1H), 4.35-4.45 (m, 1H), 4.75-4.82 (m, 1H), 7.91 (s, 1H), 8.12 (s, 1H). MS (ESI, pos. ion) m/z 445 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11]N.[Cl:13][C:14]1[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20](=O)[CH3:21])=[CH:16][CH:15]=1>CC#N.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]2[C:3]=1[NH:11][C:20]([CH3:21])=[C:19]2[O:18][C:17]1[CH:16]=[CH:15][C:14]([Cl:13])=[CH:24][CH:23]=1
Reactant: CC(=O)COc1ccc(Cl)cc1
Reactant: NNc1cc([N+](=O)[O-])ccc1Br
Solvent: CC#N
Solvent: O
Product: Cc1[nH]c2c(Br)ccc([N+](=O)[O-])c2c1Oc1ccc(Cl)cc1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
A mixture of the compound from (i) (2.4 g) and 1-(4-Chloro-phenoxy)-propan-2-one (1.65 g) in MeCN (20 ml) and water (5 ml) was stirred for 16 h. The volatiles were removed in vacuo. AcOH (50 ml) was added and the reaction heated at 75° C. for 72 h. The volatiles were evaporated under reduced pressure and the residue was purified by chromatography on silica eluting with 5% ethylacetate/iso-hexane. Yield 0.34 g
Reaction SMILES: [NH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.Cl[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]>C(Cl)Cl>[N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: C1=CCNC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC=CC1
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of 2,5-dihydro-1H-pyrrole (3.3 mL, 43.4 mmol) and Et N (9 mL, 65.1 mmol) in DCM (200 mL) at 0° C. was added dropwise benzyl chloroformate (7.3 mL, 52 mmol). After 1 h, the solution was partitioned between H O-DCM. The organic phase was back extracted several times with DCM and the combined organic fractions were dried (Na SO), concentrated and purified via column chromatography (silica, DCM) yielding the title compound (6 g, 68%) as a yellow oil: LCMS ES (m/e) 204 (M+H).
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[O:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.Cl[CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N+:40]([O-:42])=[O:41]>C(N(CC)CC)C>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[O:16][CH:17]1[CH2:18][CH2:19][N:20]([CH2:30][CH2:31][CH2:32][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[N+:40]([O-:42])=[O:41])[CH2:21][CH2:22]1
Reactant: O=[N+]([O-])c1ccccc1OCCCCl
Reactant: Clc1ccccc1C(OC1CCNCC1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1OCCCN1CCC(OC(c2ccccc2)c2ccccc2Cl)CC1
Reaction time: 15 h
Yield: 73.8 %

Procedure:
Into 50 ml of toluene were dissolved 3.02 g of 4-[(2-chlorophenyl)-phenylmethoxy]piperidine, 2.59 g of 1-chloro-3-(2-nitrophenoxy)propane and 3.04 g of triethylamine, and the resultant solution was heated under reflux with stirring for 15 hours. After cooling, the reaction solution was washed with water, and the solvent was removed under reduced pressure. The residue was eluted with methanol-chloroform (1:50) by silica gel column chromatography to give 3.55 g of oily 4-[(2-chlorophenyl)-phenylmethoxy]-1-[3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=1.[H-].[Na+].CN(C)C=O.Cl[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[N+:24]([O-:26])=[O:25]>C(O)(=O)C>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([S:1][C:2]2[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=2)=[C:17]([N+:24]([O-:26])=[O:25])[CH:18]=1
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Cn1ccnc1S
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1ccc(Sc2nccn2C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
To a mixture of 2-mercapto-1-methylimidazole (1.14 g, 10 mmoles), 0.6 of 60% sodium hydride in mineral oil and 20 ml of N,N-dimethylformamide was added 1.88 g (10 mmoles) of 4-chloro-3-nitroanisole. The mixture was stirred at room temperature for 0.5 hours and then heated at 90°-100° C. for 4 hours. After cooling in an icebath, 0.5 ml of acetic acid was added and the mixture was partitioned between dichloromethane and dilute sodium bicarbonate. The organics were concentrated on a steam bath to a small volume and the residue was chromatographed on silica gel using ethyl acetate as the eluent. The fractions containing the product were combined and concentrated to give 1.0 g (38%) of the product, mp 117°-120° C.).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([NH:14][CH3:15])[CH:8]=[N:7]2.Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=1.O>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([N:14]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([C:25]([F:28])([F:26])[F:27])[CH:19]=1)[CH3:15])[CH:8]=[N:7]2
Reactant: Fc1ccc(CBr)cc1C(F)(F)F
Reactant: CNc1cnc2cc(Br)ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1ccc(F)c(C(F)(F)F)c1)c1cnc2cc(Br)ccc2n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67.3 %

Procedure:
To a suspension of sodium hydride (0.08 g, 1.5 eq, 3.37 mmol) in DMF (15 mL) was added (6-Bromo-quinoxalin-2-yl)-methyl-amine (0.6 g, 1.0 eq, 2.51 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes. A mixture of 4-(bromomethyl)-1-fluoro-2-(trifluoromethyl)benzene (0.7 g, 1.2 eq. 2.72 mmol) in DMF (15 mL) was added at room temperature and the reaction mixture was stirred for 2.0 hours at 0° C. After completion of the reaction, cold water (180 mL) was added and the reaction mixture was stirred for 15 minutes then filtered. The solid was dried under vacuum to afford the title compound (0.7 g, 67%).
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[CH:10][C:9]2=[O:23]>O.C(O)C>[C:1]([CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[CH:10][C:9]2=[O:23])#[N:2]
Reactant: [C-]#N
Reactant: O=c1cc(-c2ccc(Cl)cc2)oc2ccc(CBr)cc12
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccc2oc(-c3ccc(Cl)cc3)cc(=O)c2c1
Temperature: 60 °C

Procedure:
3.2 g (0.05 mole) of potassium cyanide dissolved in 50 ml of water is placed in a reaction vessel. The solution is heated to 60° C and a solution of 8.3 g (0.023 mole) of 6-bromomethyl-2-(p-chlorophenyl)chromone in 1600 ml of ethanol is added in four portions, one every 20 minutes. Once the addition is complete the mixture is refluxed for 3 hours, evaporated to dryness and dissolved in water. The solid is filtered off and recrystallised from alcohol.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[Cl:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[N:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: OB(O)c1ccc(Cl)nc1
Product: Cc1c2n(c3c(-c4ccc(Cl)nc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, light yellow solid (49 mg, 57%), MS (ISP) m/z=346.4 [(M+H)+], mp 276° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) (78.4 mg, 0.25 mmol) and commercially available 6-chloro-pyridin-3-ylboronic acid (51.1 mg, 0.325 mmol).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][C:6](Cl)=[O:7])[CH2:3][CH2:2]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([NH2:27])=[N:18][N:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[N:21][C:20]=23)=[CH:12][C:11]=1[CH3:28]>C(Cl)Cl.N1C=CC=CC=1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([NH:27][C:6](=[O:7])[CH2:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[N:18][N:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[N:21][C:20]=23)=[CH:12][C:11]=1[CH3:28]
Reactant: O=C(Cl)CCC1CC1
Reactant: Cc1cc(C)n2nc(N)c(-c3ccc(Cl)c(C)c3)c2n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C)n2nc(NC(=O)CCC3CC3)c(-c3ccc(Cl)c(C)c3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
A solution of the product from Example 114D (40.9 mg, 0.308 mmol) in CH2Cl2 (2 mL) was added to a stirring solution of the product from Example 47C (49.5 mg, 0.173 mmol) in pyridine (1.5 mL) at room temperature. The solution was stirred at room temperature for 1 hour, and then concentrated under vacuum. Methanol (2 mL) was added, and the mixture was concentrated under vacuum. The residue was crystallized from 60% EtOH-water (8 mL) to provide the title compound (52 mg). 1H NMR (300 MHz, CD3OD) δ ppm 0.01-0.14 (m, 2H) 0.37-0.52 (m, 2H) 0.66-0.82 (m, 1H) 1.48-1.65 (m, 2H) 2.40 (s, 3H) 2.50 (t, J=7.0 Hz, 2H) 2.57 (s, 3H) 2.72 (s, 3H) 6.88 (s, 1H) 7.37 (d, J=8.1 Hz, 1H) 7.55 (dd, J=8.6, 1.5 Hz, 1H) 7.65 (d, J=1.0 Hz, 1H)); MS (ESI) m/z 383/385 (M+H)+; Anal. Calculated for C21H23N4OCl: C, 65.87; H, 6.05; N, 14.63. Found: C, 65.56; H, 6.08; N, 14.63.
Reaction SMILES: C(O)(=O)/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7]C)[CH:5]=1.[C:15]([O-])([O-])=O.[K+].[K+].N1C=CN=C1>CN(C)C=O>[CH:3]([C:4]1[CH:5]=[C:6]([OH:7])[C:9]([O:10][CH3:15])=[CH:11][CH:12]=1)=[CH2:2]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=Cc1ccc(OC)c(O)c1
Yield: 59 %

Procedure:
A mixture of Ferulic acid (0.0083 mol), K2CO3 (10%, 3 ml), imidazole (1 mL) and dimethylformamide (15 ml) were taken in a 250 ml Erlenmeyer flask fitted with a loose funnel at the top. The flask was shaken well and placed inside the microwave oven over an ice bath and irradiated for 30 minutes in parts. After completion of reaction, it was worked up and purified as in example V and provided sweet and pleasant smelling viscous liquid. 59% yield; (Spectral data as in example V)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pt]=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][O:15]1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccco1)C(=O)O
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCO1)C(=O)O
Yield: 91.2 %

Procedure:
In a Parr shaker bottle was placed (S)-2-t-butoxycarbonylamino-3-furan-2-yl-propionic acid (3.88 g, 15.22 mmol), platinum oxide (200 mg) and ethyl acetate (40 mL). The bottle was then placed on the Parr shaker at 50 psi of hydrogen pressure for 5 h. The reaction was then filtered through a pad of celite and washed with ethyl acetate and concentrated in vacuo to afford (S)-2-t-butoxycarbonylamino-3-(tetrahydro-furan-2-yl)-propionic acid (3.60 g, 91%) as a yellow oil: LR-ES-MS m/z calculated for C12H21NO5 [M]+ 259, observed [M+H]+ 260.