Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[N:19](COCC[Si](C)(C)C)[CH:20]=[C:21]([C:23]#[N:24])[N:22]=3)=[O:17])=[C:11]([C:33]3[CH2:38][CH2:37][C:36]([CH3:40])([CH3:39])[CH2:35][CH:34]=3)[CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl.CCO>[C:1]([C:3]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[NH:19][CH:20]=[C:21]([C:23]#[N:24])[N:22]=3)=[O:17])=[C:11]([C:33]3[CH2:38][CH2:37][C:36]([CH3:40])([CH3:39])[CH2:35][CH:34]=3)[CH:10]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1)#[N:2]
Reactant: CC1(C)CC=C(c2cc(C3(C#N)CCCCC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(C3(C#N)CCCCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Yield: 43 %

Procedure:
A solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [4-(1-cyano-cyclohexyl)-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (66.0 mg, 0.118 mmol, as prepared in the previous step) in CH2Cl2 (6 mL) was treated with EtOH (3 drops) and TFA (0.8 mL) at RT for 2 h. Solvents were evaporated in vacuo. Purification of the residue by RP-HPLC (C18) with 20-80% CH3CN in 0.1% TFA/H2O over 25 min afforded the title compound (25.7 mg, 43%) as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.20 (d, 1H, J=8.8 Hz), 7.93 (s, 1H), 7.37 (dd, 1H, J=8.8, 2.0 Hz), 7.26 (d, 1H, J=2.0 Hz), 5.73-5.67 (m, 1H), 2.29-2.21 (m, 2H), 2.08-1.98 (m, 4H), 1.88-1.68 (m, 6H), 1.58-1.50 (m, 2H), 1.02 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C26H29N5O, 428.2 (M+H), found 428.2.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[C:16](/[C:22](/[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][O:38]1)=[CH:23]/[C:24]([O:26][CH3:27])=[O:25])=[CH:17]\[C:18]([O:20][CH3:21])=[O:19]>CO>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[C:22]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][O:38]1)[CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)/C=C(CCCCCCCCOC1CCCCO1)/C(=C/C(=O)OC)CCCCCCCCOC1CCCCO1
Solvent: CO
Product: COC(=O)CC(CCCCCCCCOC1CCCCO1)=C(CCCCCCCCOC1CCCCO1)CC(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A flame-dried round-bottomed flask was charged with Mg° (15 equiv, 18.75 mmol, 456 mg) and equipped with a condenser. (2E,4E)-dimethyl 3,4-bis(8-((tetrahydro-2H-pyran-2-yl)oxy)octyl)hexa-2,4-dienedioate (1 equiv, 744 mg, 1.25 mmol) was added in MeOH (16 mL) and the reaction was stirred at rt. After ˜30 min, the reaction began refluxing and was left to reflux for ˜45 min upon which time the reaction was permitted to cool to it, quenched with sat. aq. NH4Cl (5 mL), diluted with Et2O (15 mL), and H2O (20 mL). The liquid was decanted into a separatory funnel and the remaining solid was washed several times with Et2O. The layers were separated and the aqueous layer extracted with Et2O (3×20 mL). The combined organic layers were washed with brine (30 mL), dried with Na2SO4 and concentrated in vacuo to afford Dimethyl 3,4-bis(8-((tetrahydro-2H-pyran-2-yl)oxy)octyl)hex-3-enedioate (565 mg crude mass, ˜90% pure by 1HNMR, 0.95 mmol, 76%) as an inseparable 2:1 mixture of isomers which was used in the next reaction without further purification. TLC Rf=0.41 (20% EtOAc/Hex); 1HNMR (500 MHz): δ 4.61-4.56 (2H), 3.91-3.85 (2H), 3.77-3.70 (2H), 3.67 (s, 4H), 3.66 (s, 2H), 3.54-3.47 (2H), 3.42-3.35 (2H), 3.12 (s, 2.7H), 3.11 (s, 1.3H), 2.16-2.07 (4H), 1.90-1.80 (2H), 1.76-1.69 (2H), 1.63-1.49 (12H), 1.40-1.24 (20H); 13CNMR (125 MHz): δ 172.4, 172.2, 130.7, 130.6, 98.9, 67.7, 62.4, 51.8, 37.6, 37.2, 33.3, 32.9, 30.8, 29.8, 29.71, 29.68, 29.49, 29.47, 28.3, 28.1, 26.2, 25.5, 19.7; FTIR: 2926, 2854, 1737, 1434, 1295, 1200, 1156, 1136, 1119, 1078, 1022, 988, 869, 814 cm−1; HRMS-ESI: calc. for C34H60NaO8(M+Na)+: 619.4186. found: 619.4174.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:39][S:36]([C:33]3[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:35][CH:34]=3)(=[O:38])=[O:37])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reactant: COc1ccc(S(N)(=O)=O)cc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccc(OC)cc2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 4-methoxybenzenesulfonamide in accordance with Procedure 1, Method B described hereinabove. Yield (24%); 1H NMR (d6-DMSO) δ 12.04 (br s, 1H), 7.83 (d, J=8.8 Hz, 2H), 7.38-7.07 (m, 15H), 6.84 (d, J=8.0 Hz, 2H), 6.39 (d, J=15.7 Hz, 1H), 3.80 (s, 3H), 2.35 (q, J=7.3 Hz, 2H), 0.82 (t, J=7.3 Hz, 3H); APcI m/z: 525 (M+H+).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[CH:11]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[O:41][CH2:40][CH2:39][CH2:38]3)O1>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].O.C(O)C>[C:17]([O:16][CH:11]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[C:2]=1[C:35]1[CH:44]=[CH:43][C:42]2[O:41][CH2:40][CH2:39][CH2:38][C:37]=2[CH:36]=1)[C:12]([O:14][CH3:15])=[O:13])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC1(C)OB(c2ccc3c(c2)CCCO3)OC1(C)C
Reactant: COC(=O)C(OC(C)(C)C)c1nc2ccccn2c1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)C(OC(C)(C)C)c1nc2ccccn2c1-c1ccc2c(c1)CCCO2
Temperature: 85 °C
Yield: 44.6 %

Procedure:
To a solution of methyl 2-{3-bromoimidazo[1,2-a]pyridin-2-yl}-2-(tert-butoxy)acetate (25d) (60 mg, 0.175 mmol), sodium carbonate (75 mg, 0.70 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman (82 mg, 0.32 mmol) and palladium tetrakis(triphenylphosphine) (20 mg, 0.018 mmol) in a mixture of toluene (1.1 mL), water (0.55 mL) and ethanol (0.48 mL) was heated at 85° C. overnight. After cooling to room temperature, the mixture was poured into water (10 mL). The aqueous layer was extracted with ethyl acetate (2×5 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (dichloromethane/ethyl acetate 50/50). The residue containing target compound was dissolved in ethyl acetate (5 mL) and washed with 1M hydrochloric acid aqueous solution (5 mL). The acidic layer was basified with a saturated solution of sodium hydrogenocarbonate and extracted with ethyl acetate (2×5 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide the desired product (25e) (31 mg, 0.078 mmol, 45%).
Reaction SMILES: Br[C:2]1[C:3](C)=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH3:11][S:12]([NH:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)(=[O:14])=[O:13]>>[CH3:8][N:6]1[C:5](=[O:9])[CH:4]=[CH:3][C:2]([C:20]2[CH:21]=[C:16]([NH:15][S:12]([CH3:11])(=[O:13])=[O:14])[CH:17]=[CH:18][CH:19]=2)=[CH:7]1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: Cc1cc(=O)n(C)cc1Br
Product: Cn1cc(-c2cccc(NS(C)(=O)=O)c2)ccc1=O

Procedure:
5-Bromo-1,4-dimethylpyridin-2-one was treated with [3-(methanesulfonamido)phenyl]boronic acid in a manner similar to Example 94 to give the title compound as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.43 (t, J=8.0 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.16 (s, 1H), 7.07 (d, J=7.6 Hz, 1H), 6.71 (s, 1H), 6.69 (s, 1H), 3.67 (s, 3H), 3.07 (s, 3H), 2.16 (s, 3H). LCMS (M+H)+ 293.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>C(#N)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:5]2[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Clc1ncc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc(Br)cn2)CC1

Procedure:
A mixture of 5-bromo-2-chloro-pyrimidine (1.67 g, 8.63 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.08 g, 10.36 mmol, 1.2 equiv; commercially available) in acetonitrile (10 mL) was heated by microwave irradiation to 120° C. for 40 min. The organic phase was concentrated under reduced pressure and the residue purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 1.48 g (48%) of the title compound. MS (ISP): 357.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:17])[N:9]([CH3:16])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[I:18]I>CN(C)C=O>[Br:1][C:2]1[C:7]2[C:8](=[O:17])[N:9]([CH3:16])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[I:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2cncn2-c2cccc(Br)c2C1=O
Reactant: II
Solvent: CN(C)C=O
Product: CN1Cc2c(I)ncn2-c2cccc(Br)c2C1=O

Procedure:
12.80 g (44 mmol) of 7-bromo-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was stirred at 95° for 3.5 hours with 39 g (154 mmol) of iodine in 80 ml of N,N-dimethylformamide. The reaction mixture was evaporated, the residue was taken up in methylene chloride and water and decolorized by the addition of sodium thiosulphate. The mixture was filtered and the filtrate was evaporated. After chromatography of the residue on silica gel while eluting with ethyl acetate and recrystallization from methylene chloride and ethyl acetate there was obtained 7-bromo-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 203°-204°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:16]([O:20][C:21](=[O:33])[NH:22][C@H:23]([CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[CH2:24]Br)([CH3:19])([CH3:18])[CH3:17].N12CCCN=C1CCCCC2.C(OC(=O)C)C>CN(C)C=O.O>[C:16]([O:20][C:21](=[O:33])[NH:22][C@H:23]([CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[CH2:24][N:13]1[CH2:14][CH2:15][CH:10]([C:8](=[O:9])[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:11][CH2:12]1)([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@@H](CBr)Cc1cccnc1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1cccnc1)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(4-Fluoro-phenyl)-piperidin-4-yl-methanone (0.15 g, 0.73 mmol) is added to a solution of ((R)-2-Bromo-1-pyridin-3-ylmethyl-ethyl)-carbamic acid tert-butyl ester (0.21 g, 0.66 mmol) and 1,8 diazabicyclo[5.4.0]undec-7-ene (0.12 ml, 0.79 mmol) in dimethylformamide (3 ml). The reaction mixture is stirred at ambient temperature for 24 hours prior to partioning between ethylacetate and water. The ethylacetate is dried over magnesium sulphate and evaporated. The crude product is purified by flash silica chromatography (97:3 dichloromethane: methanol elution) to afford {(R)-2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-1-pyridin-3-ylmethyl-ethyl}-carbamic acid tert-butyl ester. 1H NMR (400 MHz, CDCl3) δ 1.36 (s, 9H), 1.68-1.85 (br m, 4H), 2.00-2.38 (br m, 4H), 2.78-2.91 (m, 4H), 3.05-3.19 (m 1H), 3.81-3.93 (m 1H) 7.05 (t J 8.8 2H), 7.12-7.18 (m 1H), 7.48 (d J 7.9 1H), 7.85-7.93 (dd J 8.8 5.4 2H), 8.36 (d J 1.5 1H), 8.40 (dd J 4.9 1.5 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([Br:9])=[C:7]([C:10](=[O:12])N)[S:6][N:5]=1)[CH3:2].N([O-])=[O:14].[Na+]>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]1[C:8]([Br:9])=[C:7]([C:10]([OH:12])=[O:14])[S:6][N:5]=1)[CH3:2]
Reactant: O=N[O-]
Reactant: CCOc1nsc(C(N)=O)c1Br
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCOc1nsc(C(=O)O)c1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
3-Ethoxy-4-bromo-5-carbamoylisothiazole (2.51 g, 0.01 mol) was dissolved in 20 ml of trifluoroacetic acid and the solution cooled to 0° to 5° C. Sodium nitrite (2.76 o, 0.04 mol) was added in small portions to the stirred solution over a five minute period. Stirring was continued for 10 minutes at the same temperature and the reaction mixture poured into 150 ml of ice water. The title compound separated as a white solid (2.2 g, 88%, mp 151°-152.5° C.) and was filtered, washed with ice water and dried.
Reaction SMILES: [CH3:1][S:2][CH:3]1[CH:8]([CH:9]([CH3:11])[CH3:10])[CH2:7][CH2:6][CH:5]([CH3:12])[CH2:4]1.[OH:13]O>C(O)(=O)C>[CH3:1][S:2]([CH:3]1[CH:8]([CH:9]([CH3:11])[CH3:10])[CH2:7][CH2:6][CH:5]([CH3:12])[CH2:4]1)=[O:13]
Reactant: CSC1CC(C)CCC1C(C)C
Reactant: OO
Solvent: CC(=O)O
Product: CC1CCC(C(C)C)C(S(C)=O)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
p-Menth-3-yl methyl sulphide, prepared as in Part A (1.5 g., 8 mmoles), hydrogen peroxide (1 ml. of 30% solution) and glacial acetic acid (25 ml.) were stirred at room temperature for 17 hours. The mixture was then poured into ferrous sulphate solution and extracted with ether. The ether extracts were washed with sodium carbonate solution and then dried (MgSO4). Removal of the solvent left an oil which was purified by column chromatography and distillation to give p-menth-3-yl methyl sulphoxide, b.p. 88°/0.03 mm. (Found C, 65.3; H, 10.9. C11H22OS requires C, 65.4; H, 10.9%).
Reaction SMILES: C1(CCOC2C=CC(C(NC(CC3C=CC(CCC)=CC=3)C(NCCO)=O)=O)=CC=2)CC1.[F:33][CH:34]([F:71])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40](/[CH:43]=[C:44](\[NH:51][C:52](=[O:70])[C:53]2[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH2:61][C:62]3[CH:67]=[CH:66][C:65]([O:68][CH3:69])=[CH:64][CH:63]=3)=[CH:55][CH:54]=2)/[C:45]([NH:47][CH2:48][CH2:49][OH:50])=[O:46])=[CH:39][CH:38]=1>>[F:33][CH:34]([F:71])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH:44]([NH:51][C:52](=[O:70])[C:53]2[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH2:61][C:62]3[CH:63]=[CH:64][C:65]([O:68][CH3:69])=[CH:66][CH:67]=3)=[CH:55][CH:54]=2)[C:45]([NH:47][CH2:48][CH2:49][OH:50])=[O:46])=[CH:39][CH:38]=1
Reactant: COc1ccc(CCOc2ccc(C(=O)N/C(=C\c3ccc(OCC(F)F)cc3)C(=O)NCCO)cc2)cc1
Agent: CCCc1ccc(CC(NC(=O)c2ccc(OCCC3CC3)cc2)C(=O)NCCO)cc1
Product: COc1ccc(CCOc2ccc(C(=O)NC(Cc3ccc(OCC(F)F)cc3)C(=O)NCCO)cc2)cc1
Yield: 72.7 %

Procedure:
A reaction similar to that described in Example (1 (1e) was conducted using N-((Z)-2-[4-(2,2-difluoroethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-[2-(4-methoxyphenyl)ethoxy]benzamide (200 mg) to give 146 mg of the title compound (white powder).
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:8]([O:30][CH3:31])=[CH:9][CH:10]=[C:11]3[C:16]=2[N:15]([CH2:17][CH:18]=O)[C:14](=[O:20])[CH:13]=[C:12]3[NH:21][C:22]2[C:27]([Cl:28])=[CH:26][N:25]=[CH:24][C:23]=2[Cl:29])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:33][NH:34][CH3:35].C(N(CC)CC)C.[BH4-].[Na+].N>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[CH:1]1([O:6][C:7]2[C:8]([O:30][CH3:31])=[CH:9][CH:10]=[C:11]3[C:16]=2[N:15]([CH2:17][CH2:18][N:34]([CH3:35])[CH3:33])[C:14](=[O:20])[CH:13]=[C:12]3[NH:21][C:22]2[C:23]([Cl:29])=[CH:24][N:25]=[CH:26][C:27]=2[Cl:28])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNC
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)n(CC=O)c2c1OC1CCCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)n(CCN(C)C)c2c1OC1CCCC1
Reaction time: 8 h

Procedure:
Titanium (IV) isopropoxide (496 mg, 1.74 mmol) and 2-(8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxoquinolin-1(2H)-yl)acetaldehyde (400 mg, 0.87 mmol) were added sequentially to a solution of dimethylamine hydrochloride (144 mg, 1.74 mmol), triethylamine (176 mg, 1.74 mmol), and absolute ethanol (20 mL). After stirring overnight, sodium borohydride (50 mg, 1.3 mmol) was added. After an additional 3 h, the reaction was poured into aq. ammonia (30 mL) and then filtered—washing with dichloromethane. The filtrate was extracted with dichloromethane (50 mL×3). The combined extracts were dried, filtered, concentrated, and purified by reverse-phase HPLC to give 8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-1-(2-(dimethylamino)ethyl)-7-methoxyquinolin-2(1H)-one: 1H NMR (400 MHz, DMSO-d6): δ 8.75 (s, 1H), 8.73 (s, 2H), 7.91 (d, 1H), 7.12 (d, 1H), 4.94 (s, 1H), 4.71 (t, 2H), 4.58 (m, 1H), 3.90 (s, 3H), 2.22 (m, 2H), 2.04 (s, 6H), 1.80-1.50 (m, 8H); MS (ESI): 491.0.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH:7]2[CH2:10][CH:11]=[CH:12][CH2:13][CH:6]2[C:5]1=[O:14].[C:15]([O:30]CC(C)C)(=O)[CH:16]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:17]1[C:18]([O:20][CH2:21][CH:22](C)C)=[O:19]>>[C:18]([O:20][CH2:21][CH2:22][N:4]1[C:5](=[O:14])[CH:6]2[CH2:13][CH:12]=[CH:11][CH2:10][CH:7]2[C:8]1=[O:9])(=[O:19])[CH:17]1[CH2:25][CH2:26][CH2:27][CH2:28][CH:16]1[C:15]([O:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH:7]2[CH2:10][CH:11]=[CH:12][CH2:13][CH:6]2[C:5]1=[O:14])=[O:30]
Reactant: O=C1C2CC=CCC2C(=O)N1CCO
Reactant: CC(C)COC(=O)C1CCCCC1C(=O)OCC(C)C
Product: O=C(OCCN1C(=O)C2CC=CCC2C1=O)C1CCCCC1C(=O)OCCN1C(=O)C2CC=CCC2C1=O
Yield: 101 %

Procedure:
N-(2-Hydroxyethyl)-1,2,3,6-tetrahydrophthalimide (195.2 g, 1 mol) was dissolved in diisobutyl hexahydrophthalate (142.2 g, 0.5 mol). The mixture was treated as described in example 1 to obtain 266 g of brown crude bis[2-(1,2,3,6-tetrahydrophthalimido)ethyl] hexahydrophthalate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([F:11])[C:8](F)=[C:7]([O:13][CH3:14])[C:6]=1[F:15])[CH3:2].[C:17]([O:21][C:22](=[O:29])[NH:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:26]2[CH2:27][CH2:28][CH:24]([NH:23][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:29])[CH2:25]2)=[C:7]([O:13][CH3:14])[C:6]=1[F:15])[CH3:2]
Reactant: CCOC(=O)c1cc(F)c(F)c(OC)c1F
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(F)c(N2CCC(NC(=O)OC(C)(C)C)C2)c(OC)c1F
Yield: 77.6 %

Procedure:
A solution of 2,4,5-trifluoro-3-methoxybenzoic acid ethyl ester (Example 1f, 2.821 g, 12.05 mmol), pyrrolidin-3-ylcarbamic acid tert-butyl ester (3.310 g, 17.77 mmol), and triethylamine (9.13 g, 12.6 mL, 90.23 mmol) in acetonitrile (50 mL) is heated at 40° C. under nitrogen for 2 days. The yellow solution is concentrated to near dryness and poured into saturated NaHCO3 solution and extracted with dichloromethane. The combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue is purified by flash column chromatography (1:7 ethyl acetate/hexanes) to afford the title compound as a yellow solid (3.743 g). MS EI: m/z 401 (MH+).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1.Cl.CCN(C(C)C)C(C)C.Br[C:24]1[N:29]=[CH:28][C:27]([Br:30])=[CH:26][N:25]=1>CC(N(C)C)=O>[Br:30][C:27]1[CH:26]=[N:25][C:24]([N:2]([CH2:3][C@H:4]2[CH2:9][CH2:8][C@H:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]2)[CH3:1])=[N:29][CH:28]=1
Reactant: Brc1cnc(Br)nc1
Reactant: CNC[C@H]1CC[C@H](C(=O)O)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CN(C[C@H]1CC[C@H](C(=O)O)CC1)c1ncc(Br)cn1
Temperature: 120 °C

Procedure:
A mixture of 0.42 g (2.0 mmol) of trans-4-methylaminomethyl-cyclohexanecarboxylic acid•HCl, 1.85 mL (1.1 mmol) of Huenig's base and 0.57 g (2.4 mmol) of 2,5-dibromo-pyrimidine [Brown and Arantz, J. Chem. Soc. C Issue 10, 1889-1891 (1971)] in 2 mL of DMA was placed in the microwave and heated to 120° C. for 1 h. The solvent was evaporated, partitioned between Et2O (×3)/aqueous 10% KH2PO4, dried over Na2SO4 and evaporated to yield 0.604 g (92%) of trans-4-{[(5-bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-cyclohexanecarboxylic acid, MS: 326 (M−H−, 1Br), MP: 172-174° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[C:34]1([CH2:40][CH2:41][NH2:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([NH:42][CH2:41][CH2:40][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: NCCc1ccccc1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(NCCc4ccccc4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and phenylethylamine. ES-MS m/e (%): 490 (M+H+, 100).
Reaction SMILES: CN(C)C=O.Cl.Cl[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[NH2:16][C:17](=[O:48])[C:18]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[O:29][CH2:30][C:31]([OH:33])=[O:32])[N:22]([CH2:34][C:35]2[CH:36]=[C:37]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:38]=[CH:39][CH:40]=2)[C:21]=1[CH3:47])=[O:19].[Na]>O>[NH2:16][C:17](=[O:48])[C:18]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[O:29][CH2:30][C:31]([O:33][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:32])[N:22]([CH2:34][C:35]2[CH:36]=[C:37]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:38]=[CH:39][CH:40]=2)[C:21]=1[CH3:47])=[O:19]
Reactant: ClCCN1CCOCC1
Reactant: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cccc2n1Cc1cccc(-c2ccccc2)c1
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)OCCN3CCOCC3)cccc2n1Cc1cccc(-c2ccccc2)c1
Temperature: 60 °C

Procedure:
In a flask containing 10 ml of dimethylformamide was added with stirring 133 mg. of 4-(2-chloroethyl)morpholine hydrochloride (available from Aldrich Chemical Co., Milwaukee, Wis. USA, Item No. C4,220-3) and 231 mg. of CsCO3 and 300 mg. of ((3-(2-amino-1,2-dioxoethyl)-1-((1,1′-biphenyl)-3-ylmethyl)-2-methyl-1H-indol-4-yl)oxy)acetic acid, sodium salt. The slurry was heated to 60° C. until a solution formed. Heating was continued overnight until reaction was complete. 20 ml of H2O was added to the flask and the organic soluble phase extracted with three 20 ml. portions of ethyl acetate. The ethyl acetate solution was washed with water and dried over and dried over Na2SO4. Removal of solvent gave product verified by IR and NMR to be the title compound. Molecular Formula: C32H22N3O6
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:4]=2[O:3]1.ClC1C=CC=C(C(OO)=[O:31])C=1>ClCCl>[CH3:1][C:2]1([CH3:22])[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:31])[C:5]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:4]=2[O:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccnc1C1CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Solvent: ClCCl
Product: Cc1ccc[n+]([O-])c1C1CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
248 mg of 3.4-dihydro-2,2-dimethyl-4-(3-methyl-2-pyridyl)-6-nitro-2H-1-benzopyran were dissolved in 20 ml of dichloromethane at room temperature and 222 mg of m-chloroperbenzoic acid were added. After stirring at room temperature overnight the solution was washed in succession with sodium bisulphite solution, sodium bicarbonate solution and water. The organic phase was dried over sodium sulphate and evaporated. The resulting solid was triturated with diethyl ether, filtered off and recrystallized from acetonitrile to give 133 mg of 2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1-benzopyran-4-yl)-3-methylpyridine N-oxide of melting point 218°-220° C.