Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9](=[C:12]([C:18](OCC)=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH3:11])[CH3:10].N1C=CN=C1>CCOC(C)=O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18]([C:12](=[C:9]([CH3:10])[CH3:11])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:19])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)C
Reactant: Nc1ccc(F)cc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)Nc1ccc(F)cc1)=C(C)C
Temperature: 200 °C
Reaction time: 3 h
Yield: 38.7 %

Procedure:
To a solution of 4-fluoroaniline (2 g, 18 mmol) in diethyl isopropylidenemalonate (10 g, 50 mmol) is added 1H-imidazole (0.25 g, 3.67 mmol). The reaction mixture is stirred at 200° C. under N2 for 3 hours. After the reaction is cooled, silica gel is added. The mixture is loaded onto a silica gel column, and eluted first with PE and then PE:EtOAc (3:1) to give the product (1.85 g, 39% yield). MS (m/z): 266.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:6]=1[O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:4]>C1COCC1.[C].[Pd]>[NH2:20][C:18]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:19]=1
Reactant: CCOC(=O)CCCOc1ccc([N+](=O)[O-])cc1C(=O)OC
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCCOc1ccc(N)cc1C(=O)OC
Reaction time: 4 h
Yield: 102.8 %

Procedure:
In THF (25 ml) was dissolved ethyl 4-(2-methoxycarbonyl-4-nitrophenoxy)butyrate (2.37 g, 7.61 mmol), and to the mixture was added 10% palladium-carbon (containing 50% water, 0.94 g). The mixture was subjected to catalytic reduction at room temperature for 4 hours. Insoluble materials were filtered off, and the filtrate was dried with anhydrous magnesium sulfate and concentrated under reduced pressure to give ethyl 4-(4-amino-2-methoxycarbonylphenoxy)butyrate (2.20 g).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]2[NH:12][CH:11]=[N:10][N:9]=2)=[C:5]([Br:7])[N:6]=1.[H-].[Na+].[CH3:15][Si:16]([CH2:19][CH2:20][O:21][CH2:22]Cl)([CH3:18])[CH3:17].CCOC(C)=O.CCCCCC>CN(C=O)C>[Br:1][C:2]1[S:3][C:4]([C:8]2[N:12]=[CH:11][N:10]([CH2:22][O:21][CH2:20][CH2:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[N:9]=2)=[C:5]([Br:7])[N:6]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1nc(Br)c(-c2nnc[nH]2)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cnc(-c2sc(Br)nc2Br)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66.8 %

Procedure:
To the solution of 3-(2,4-dibromo-1,3-thiazol-5-yl)-4H-1,2,4-triazole (1.16 g, 3.74 mmol) in dry DMF (5.0 mL) at 0° C. was added portionwise sodium hydride (60%, 0.180 g, 4.49 mmol). The ice bath was removed, mixture was stirred for 5 min. at ambient temperature and cooled with ice bath. SEM chloride (0.795 mL, 4.49 mmol) in dry DMF (2.0 mL) was added dropwise and the mixture was stirred at room temperature for 2 hours. The mixture was quenched with ice-water, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, evaporated to give a crude oil. Chromatograph in a silica column using EtOAc/hexane (0/100 to 20/80) afforded white solid product (1.10 g, 67%). LCMS: (FA) ES+ 441. 1H NMR (400 MHz, d1-chloroform) 8.29 (s, 1H), 5.54 (s, 2H), 3.71 (t, J=8.28 Hz, 2H), 0.95 (t, J=8.28 Hz, 2H), 0.00 (s, 9H).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[C:10]([F:17])[CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:27][C:26]=2[F:36])=[CH:21][CH:20]=1.C(OC1(C2C=CC(CCCCC)=CC=2)C(F)=CC(C2C=CC=CC=2)=C(F)C1)CCCCC>>[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:27][C:26]=3[F:36])=[CH:23][CH:24]=2)=[C:10]([F:17])[CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(B(O)O)c(F)c1
Reactant: CCCCCc1ccc(-c2ccc(Br)cc2)c(F)c1
Agent: CCCCCCOC1(c2ccc(CCCCC)cc2)CC(F)=C(c2ccccc2)C=C1F
Product: CCCCCCOc1ccc(-c2ccc(-c3ccc(CCCCC)cc3F)cc2)c(F)c1

Procedure:
The product from 3B is coupled with 4'-bromo-2-fluoro-4-pentylbiphenyl in an analogous manner as described for 1G.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[N:16]3[C:17]([CH3:20])=[N:18][N:19]=[C:15]3[C@H:14]([CH2:21][C:22]([NH:24][CH2:25][CH3:26])=[O:23])[N:13]=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:11]=2[CH:34]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH3:43][O:44][C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][CH:50]=1.C1(C)C=CC=CC=1>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.C(O)C>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:12]2[C:11]3[CH:34]=[C:7]([C:49]4[CH:48]=[CH:47][CH:46]=[C:45]([O:44][CH3:43])[CH:50]=4)[CH:8]=[CH:9][C:10]=3[N:16]3[C:17]([CH3:20])=[N:18][N:19]=[C:15]3[C@H:14]([CH2:21][C:22]([NH:24][CH2:25][CH3:26])=[O:23])[N:13]=2)=[CH:32][CH:31]=1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2-n2c(C)nnc21
Reactant: COc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3cccc(OC)c3)ccc2-n2c(C)nnc21
Temperature: 120 °C

Procedure:
(S)-6-(4-Chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl trifluoromethanesulfonate (for a preparation see Intermediate 3) (100 mg), bis(triphenylphosphine)palladium(II) chloride (12.95 mg), potassium carbonate (128 mg) and 3-methoxyphenylboronic acid (33.6 mg) were added to a 2-5 ml microwave vial. Toluene (2 ml) and ethanol (2 ml) were added to the vial and the reaction mixture was heated at 120° C. for 20 min (microwave). The reaction mixture was filtered through Celite™ and the filter bed was washed with ethanol. The solvent was evaporated and the residue was chromatographed (0-5% methanol:DCM), triturated with diethyl ether and dried in a vacuum dessicator at 40° C. overnight to give (S)-2-(6-(4-chlorophenyl)-8-(3-methoxyphenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide as a cream solid (59.6 mg). LCMS (formate): MH+ 500/502, RT 1.09 min
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:6]=1[NH2:17])(=[O:4])=[O:3].[F:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([S:29](Cl)(=[O:31])=[O:30])[CH:23]=[CH:22]2>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=2)[CH:8]=[CH:7][C:6]=1[NH:17][S:29]([C:24]1[CH:23]=[CH:22][C:21]2[C:26](=[CH:27][CH:28]=[C:19]([F:18])[CH:20]=2)[CH:25]=1)(=[O:30])=[O:31])(=[O:4])=[O:3]
Reactant: O=S(=O)(Cl)c1ccc2cc(F)ccc2c1
Reactant: CS(=O)(=O)c1cc(-c2ccncc2)ccc1N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1cc(-c2ccncc2)ccc1NS(=O)(=O)c1ccc2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
To a solution of 2-methanesulfonyl-4-pyridin-4-yl-phenylamine (cf. Example 20c, 0.27 g) and 6-fluoro-naphthalene-2-sulfonyl chloride (0.148 g; cf. Brown, George Robert; Stokes, Elaine Sophie Elisabeth; Waterson, David; Wood, Robin. WO 9706802) in dichloromethane (1.0 ml) was added DMAP (0.037 g). The reaction mixture was stirred at rt for 2 h and directly chromatographed on silica gel using heptane/ethyl acetate as eluent to produce the title compound (0.098 g) as a colorless foam. MS (ISP): 457.3 (M+H)+
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[CH3:31][O:32][C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)=[O:34].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:31][O:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([C:18]2[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=2)=[CH:37][CH:36]=1)=[O:34]
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(C2=COCCN2C(=O)OC(C)(C)C)cc1
Temperature: 65 °C
Yield: 50.3 %

Procedure:
Tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate (20 g, 46.1 mmol) and (4-methoxycarbonylphenyl)boronic acid (9.0 g, 49.8 mmol) were dissolved in acetonitrile (300 ml). A solution of potassium phosphate (19.6 g, 92.3 mmol) in water (75 ml) was added, followed by bis(tri-tert-butylphosphine)palladium (0) (2.36 g, 4.61 mmol). Nitrogen was bubbled through the stirred mixture for 40 minutes, then the mixture was heated to 65° C. for 2 hours. The mixture was cooled and diluted with ethyl acetate (1 L) and water (200 ml). The organic phase was separated and washed with sat NaHCO3 (3×200 ml), then brine (200 ml), dried (MgSO4), filtered and partially concentrated to 50 ml. Solid material was removed by filtration (700 mg). The filtrate was concentrated to a brown solid. The crude was purified on silica gel, eluting with 0-10% ethyl acetate/petrol. This gave the title compound as a white solid (7.4 g, 50%); 1H-NMR (CDCl3) 1.13 (9H, s), 3.80 (2H, t), 3.93 (3H, s), 4.20 (2H, t), 6.36 (1H, s), 7.31 (2H, d), 7.98 (2H, d); 13C-NMR (CDCl3) 27.7, 41.5, 52.0, 66.8, 124.5, 129.6, 133.7; MS ES(+) 264.1 (M+-tBu); Anal. Calcd for C12H21NO5: C, 63.94; H, 6.63; N, 4.38. Found: C, 63.83; H, 6.53; N, 2.23.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:13])[C:9](OC)=[O:10].O>O1CCCC1>[CH3:13][C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:7])[CH2:9][OH:10]
Reactant: COC(=O)C(C)(C)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CO)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of lithium aluminum hydride (1.71 g) in tetrahydrofuran (50 ml) was dropwise added a solution of methyl 2-methyl-2-phenylpropionate (7.97 g) in tetrahydrofuran (20 ml) under ice cooling and the mixture was stirred at room temperature for 30 minutes. To the reaction solution was dropwise added water and then a saturated aqueous solution of sodium bicarbonate, and the solution was extracted with ether. The ehter layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resultant residue was subjected to silica gel (100 g) column chromatography. Elution with a mixture solution of hexane-ethyl acetate (2:1) gave 6.32 9 of 2-methyl-2-phenylpropanol.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][CH:4]=1.[OH:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2>>[N:19]1[C:20]2[C:15](=[C:14]([O:13][CH2:2][C:3]3[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=3)[CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Oc1cccc2ncccc12
Product: O=C(O)c1ccc(COc2cccc3ncccc23)cc1

Procedure:
Methyl 4-(bromomethyl)benzoate was alkylated with commercially available 5-hydroxyquinoline using the analogous procedure as used for Example 202. MS found: (M+H)=280.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[C:9]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)(=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:9]([N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=2)[CH2:14][CH2:13]1)(=[O:11])[CH3:10]
Reactant: CC(=O)N1CCNCC1
Reactant: Fc1cccc(F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)N1CCN(c2cccc(F)n2)CC1
Yield: 99.9 %

Procedure:
A solution of 2,6-difluoropyridine (9.0 g), 1-acetylpiperazine (5.0 g) and potassium carbonate (8.1 g) in acetonitrile (100 ml) was refluxed under heating for 18 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a pale-brown solid (8.7 g). The obtained pale-brown solid was crystallized from ethyl acetate-hexane to give the title compound (5.5 g) as pale-brown crystals.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=[O:4].[CH:21]1([C:27](O)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[F:20][C:16]1[CH:15]=[C:14]([CH:6]([NH:5][C:3]([CH2:2][NH:1][C:27]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:28])=[O:4])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: NCC(=O)NC(c1cccc(F)c1)c1cccc(F)c1
Reactant: O=C(O)C1CCCCC1
Product: O=C(CNC(=O)C1CCCCC1)NC(c1cccc(F)c1)c1cccc(F)c1

Procedure:
Prepared in analogy to example 1.12 from 2-amino-N-[bis-(3-fluoro-phenyl)-methyl]-acetamide (example 3.4) and cyclohexane-carboxylic acid.
Reaction SMILES: Cl[C:2]1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[Cl:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:42]=[C:43]([CH2:56][CH3:57])[C:44]([NH:49][C@H:50]2[CH2:54][O:53][CH2:52][C@H:51]2[OH:55])=[N:45][C:46]=1[CH2:47][CH3:48].IC>>[Cl:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:42]=[C:43]([CH2:56][CH3:57])[C:44]([NH:49][C@H:50]2[C@@H:51]([O:55][CH3:2])[CH2:52][O:53][CH2:54]2)=[N:45][C:46]=1[CH2:47][CH3:48]
Reactant: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@H]1COC[C@H]1O
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Solvent: CI
Product: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1COC[C@@H]1OC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting of cis-(+/−)-4-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}tetrahydrofuran-3-ol and iodomethane and making non-critical variations provided the title compound as a colorless semi-solid. IR (liq.) 2970, 2936, 2874, 1606, 1566, 1483, 1441, 1397, 1287, 1230, 1203, 1182, 1126, 1076, 1049 cm−1; OAMS supporting ions at: ESI+ 392.1; MS (EI) m/z 391 (M+); HRMS (FAB) calcd for C20H26CLN3O3+H1 392.1741, found 392.1758. Anal. Calcd for C20H26ClN3O3: C, 61.30; H, 6.69; N, 10.72. Found: C, 61.16; H, 6.47; N, 10.65.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:19])[C:7](=[O:18])[C:8]3([CH2:17][CH2:16]3)[CH2:9][N:10]([CH:13]([CH3:15])[CH3:14])[C:11]=2[N:12]=1.[NH2:20][C:21]1[C:35]([Cl:36])=[CH:34][C:24]([C:25]([NH:27][C@@H:28]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29]2)=[O:26])=[C:23]([F:37])[CH:22]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Pd+2].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[Cl:36][C:35]1[C:21]([NH:20][C:2]2[N:3]=[CH:4][C:5]3[N:6]([CH3:19])[C:7](=[O:18])[C:8]4([CH2:17][CH2:16]4)[CH2:9][N:10]([CH:13]([CH3:15])[CH3:14])[C:11]=3[N:12]=2)=[CH:22][C:23]([F:37])=[C:24]([CH:34]=1)[C:25]([NH:27][C@@H:28]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29]1)=[O:26]
Reactant: CC(C)N1CC2(CC2)C(=O)N(C)c2cnc(Cl)nc21
Reactant: CN1CC[C@@H](NC(=O)c2cc(Cl)c(N)cc2F)C1
Agent: [Pd+2]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1COCCO1
Product: CC(C)N1CC2(CC2)C(=O)N(C)c2cnc(Nc3cc(F)c(C(=O)N[C@@H]4CCN(C)C4)cc3Cl)nc21
Temperature: 100 °C
Yield: 89.6 %

Procedure:
2′-chloro-9′-isopropyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 208; 88 mg, 0.32 mmol), 4-amino-5-chloro-2-fluoro-N-[(3R)-1-methylpyrrolidin-3-yl]benzamide (Intermediate 207; 101 mg, 0.36 mmol) and XANTPHOS (17 mg, 0.03 mmol) were dissolved in 1,4-dioxane (7.5 mL). Caesium carbonate (229 mg, 0.65 mmol) was added and the system purged with a stream of nitrogen for 15 minutes before tris(dibenzylideneacetone) palladium (II) (18 mg, 0.02 mmol) was added. The apparatus was evacuated and backfilled with nitrogen (×3) and then heated at 100° C. for 3 hours. The mixture was cooled, filtered and the filtrate absorbed on to an SCX column, which was washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by column chromatography (2.5% 7N ammonia in MeOH/DCM) to yield the title compound as a pale yellow foam (148 mg, 90%).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:10]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[N:9]=[N:8][CH:7]=1)CCC.[CH3:27][NH:28][C:29]([C:31]1[C:32](=[O:49])[N:33]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:48])([F:47])[F:46])[CH:40]=2)[C:34]([CH3:38])=[C:35](I)[CH:36]=1)=[O:30]>COCCOC>[CH3:27][NH:28][C:29]([C:31]1[C:32](=[O:49])[N:33]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:48])([F:46])[F:47])[CH:40]=2)[C:34]([CH3:38])=[C:35]([C:6]2[N:10]([C:11]3[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=3)[N:9]=[N:8][CH:7]=2)[CH:36]=1)=[O:30]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnnn1-c1ccc(C#N)cc1
Reactant: CNC(=O)c1cc(I)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Solvent: COCCOC
Product: CNC(=O)c1cc(-c2cnnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 100 °C
Yield: 38 %

Procedure:
4-(5-Tributylstannanyl-[1,2,3]triazol-1-yl)-benzonitrile (0.107 g, 0.22 mmol), 5-iodo-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid methylamide (0.05 g, 0.11 mmol), Pd(PBut3)2 (10 mg) and DME (2 ml) were placed in a tube for microwave synthesis. The mixture was degassed with argon and heated in a synthesis microwave heater (CEM) at 100° C. (max 150 W) for 10 minutes. The solvent was removed in vacuo giving a crude product which was purified on silica and then further purified on preparative HPLC. The pure fractions were freeze-dried giving 20 mg (40%) of the title compound.
Reaction SMILES: [O-2].[Cd+2:2].[CH2:3]([C:17]([OH:19])=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:3]([C:17]([O-:19])=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cd+2:2].[CH2:3]([C:17]([O-:19])=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCC(=O)O
Agent: [Cd+2]
Agent: [O-2]
Product: CCCCCCCCCCCCCCC(=O)[O-]
Temperature: 90 °C

Procedure:
Cadmium oxide (0.127 g, 1 mmol) and tetradecylcarboxylic acid (0.500 g) were reacted at 220° C. for 10 min, cooled to 90° C., then a cadmium tetradecylcarboxylate (precursor) was formed. Into said system, toluene (10 ml), trioctylphosphine oxide (3.866 g) and trioctylphosphine (3.7 g) were added. Then, a 0.05 M aqueous solution of sodium sulfide (10 ml) was added. After the system was reacted at 90° C. for 3 h, a clear yellow sol containing CdS nanoparticle was obtained. Said sol has the typical exciton absorption peak of CdS nanoparticle, can result in a quantum size effect and emit a fairly strong blue light under the irradiation of a UV lamp.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([OH:28])=[O:27])=[C:24]([CH:29]([OH:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[N:23]=[C:22]2[CH2:35][CH2:36][CH3:37])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:39]1[C:43](=[O:44])[CH2:42][CH2:41][C:40]1=[O:45]>>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([O:28][N:39]3[C:43](=[O:44])[CH2:42][CH2:41][C:40]3=[O:45])=[O:27])=[C:24]([CH:29]([OH:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[N:23]=[C:22]2[CH2:35][CH2:36][CH3:37])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1O
Reactant: CCCc1nc(C(O)C(C)(C)C)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Product: CCCc1nc(C(O)C(C)(C)C)c(C(=O)ON2C(=O)CCC2=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 89.8 %

Procedure:
Following a procedure similar to that described in Example 52(a), but using 300 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-4-(1-hydroxy-2,2-dimethylpropyl)-2-propylimidazole-5-carboxylic acid [prepared as described in step (e) above], 110 mg of N-hydroxysuccinimide and 130 mg of N,N-dicyclohexylcarbodiimide, 321 mg of the title compound were obtained as an amorphous solid.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:7]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Ni]>[NH2:1][C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:7]([S:14]([NH2:17])(=[O:15])=[O:16])=[CH:6][CH:5]=1
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])c2c1CCCC2
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(S(N)(=O)=O)c2c1CCCC2
Yield: 95.7 %

Procedure:
A suspension of 1,2,3,4-tetrahydro-8-nitro-5-naphthalenesulfonamide (3.1 g, 12 mmol) in 150 ml of ethanol was hydrogenated at room temperature and atmospheric pressure over Raney-Ni. After the theoretical absorption, the reaction mixture was filtered and concentrated to dryness to give 2.6 g (95%) of the title compound. M.p. 216°-219° C. (ethanol); 1H-NMR (DMSO-d6): 1.50-1.93 (m, 4H, 2CH2), 2.17-2.57 (m, 2H, CH2), 2.83-3.17 (m, 2H, CH2), 5.29 (broad s, 2H, NH2), 6.38 (d,J=9Hz, 1H, ArH), 6.75 (broad s, 1H, SO ), 7.35 (d,J=9Hz, 1H, ArH).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])=[O:5])C.[OH-].[K+]>CO>[CH3:11][C:9]1[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[N:8]=1
Reactant: CCOC(=O)c1sc(C)nc1-c1ccccc1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(-c2ccccc2C)c(C(=O)O)s1
Temperature: 50 °C
Yield: 81.7 %

Procedure:
A mixture of 2-methyl-4-o-tolyl-thiazole-5-carboxylic acid ethyl ester (0.84 g, 3.20 mmol, 1.0 equiv) and potassium hydroxide (0.36 g, 6.40 mmol, 2.0 equiv) in 50% aqueous methanol (10 mL) was heated to 50° C. for 5 hours. The mixture was concentrated, and the residue diluted with water and acidified to about pH 1 by the addition of 6N HCl solution. The resultant solution was extracted with ethyl acetate (3×). The combined extracts were dried over magnesium sulphate, filtered, and concentrated under vacuum to afford 0.61 g (81%) of 2-methyl-4-o-tolyl-thiazole-5-carboxylic acid as a solid. LCMS (ESI) m+H=234.0; 1H NMR (400 MHz, CDCl3) δ: 7.32-7.17 (m, 4H), 2.75 (s, 3H), 2.17 (s, 3H).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([NH2:6])=[O:5].[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C)C=O>[C:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:7])[CH2:2][CH2:3][C:4]([NH2:6])=[O:5]
Reactant: NC(=O)CCC(=O)O
Reactant: ClCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)CCC(=O)OCc1ccccc1

Procedure:
A mixture of 23.4 g. (0.20 mole) of succinamic acid, 25.4 g. (0.20 mole) of benzyl chloride, 20.2 g. (0.20 mole) triethylamine and 250 ml. dimethylformamide is stirred at 95°C. for 20 hours. The reaction mixture is diluted with 500 ml. water and the product extracted into two 200 ml. portions of ethyl ether. The combined ether extracts are washed with two 50 ml. portions of saturated sodium bicarbonate solution, then two 50 ml. portions of water and dried over anhydrous magnesium sulfate. After filtering, the solution is concentrated at 15 - 20 mm. and 40°C. to give benzyl succinamate.