Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]=1[NH2:14].[CH3:15][C:16]1[N:17]=[C:18]([S:21](Cl)(=[O:23])=[O:22])[S:19][CH:20]=1.COC(C)(C)C>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]=1[NH:14][S:21]([C:18]1[S:19][CH:20]=[C:16]([CH3:15])[N:17]=1)(=[O:23])=[O:22]
Reactant: Cc1csc(S(=O)(=O)Cl)n1
Reactant: COCOc1cc2c(cc1N)CCC2
Solvent: c1ccncc1
Solvent: COC(C)(C)C
Product: COCOc1cc2c(cc1NS(=O)(=O)c1nc(C)cs1)CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.30 g of 6-(methoxymethoxy)indan-5-amine was dissolved in 33.0 mL of pyridine and 157 mL of a 0.54 M 4-methyl-1,3-thiazole-2-sulfonylchloride/tert-butyl methyl ether solution was added thereto, followed by stirring overnight at room temperature. The reaction liquid was concentrated under reduced pressure, to the residue were added water and ethyl acetate, and the insoluble materials were removed by filtration. After the filtrate was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=73:27 to 60:40) to obtain 4.79 g of N-[6-(methoxymethoxy)-2,3-dihydro-1H-inden-5-yl]-4-methyl-1,3-thiazole-2-sulfonamide.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[N:5]2[CH:9]=[CH:10][CH:11]=[N:12][C:4]2=[N:3]1>[Pd].C(O)(=O)C>[CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[N:5]2[CH2:9][CH2:10][CH2:11][N:12]=[C:4]2[NH:3]1
Reactant: CC1CC(C)N2C=CC=NC2=N1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1CC(C)N2CCCN=C2N1

Procedure:
0.5 g 2,4-dimethyl-3,4-dihydro-2H-pyrimido[1,2-a]pyrimidine hydroperchlorate was heated for 8 h in an acetic acid solution with palladium on activated charcoal, with H2 fed in. Subsequent filtration, removal of the solvent and addition of diethyl ether yielded the 2,4-dimethyl-1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine hydroacetate in the form of colorless crystals, which were recrystallized from ethanol.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11](B(O)O)=[CH:10][C:9]=2[F:17])=[CH:4][N:3]=1.Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([NH:28][CH2:29][C@H:30]([OH:32])[CH3:31])(=[O:27])=[O:26]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25]([NH:28][CH2:29][C@H:30]([OH:32])[CH3:31])(=[O:27])=[O:26])=[CH:10][C:9]=2[F:17])=[CH:4][N:3]=1
Reactant: Nc1ncc(-c2ncc(B(O)O)cc2F)cn1
Reactant: C[C@@H](O)CNS(=O)(=O)c1ccccc1Br
Product: C[C@@H](O)CNS(=O)(=O)c1ccccc1-c1cnc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 427 using (6-(2-aminopyrimidin-5-yl)-5-fluoropyridin-3-yl)boronic acid and (R)-2-bromo-N-(2-hydroxypropyl)benzenesulfonamide. MS (ESI): mass calcd. for C18H18FN5O3S, 403.11; m/z found, 404.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 9.02 (d, J=0.8, 2H), 8.52-8.47 (m, 1H), 8.09 (dd, J=7.9, 1.4, 1H), 7.81 (dd, J=11.9, 1.8, 1H), 7.72 (m, 1H), 7.66 (m, 1H), 7.46 (dd, J=7.5, 1.4, 1H), 3.74-3.59 (m, 1H), 2.84-2.66 (m, 2H), 1.06 (d, J=6.3, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[S:35])=[C:29]([O:36][C:37]([F:40])([F:39])[F:38])[CH:28]=1>C(#N)C>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:34]([NH:33][C:30]4[CH:31]=[CH:32][C:27]([Br:26])=[CH:28][C:29]=4[O:36][C:37]([F:40])([F:38])[F:39])=[S:35])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: FC(F)(F)Oc1cc(Br)ccc1N=C=S
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: CC#N
Product: CN(C)CCN1C(=O)c2cccc3cc4cccc(NC(=S)Nc5ccc(Br)cc5OC(F)(F)F)c4c(c23)C1=O
Temperature: 25 °C
Yield: 94 %

Procedure:
200 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.60 mmole) were dissolved in 15 ml of acetonitrile. 357 mg (2 molar equivalents) of 4-bromo-2-(trifluoromethoxy)phenyl isothiocyanate was added and the reaction mixture was maintained at room temperature for 16 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 356 mg of the desired product (formula shown hereinabove) were isolated as a red powder (yield=94%) which was characterized as follows:
Reaction SMILES: [H-].[Na+].C(O[C:6](=[O:14])/[CH:7]=[C:8](\[NH2:13])/[C:9]([F:12])([F:11])[F:10])C.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[C:18]([N+:25]([O-:27])=[O:26])[CH:17]=1>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:6](=[O:14])[CH:7]=[C:8]([C:9]([F:10])([F:11])[F:12])[NH:13][C:23]2=[O:24])=[C:18]([N+:25]([O-:27])=[O:26])[CH:17]=1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: O=C=Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: -30 °C
Reaction time: 0.33 h

Procedure:
To a suspension of sodium hydride (60% dispersion in oil, 2.5 g) in anhydrous N,N-dimethylformamide (100 ml) was added dropwise a solution of ethyl-3-amino-4,4,4-trifluorocrotonate in toluene (50 ml) at 0° C. under nitrogen atmosphere. After addition, the mixture was stirred for 20 min at same temperature, then cooled to −30° C. A solution of (4-chloro-2-nitrophenyl)isocyanate in toluene (50 ml) was added dropwise. After stirring for 20 min, the cold bath was removed and the resulting mixture was stirred overnight at ambient temperature. The reaction mixture was partitioned between ethyl acetate and 1N-hydrochloric acid. The organic phase was washed with brine (×2) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel eluted with ethyl acetate and hexane (1:1) to afford 3-(4-chloro-2-nitrophenyl)-6-trifluoromethyl-2,4 (1H, 3H)-pyrimidinedione (10.2 g) as a yellow solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=O.[NH3:24]>>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[CH:7]=[N:6][C:5]([C:3]([NH2:24])=[O:2])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: N
Product: NC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (40 mg, 0.13 mmol) and ammonia (10 mL, 7 M in MeOH) was stirred at r.t. for 16 h. The solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (5-60% EtOAc/hexanes+2% AcOH) to give 18 mg of the title compound as a light yellow solid. MS: (+) m/z 296.06 (M+1).
Reaction SMILES: [C:1]([NH:8][C:9]1([CH:14]=O)[CH2:13][CH2:12][CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C:9]1([CH2:14][NH:21][C:20]2[CH:22]=[CH:23][C:17]([Br:16])=[CH:18][CH:19]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: Nc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)NC1(C=O)CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1(CNc2ccc(Br)cc2)CCCC1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
To a solution of N-Boc-cycloleucinal (5.33 g, 25 mmol) and 4-bromoaniline (4.3 g, 25 mmol) in dichloroethane (160 mL) was added sodium triacetoxyborohydride (10.6 g, 50 mmol) portionwise. After the addition, the resulting mixture was stirred at rt for over night. The reaction mixture was quenched with saturated NaHCO3, and extracted with DCM (4×100 mL). The combined DCM was dried (Na2SO4) and concentrated. The residue was subjected to flash column (10-30% EtOAc in hexane) to give the desired product as a white solid (8.3 g, 90%). MS (MH+ 369 and 371).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:3]=1[C:20]#[N:21].S(=O)(=O)(O)[OH:23].[OH-].[NH4+]>>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:3]=1[C:20]([NH2:21])=[O:23]
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(-c2nn(-c3ccccc3)c(N)c2C#N)cc1
Agent: [NH4+]
Agent: [OH-]
Product: Cc1ccc(-c2nn(-c3ccccc3)c(N)c2C(N)=O)cc1
Temperature: 50 °C

Procedure:
While maintaining an internal reaction temperature of 10°-15° C., 5-amino-4-cyano-3-(4'-methylphenyl)-1-phenylpyrazole (3.4 g, 12 mmol) was added in a portionwise manner to concentrated sulfuric acid (15 mL). After the addition was complete, the reaction mixture was heated at 50° C. for 4 hours. The reaction was cooled, poured over ice, neutralized with concentrated ammonium hydroxide and extracted with EtOAc. The organic layer was washed with water, dried (Na2SO4), filtered and concentrated in vacuo. The resulting solids were recrystallized from MeOH/H2O to afford 3.0 g of the title compound; m.p. 190°-191° C.
Reaction SMILES: C(N(CC)CC)C.I[CH2:9][C:10]([NH2:12])=[O:11].[C:13]1([C:19]2[C:20]3[N:21]([CH2:36][CH2:37][N:38]=3)[C:22]3[C:27]([N+:28]=2[O-:29])=[CH:26][CH:25]=[C:24]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:23]=3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[O-:29][N+:28]1[C:27]2[C:22](=[CH:23][C:24]([N:30]3[CH2:35][CH2:34][N:33]([CH2:9][C:10]([NH2:12])=[O:11])[CH2:32][CH2:31]3)=[CH:25][CH:26]=2)[N:21]2[CH2:36][CH2:37][N:38]=[C:20]2[C:19]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC(=O)CI
Reactant: [O-][N+]1=C(c2ccccc2)C2=NCCN2c2cc(N3CCNCC3)ccc21
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=O)CN1CCN(c2ccc3c(c2)N2CCN=C2C(c2ccccc2)=[N+]3[O-])CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
Triethylamine (0.75 g, 0.0072 mol.) was added to a solution of iodoacetamide (0.59 g, 0.0032 mol.) and 1,2-dihydro-4-phenyl-8-piperazinylimidazo[1,2-a]quinoxaline 5-oxide (1.0 g, 0.0029 mol.) in ethanol (50 ml) and the reaction mixture stirred overnight at room temperature. The resulting precipitate was removed by filtration, washed with ethanol and then ether. Recrystallization from ethanol yielded 2-[4-(1,2-dihydro-5-oxido-4-phenylimidazo[1,2-a]-quinoxalin-8-yl)piperazinyl]acetamide, (0.63 g) as bright yellow crystals, m.p. 225°-227° C. (Found: C, 63.50; H, 5.89; N, 19.72%; C22H24N6O6.O.75H2O requires C, 63.23; H, 6.11; N, 20.12%) represented by the structural formula: ##STR32##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20]C)[CH:15]=1.B(Br)(Br)Br.O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]2[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1
Reactant: COc1cccc(-c2cc(OC)nc3ccc(Br)cc23)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: COc1cc(-c2cccc(O)c2)c2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.9 %

Procedure:
To a solution of 6-bromo-4-(3-methoxy-phenyl)2-methoxy-quinoline (1.31 g, 3.81 mmol) in dichloromethane (CH2Cl2. 30 ml) was added a solution of BBr3 in CH2Cl2 (1 M, 11.4 ml, 1 1.4 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. It was poured into water. The organic layer was washed with brine, dried over MgSO4 and concentratred to give the tiltle compound of example 34A (640 mg, 41% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[N:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][CH:21]=2)O1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.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>[C:26]([C:24]1[N:25]=[C:20]([C:2]2[N:7]=[N:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=2)[CH:21]=[CH:22][CH:23]=1)#[N:27]
Reactant: COC(=O)c1ccc(Cl)nn1
Reactant: CC1(C)OB(c2cccc(C#N)n2)OC1(C)C
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: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cccc(C#N)n2)nn1
Temperature: 85 °C
Yield: 54.8 %

Procedure:
Methyl 6-chloropyridazine-3-carboxylate (S49, 34 mg, 0.19 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (45 mg, 0.19 mmol), K2CO3 (51 mg, 0.39 mmol), and (Ph3P)4Pd (34 mg, 0.029 mmol) were slurried in DMF (0.3 M). The reaction vessel was evacuated and refilled with argon three times. The mixture was warmed at 85° C. for 16 h. The reaction mixture was cooled and diluted with EtOAc, washed with 9:1 NH4OH:saturated aqueous NH4Cl and saturated aqueous NaCl, and then dried over Na2SO4 Evaporation yielded the crude product that was purified by flash chromatography (SiO2, 1.5×14 cm, 20-100% EtOAc-hexanes) to afford the title compound (25 mg, 53%) as a white solid: 1H NMR (CDCl3, 600 MHz) δ 9.03 (d, 1H, J=8.1 Hz), 8.75 (d, 1H, J=8.7 Hz), 8.36 (d, 1H, J=8.7 Hz), 8.09 (t, 1H, J=7.9 Hz), 7.84 (d, 1H, J=7.6 Hz), 4.12 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 164.4, 158.2, 154.4, 151.7, 138.7, 133.9, 129.8, 128.7, 125.5, 125.4, 116.9, 53.6; HRMS-ESI-TOF m/z 241.0721 ([M+H]+, C12H8N4O2 requires 241.0720).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH:30]([C:32]1[CH:42]=[CH:41][C:35]([O:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:34][CH:33]=1)=O>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:30][C:32]3[CH:42]=[CH:41][C:35]([O:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:34][CH:33]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccc(OCC(=O)O)cc1
Product: O=C(O)COc1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [4-(3-aminophenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and (4-formyl-phenoxy)-acetic acid according to the procedure of Example 66. MS (ESI) m/z 557.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[C:7]([C:12](O)=[O:13])[CH:8]=[CH:9][CH:10]=2)[O:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[CH:3]1.C(Cl)[Cl:26]>CN(C=O)C>[O:1]=[C:2]1[C:11]2[C:6](=[C:7]([C:12]([Cl:26])=[O:13])[CH:8]=[CH:9][CH:10]=2)[O:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[CH:3]1
Reactant: O=C(O)c1cccc2c(=O)cc(-c3cccc(C(F)(F)F)c3)oc12
Reactant: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc2c(=O)cc(-c3cccc(C(F)(F)F)c3)oc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Oxallylchloride (285 mg, 2.24 mmol) was added to a solution of 4-oxo-2-(3-(trifluoromethyl)phenyl)-4H-chromene-8-carboxylic acid 35 (250 mg, 0.75 mmol) in CH2Cl2 (15 mL) followed by DMF (1 drop). The reaction mixture was stirred at room temperature for 12 h. The volatiles were concentrated and the crude residue was dissolved in CH2Cl2. The solvent was evaporated and the crude product dried under vacuum and used without further purification.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH:10]([N:13]=[C:14]=[O:15])([CH3:12])[CH3:11].O>CS(C)=O>[F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[N:6]([C:14](=[O:15])[NH:13][CH:10]([CH3:12])[CH3:11])[CH:7]=1
Reactant: CC(C)N=C=O
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)NC(=O)n1cc(F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.3 %

Procedure:
13.0g (0.1 mole) of 5-fluorouracil was dissolved in 100ml of dimethyl sulfoxide, then 9.4g (0.11mole) of isopropyl isocyanate was added thereto at room temperature and stirred at the same temperature for 15 hours. The reaction mixture was poured into 800ml of water. The resultant precipitate was filtered off, washed with water and dried to give 14.7g (68.5% yield) of 5-fluoro-1-(iso-propylcarbamoyl)-uracil melting at 275°-285° C (decomposition).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[C:11]3=[C:12]4[CH:18]=[CH:17][NH:16][C:13]4=[N:14][CH:15]=[C:10]3[NH:9][N:8]=2)[CH2:2]1.Cl[C:20]1[N:25]=[N:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>CCO>[C:7]1([CH:3]2[CH2:4][CH2:5][CH2:6][N:1]([C:20]3[N:25]=[N:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[CH2:2]2)[C:11]2=[C:12]3[CH:18]=[CH:17][NH:16][C:13]3=[N:14][CH:15]=[C:10]2[NH:9][N:8]=1
Reactant: N#Cc1ccc(Cl)nn1
Reactant: c1cc2c(ncc3[nH]nc(C4CCCNC4)c32)[nH]1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2CCCC(c3n[nH]c4cnc5[nH]ccc5c34)C2)nn1
Temperature: 120 °C
Yield: 7.1 %

Procedure:
A mixture of 1-(piperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine (0.16 g, 0.65 mmol, Example #26, Step E) and 6-chloropyridazine-3-carbonitrile (0.090 g, 0.65 mmol) with DIEA (0.37 mL, 2.12 mmol) in EtOH (3 mL) was heated at about 120° C. for about 15 min in a microwave reactor (250 psi maximum pressure, 1 min ramp, 300 max watts). The crude material was purified by RP-HPLC (Table 2, Method h) to give 6-(3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)piperidin-1-yl)pyridazine-3-carbonitrile (0.016 g, 24%): LC/MS (Table 2, Method a) Rt=1.76 min; m/z: 345 (M+H)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].ClC(Cl)(Cl)[C:9]([O:11][CH2:12][CH3:13])=[O:10]>CN(C)C1C=CN=CC=1>[C:9]([N:3]1[CH2:4][CH2:5][O:1][C:2]1=[O:6])([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(Cl)(Cl)Cl
Reactant: O=C1NCCO1
Agent: CN(C)c1ccncc1
Product: CCOC(=O)N1CCOC1=O
Temperature: 120 °C
Yield: 88.7 %

Procedure:
A mixture of 2-oxazolidinone (9.0 g, 0.10 mole) and 25 ml (0.18 mole) of ethyl trichloroacetate were heated to 120° C. in an oil bath. A small amount (ca 50 mg) of 4-dimethylaminopyridine was added to the stirred solution, during which time vigorous reflux began. After removing most of the chloroform by a Dean-Stark trap, the dark solution was allowed to cool to room temperature. Bulb to bulb distillation at 105° C.-120° C. (0.05 mm) yielded 14.1 g (0.0887 mole, 89 percent yield) of the product as a clear liquid which solidified to a colorless solid (mp 40° C.-44° C.) on standing at room temperature. Spectral data confirmed its structure.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:9](=[O:10])[CH2:8][N:7]([CH2:11][CH:12]([OH:21])[CH2:13][C:14](OCC(C)C)=[O:15])C1C(C)C)(=[O:3])[NH2:2]>CN(C)C=O.O>[OH:21][CH:12]1[CH2:11][N:7]([CH2:8][C:9]([NH:5][CH2:4][C:1]([NH2:2])=[O:3])=[O:10])[C:14](=[O:15])[CH2:13]1
Reactant: CC(C)COC(=O)CC(O)CN1CC(=O)N(CC(N)=O)C1C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)CNC(=O)CN1CC(O)CC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 0 %

Procedure:
A solution of 11.8 g (34.3 mol) of 2-methylpropyl 3-carbamoylmethyl-Beta-hydroxy-2-(1-methylethyl)-4-oxo-1-imidazolidinebutanoate in 90 ml of dimethylformamide and 10 ml of water was gently refluxed (external temp. 130° C.) for 24 hours. The solvent was evaporated under reduced pressure. The oily residue was taken up with 40 ml of ethanol and stirred at 0° C. for 30 minutes. The precipitate was collected and crystallized from ethanol/isopropanol 1:1 to give 2.5 g of the title compound as a white powder, m.p. 158°-160° C. Mass spectrum (E.I., 70 eV, 1.5 mA), m/z=197 (M+ --H2O), 180. IR spectrum (oil mull): 3420, 3320, 3220, 1680, 1655 and 1630 cm-1.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][Si](C=[N+]=[N-])(C)C>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)Cc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2)cc1
Solvent: CO
Product: COC(=O)Cc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2)cc1

Procedure:
To a solution of 1.55 g of 4-[1-(benzyloxycarbonyl)-piperidin-4-yl]phenylacetic acid in methanol (20 ml) was added 13.2 ml of trimethylsilyldiazomethane (2 M solution in hexane) and the resulting mixture was reacted at room temperature for 1 hour. After distilling off the reaction mixture under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 1.0 of the title compound as a colorless oily substance.
Reaction SMILES: [Cl-].[O:2]([C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:19][CH:18]=1>>[O:2]([C:9]([CH3:14])([CH3:13])[C:10]([N:25]1[CH2:24][CH2:23][N:22]([CH2:21][C:20]2[CH:28]=[CH:29][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[CH2:27][CH2:26]1)=[O:12])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(Oc1ccccc1)C(=O)O
Reactant: COc1ccc(CN2CCNCC2)cc1
Agent: [Cl-]
Product: COc1ccc(CN2CCN(C(=O)C(C)(C)Oc3ccccc3)CC2)cc1

Procedure:
By carrying out the preparation as in Example 12, but using the chloride of 2-phenoxy-2-methylpropionic acid and 1-(4-methoxybenzyl)piperazine, the title product is obtained.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([C:18]#N)([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.[O:31]1CCCC1>>[C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH3:17])([CH:18]=[O:31])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C#N)O2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C=O)O2

Procedure:
(±)-6-acetoxy-2-cyano-2,5,7,8-tetramethylchroman was reduced with diisobutylaluminum hydride as described in Example 101, with tetrahydrofuran as reaction solvent. TLC of the crude product indicated that it was partially deacetylated. The material was thus reacetylated by the process described in Example 2 to give (±)-6-acetoxy-2,5,7,8-tetramethylchroman-2-carboxaldehyde as a white solid, m.p. 88°-90°, from 30°-60° petroleum ether.