Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C(O[CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>CN(C)C=O>[CH2:20]([O:19][C:17](=[O:18])[C:16](=[CH:15][NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:21]
Reactant: Nc1ncnc2ccccc12
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CNc1ncnc2ccccc12)C(=O)OCC
Temperature: 160 °C
Reaction time: 0.33 h
Yield: 90.1 %

Procedure:
A mixture of 4-aminoquinazoline (11.6 g) and diethyl ethoxymethylenepropanedioate (19.0 g) in N,N-dimethylformamide (40 ml) was stirred for 1 hour and 20 minutes at 160° C. and then cooled to 0° C. to precipitate crystals. To the mixture was added small volume of water with stirring. The crystals were separated by filtration, washed with water, dried overnight under reduced pressure and dissolved in ethyl acetate. The resultant solution was dried over anhydrous magnesium sulfate and recrystallized from a mixture of ethyl acetate and hexane to give crystalline diethyl[(4-quinazolinylamino)methylene]propanedioate (22.7 g).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]1.Cl.Cl[C:11]1[N:16]=[CH:15][N:14]=[C:13]([N:17]2[C:21](=[O:22])[C:20]([N:23]3[CH:27]=[CH:26][N:25]=[CH:24]3)=[CH:19][NH:18]2)[CH:12]=1.[OH-].[Na+]>O.C(O)C>[N:23]1([C:20]2[C:21](=[O:22])[N:17]([C:13]3[N:14]=[CH:15][N:16]=[C:11]([N:2]4[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]4)[CH:12]=3)[NH:18][CH:19]=2)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: O=C(O)C1CNC1
Reactant: O=c1c(-n2ccnc2)c[nH]n1-c1cc(Cl)ncn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1CN(c2cc(-n3[nH]cc(-n4ccnc4)c3=O)ncn2)C1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
46 mg (0.3 mmol) of azetidine-3-carboxylic acid hydrochloride are initially charged in a mixture of 1 ml of water and 0.3 ml of ethanol. 100 mg (0.3 mmol) of the compound from Example 13A are added, and the mixture is stirred at 100° C. for 1 h. The reaction mixture is then adjusted to pH=7 using aqueous 1 N sodium hydroxide solution and stirred at 100° C. for 16 h. Once more, the mixture is adjusted to pH=7 using aqueous 1 N sodium hydroxide solution and reacted in a single mode microwave (Emrys Optimizer) at 150° C. for 1 h. The reaction mixture is concentrated under reduced pressure and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 23 mg (21% of theory)
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](Cl)[CH:10]=2)[C:5]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[C:4](=[O:17])[C:3]=1[C:18]([NH:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:19].[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+].O.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:10]=2)[C:5]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[C:4](=[O:17])[C:3]=1[C:18]([NH:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:19]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCCC2)C1=O
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(-c3ccccc3)ccc2C2(CCCC2)C1=O
Temperature: 110 °C
Reaction time: 6 h
Yield: 41.7 %

Procedure:
To 1,1-dimethylethyl N-((4′-hydroxy-2′-oxo-6′-chloro-spiro[cyclopentane-1,1′-naphthalen]-3′-yl)carbonyl)glycinate (250 mg, 616 μmol, Example 25A-B) and phenylboronic acid (113 mg, 924 μmol) were added 1,4-dioxane (3080 μL) and K2CO3 in water (924 μL, 1848 μmol). The reaction was then flushed with nitrogen for 10 minutes. Pd2(dba)3 (56.4 mg, 61.6 μmol) and X-Phos (58.7 mg, 123 μmol) were then added, and the reaction mixture was stirred at 110° C. for 6 hours. The reaction mixture was diluted with 75 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 50 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (115 mg) as an oil after preparatory LC. MS (m/z)=392(M+H-tBu)+.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1csc(C)n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1csc(CBr)n1
Yield: 44.8 %

Procedure:
A solution of ethyl 2-methylthiazole-4-carboxylate (5.0 g, 29 mmol), N-bromosuccinimide (6.2 g, 35 mmol) and azo-bis-(isobutyronitrile) (480 mg, 2.9 mmol) in carbon tetrachloride (150 ml) was heated at reflux for 18 h. The mixture was filtered and reduced. Chromatography (20% EtOAc/80% hexanes and 30% EtOAc/70% hexanes) afforded ethyl 2-bromomethylthiazole-4-carboxylate (3.25 g, 44%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>CCCCCCC.CCOC(C)=O>[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1I
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1

Procedure:
The title compound was prepared in analogy to example 72, from N-(4-iodo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 98, intermediate a) and 6-methoxypyridin-3-ylboronic acid (CAS RN 163105-89-3) and using a gradient of n-heptane:EtOAc (100:0 to 60:40) for the chromatographic separation. Colorless solid (74%). MS (ESI): m/z=456.113 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]2)=[O:7])=[CH:2]1.S1C=C[CH:21]=[C:20]1C=CC(O)=O.N1CCCC(C(OCC)=O)C1>>[S:1]1[CH:2]=[CH:21][CH:20]=[C:5]1[CH:4]=[CH:3][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)=[O:7]
Reactant: CCOC(=O)C1CCCN(C(=O)c2ccsc2)C1
Reactant: O=C(O)C=Cc1cccs1
Agent: CCOC(=O)C1CCCNC1
Product: CCOC(=O)C1CCCN(C(=O)C=Cc2cccs2)C1

Procedure:
The reaction was run in the same manner as ethyl 1-(3-thiophenecarbonyl)-3-piperidinecarboxylate, starting with 3-(2-thienyl)acrylic acid (2.6 g; 16.9 mmol) and ethyl nipecotate (2.62 ml; 16.9 mmol). The crude product was purified by chromatography on silica, eluting with 40 to 100% ethyl acetate in hexane as a step gradient, giving ethyl 1-(3-(2-thienyl)acrylyl)-3-piperidinecarboxylate (1.74 g) as an off-white solid. MS m/z (positive ion) 316 (M+Na+; 25), 294 (MH+; 100).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[C:25]([N:33]1[C:37]([CH3:39])([CH3:38])[CH2:36][NH:35][C:34]1=[O:40])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:25]([N:33]1[C:37]([CH3:38])([CH3:39])[CH2:36][N:35]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[C:4]([F:24])[CH:3]=2)[C:34]1=[O:40])(=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC1(C)CNC(=O)N1C(=O)c1ccccc1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)(C)N(C(=O)c5ccccc5)C4=O)cc3F)CC2)c(C)c1
Yield: 58 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (157 mg) described in Preparation Example 114 and 1-benzoyl-5,5-dimethylimidazolidin-2-one (105 mg) described in Preparation Example 58 and by the reaction and treatment in the same manner as in Example 511, the title compound (123 mg) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=1.[Br:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[Br:19][C:20]1[CH:25]=[C:24]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=3)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(Cl)n1
Reactant: OB(O)c1cccc(Br)c1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine (example A.1) (0.59 g, 2.0 mmol) and commercially available 3-bromo-benzeneboronic acid (0.44 g, 2.20 mmol) according to the general procedure IVa. Obtained as a white solid (0.71 g, 86%). MS (EI) 413.9 [(M)+]; mp 146° C.
Reaction SMILES: C(OC1C=CN([C:15]2[CH:20]=[CH:19][C:18]([O:21]CCN(C)C)=[CH:17][CH:16]=2)C(=O)C=1)C1C=CC=CC=1.C(OC1C=CNC(=O)C=1)C1C=CC=CC=1.[F:43][C:44]1[CH:58]=[CH:57][C:47]([CH2:48][O:49][C:50]2[CH:55]=[CH:54][NH:53][C:52](=[O:56])[N:51]=2)=[CH:46][CH:45]=1>>[F:43][C:44]1[CH:58]=[CH:57][C:47]([CH2:48][O:49][C:50]2[CH:55]=[CH:54][N:53]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[C:52](=[O:56])[N:51]=2)=[CH:46][CH:45]=1
Reactant: O=c1nc(OCc2ccc(F)cc2)cc[nH]1
Reactant: CN(C)CCOc1ccc(-n2ccc(OCc3ccccc3)cc2=O)cc1
Agent: O=c1cc(OCc2ccccc2)cc[nH]1
Product: O=c1nc(OCc2ccc(F)cc2)ccn1-c1ccc(O)cc1

Procedure:
Steps (3) and (4) of Example 1 were repeated except that 4-benzyloxy-1H-pyridin-2-one which was used in Step (3) of Example 1 was replaced with 4-(4-fluorobenzyloxy)-1H-pyrimidin-2-one, to provide the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:21]([O:20][C:18]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)Cc1ccccc1CN
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Cc1ccccc1CNC(=O)OCc1ccccc1

Procedure:
To a solution of 3.0 g (9.64mmol) tert-butyl [2-(aminomethyl)phenyl]acetate in 100 mL methylene chloride cooled to 0° C. was added 0.825 ml (5.78 mmol) benzyl chloroformate followed by 1.47 g (12.05 mmol) of 4-dimethylaminopyridine and a second 0.825 ml (5.78 mmol) portion of benzyl chloroformate. After 30 min the reaction was washed with 10% potassium hydrogen sulfate (aq) (2×30 mL), water (1×30 mL), and brine (1×30 mL), dried over sodium sulfate, filtered and concentrated to dryness in vacuo. The resulting crude oil (3.69 g) was flash chromatographed on silica gel (15% ethyl acetate in hexane) to give tert-butyl [2-({[(benzyloxy)carbonyl]amino}methyl)phenyl]acetate as a colorless oil: 1H NMR (CDCl3, 400 MHz): δ7.38-7.30 (m, 5H), 7.28-7.21 (m, 4H), 5.40 (br s, 1H), 5.12 (s, 2H), 4.40 (d, 2H, J=5.5 Hz), 3.61 (s, 2H), 1.41 (s, 9H); MS (Electrospray): M+Na=378.1; TLC Rf=0.30 (15% ethyl acetate in hexane).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([C:10]([NH:12][OH:13])=[NH:11])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:18](Cl)=O>>[CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([C:10]3[N:11]=[C:18]([C:17]4[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:15]([Cl:14])[CH:16]=4)[O:13][N:12]=3)[CH2:6][CH2:5]2)[CH2:2][CH2:3]1
Reactant: COc1ccc(C(=O)Cl)cc1Cl
Reactant: N=C(NO)C1CCN(C2CC2)CC1
Product: COc1ccc(-c2nc(C3CCN(C4CC4)CC3)no2)cc1Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 35a, starting from 1-cyclopropyl-N-hydroxypiperidine-4-carboxamidine and 3-chloro-4-methoxybenzoyl chloride.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[Cl:11][C:12]1[CH:17]=[N:16][CH:15]=[C:14](Cl)[N:13]=1.[H-].[Na+].Cl>C1COCC1>[Cl:11][C:12]1[N:13]=[C:14]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=2)[C:6]#[N:7])[CH:15]=[N:16][CH:17]=1
Reactant: Clc1cncc(Cl)n1
Reactant: N#Cc1cccc(CO)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cccc(COc2cncc(Cl)n2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-hydroxymethyl-benzonitrile (2.0 g, 15.0 mmol) and 2,6-dichloro-pyrazine (2.24 g, 15.0 mmol) in THF (150 mL) was added 60% NaH in mineral oil (0.9 g, 22.5 mmol). After stirring at ambient temperature for 2 h, the reaction mixture was poured into 1N HCl (100 mL) and extracted with Ethyl Acetate (1×250 mL). The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated to dryness. The crude material was chromatographed over Silica Gel (40 g) eluting with hexanes (1000 mL) followed by ethyl acetate (500 mL) to obtain 3.53 g of the desired pure product (I-3a) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([F:18])[CH:10]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>C(#N)C>[F:18][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[N+:15]([O-:17])=[O:16])[CH2:8][N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Cn2ccnc2)cc1F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 48.3 %

Procedure:
Potassium carbonate (1.18 g, 8.54 mmol) was added to a stirred solution of 4-(bromomethyl)-2-fluoro-1-nitrobenzene (2.0 g, 8.55 mmol) and imidazole (584 mg, 8.58 mmol) in acetonitrile (40 mL), the mixture stirred at room temperature for 3.5 h, the solvent removed under reduced pressure, and the residue partitioned between water and EA. The aqueous layer was extracted three times with EA, then the combined EA layers were extracted three times with 1M hydrochloric acid. The pH of the combined aqueous layers was adjusted to 8 with 5M aqueous sodium hydroxide, and the resulting milky solution was extracted three times with EA. The EA layers were combined, washed with brine, and dried over magnesium sulfate. Filtration and concentration gave 1-(3-fluoro-4-nitrobenzyl)-1H-imidazole (914 mg), which contained about 15% of a bis-alkylated imidazole byproduct. 1-(3-Fluoro-4-nitrobenzyl)-1H-imidazole (914 mg) was treated with an ethanolic ammonia solution (2M NH3, 55 mL) in a sealed tube heated to 80° C. for 2 days. After cooling, the solvent was removed to give 5-[(1H-imidazol-1-yl)methyl]-2-nitrobenzeneamine (1.0 g) as an orange solid. 5-[(1H-Imidazol-1-yl)methyl]-2-nitrobenzeneamine (1.0 g, 4.77 mmol) was dissolved in a 10% solution of dimethylformamide in ethanol (44 mL), and 10% palladium on carbon (130 mg, 0.12 mmol) was added. The solution was degassed and stirred under a hydrogen atmosphere using a balloon for 1 day. Following degassing, the solution was diluted with MeOH and filtered through diatomaceous earth, giving 4-[(1H-imidazol-1-yl)methyl]benzene-1,2-diamine (1.08 g) as a brown oil.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][O:6][C:7](=[O:9])[CH3:8])=[O:3].[C:10]([O:15][CH2:16][CH2:17][OH:18])(=[O:14])[C:11]([CH3:13])=[CH2:12].N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:18][CH2:17][CH2:16][O:15][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])[O:4][CH2:5][O:6][C:7](=[O:9])[CH3:8]
Reactant: C=C(C)C(=O)OCCO
Reactant: CC(=O)OCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCCOC(=O)OCOC(C)=O
Reaction time: 0.17 h
Yield: 64.6 %

Procedure:
To a solution of acetoxymethyl chloroformate (1.00 g, 0.0066 mol) and 2-hydroxyethyl methacrylate (0.86 g, 0.0066 mol) in methylene chloride (30 ml), pyridine (0.52 g, 0.0066 mol) was added at 0° C. After 10 min at 0° C. and 18 hours at 25° C. the reaction mixture was washed with aqueous hydrochloric acid (100 ml), aqueous saturated sodium hydrogen carbonate (100 ml) and water (100 ml). The solvent was removed under reduced pressure after drying (MgSO4). Flash chromatography (silicagel, hexane/ethyl acetate (3:2)) gave 1.05 g (65%) of the title product.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10](=[O:18])[CH:9]=1)[C:4]([OH:6])=[O:5].[H][H]>O.[C].[Pd]>[ClH:1].[NH2:2][CH:3]([CH2:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10](=[O:18])[CH2:9]1)[C:4]([OH:6])=[O:5]
Reactant: [H][H]
Reactant: NC(Cc1cc(=O)[nH]c2ccccc12)C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: O
Product: NC(CC1CC(=O)Nc2ccccc21)C(=O)O

Procedure:
5 Grams of 2-amino-3-(2-quinolon-4-yl)propionic acid hydrochloride was dissolved in 150 ml of water. To this solution was added 1 g of 10%-palladium carbon, then hydrogen gas was adsorbed thereto at 70° C. under a normal pressure. The catalyst was removed from the reaction mixture by filtration, then the filtrate was concentrated under a reduced pressure. The residue thus obtained was crystallized by adding acetone, then recrystallized from ethanol-ether to obtain 3.6 g of 2-amino-3-(3,4-dihydroquinolin-2-on-4-yl)propionic acid hydrochloride in the form of white powdery product.
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH2:12]([C:14](=[C:19]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:15]=[CH:16][CH:17]=[O:18])[CH3:13]>O1CCCC1>[CH2:12]([C:14](=[C:19]([C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[CH:15]=[CH:16][CH:17]([OH:18])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH3:13]
Reactant: CCC(C=CC=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CCC(C=CC(O)CC(=O)CC(=O)OC(C)(C)C)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 3 h
Yield: 71.9 %

Procedure:
The dianion of 1,1-dimethylethyl acetoacetate (20 mL of 0.5 M solution, 10 mmol) was added to a solution of 4-ethyl- 5,5-bis-(4-fluorophenyl)-2,4-pentadienal (2.0 g, 6.7 mmol) in 20 mL of tetrahydrofuran at -70° C. The mixture was stirred for 3 hours during which time the temperature was allowed to rise to -30° C. and quenched with saturated ammonium chloride solution. The mixture was extracted with diethyl ether, the extracts dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 10% ethyl acetate in hexane to give 2.2 g of the title compound as an oil. MS(CI): m/e =456 for M+ of C27H30F2O4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([N+]([O-])=O)[C:3]=1[Cl:12].P(=O)(O)(O)[OH:14].P(O)(O)(O)=O.ClC1C=C(Cl)C(Cl)=CC=1N.N([O-])=O.[Na+]>C(O)(C)C.[Pt].O>[Cl:8][C:5]1[CH:4]=[C:3]([Cl:12])[C:2]([Cl:1])=[CH:7][C:6]=1[OH:14]
Reactant: O=P(O)(O)O
Reactant: O=[N+]([O-])c1c(Cl)ccc(Cl)c1Cl
Agent: [Pt]
Agent: Nc1cc(Cl)c(Cl)cc1Cl
Agent: O=N[O-]
Solvent: O
Solvent: CC(C)O
Product: Oc1cc(Cl)c(Cl)cc1Cl
Reaction time: 1.5 h
Yield: 58 %

Procedure:
226.5 gm (1.0 mol) of 1,2,4-trichloronitrobenzene were dissolved in 226 gm of isopropanol and hydrogenated in the presence of 6.1 gm of wet 1% Platinum on charcoal at 100° C. and 100-200 psig over a 90 minutes period. The reaction mixture was filtered to remove the catalyst and the clear solution was slowly dropped into a hot solution of 1125 gm of H2O and 500 gm of phosphoric acid (5.0 mols) under vacuum to remove the isopropanol by distillation. The finely divided 2,4,5-trichloroaniline phosphate slurry was then cooled to -5° C. with good agitation and 56.9 gm (0.95 mol) of NaNO2 in 125 ml of water were added over a 15 minute period while maintaining a maximum temperature of +5° C. After 30 minutes of agitation, the reaction mixture was filtered to remove an insoluble impurity. The resulting 2,4,5-trichlorobenzenediazonium phosphate solution was then added cold (0° ±5° C.) to a boiling solution of 1000 gm of cupric sulfate heptahydrate in 2000 ml of water. As the product was formed, it was removed from the zone of reaction by steam distillation. The product in the steam distillate was extracted with two 300 ml aliquots of methylene chloride and stripped to dryness to obtain 115 gm of crude 2,4,5-trichlorophenol (0.58 mol) which analyzed to be 94.8% pure. This product was then added to a slurry of 68.0 gms (0.58 mol) of monochloroacetic acid in 190 ml of toluene and 125 ml of hydrocarbon solvent and reacted with 104.3 (1.31 moles) of 50% sodium hydroxide over a 10 minute period of time at 60°-92° C. After 15 minutes of agitation, the exothermic reaction was finished and 160 gm of a 20% hydrochloric acid solution were added to a pH of less than 2.0. Another 31 gm of toluene were added at 80°-84° C. and the organic layer was collected, cooled, filtered, washed with 30 ml of cold hydrocarbon solvent, and collected to give 80.0 gm (0.32 mol) of dry 2,4,5-trichlorophenoxyacetic acid (m.p.=148°-153° C.).
Reaction SMILES: [C:1]([C:9]1[C:10]([OH:24])=[C:11]2[CH:17]=[N:16][N:15]([CH2:18][C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)[C:12]2=[N:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](I)[CH3:32]>CN(C)C=O>[C:1]([C:9]1[C:10]([O:24][CH2:31][CH3:32])=[C:11]2[CH:17]=[N:16][N:15]([CH2:18][C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)[C:12]2=[N:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: O=C(c1ccccc1)c1cnc2c(cnn2Cc2ccco2)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1c(C(=O)c2ccccc2)cnc2c1cnn2Cc1ccco1

Procedure:
3.3 g. of 5-benzoyl-4-hydroxy-1-(2-furanyl)methyl-1H-pyrazolo[3,4-b]pyridine (0.01 mol.) are dissolved in 20 ml. of dimethylformamide. 2.8 g. of potassium carbonate and 3.1 g. of ethyl iodide are added and the mixture is warmed for 12 hours at 60°. Excess potassium carbonate is filtered off and water is added. 5-Benzoyl-4-ethoxy-1-(2-furanyl)-methyl-1H-pyrazolo[3,4-b]pyridine precipitates and is recrystallized from ethyl acetate, yield 3 g. (86%), m.p. 70°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:18]([O-])=O)=[CH:5][C:6]([CH3:17])=[C:7]([C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])[CH:8]=1.O.O.Cl[Sn]Cl.[OH-].[Na+].C(Cl)Cl>C(O)C.O>[NH2:18][C:4]1[C:3]([O:2][CH3:1])=[CH:8][C:7]([C:9]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)=[O:10])=[C:6]([CH3:17])[CH:5]=1
Reactant: COc1cc(C(=O)N2CCOCC2)c(C)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)N2CCOCC2)c(C)cc1N
Temperature: 65 °C
Yield: 92.3 %

Procedure:
To (5-methoxy-2-methyl-4-nitrophenyl)(morpholino)methanone (324 mg, 1.16 mmol) in ethanol (20 mL) and water (2 mL) was added SnCl2.2H2O (1.05 g, 4.64 mmol). The mixture was heated to 65° C. for 36 h and then 2 M aqueous sodium hydroxide solution (20 mL) and DCM (20 mL) were added. The organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo to give (4-amino-5-methoxy-2-methylphenyl)(morpholino)methanone (268 mg, 92%) as an off-white solid. LCMS (10 cm_ESCI_Formic_MeCN): [M+H]+=251 at 2.14 min. 1H NMR (400 MHz, CDCl3): δ 6.60 (s, 1H), 6.52 (s, 1H), 3.87-3.52 (br m, 6H), 3.84 (br s, 2H), 3.82 (s, 3H), 3.36-3.23 (br m, 2H), 2.17 (s, 3H).