Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:21][C:4]2([CH2:9][CH2:8][C:7]([C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[CH:6][CH2:5]2)[O:3][CH2:2]1.C(O)C.C(OCC)(=O)C>[H][H]>[CH2:2]1[O:3][C:4]2([CH2:5][CH2:6][CH:7]([C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:18])([F:20])[F:19])=[CH:12][CH:11]=3)[CH2:8][CH2:9]2)[O:21][CH2:1]1
Reactant: FC(F)(F)Oc1ccc(C2=CCC3(CC2)OCCO3)cc1
Reactant: [H][H]
Solvent: CCOC(C)=O
Solvent: CCO
Product: FC(F)(F)Oc1ccc(C2CCC3(CC2)OCCO3)cc1
Yield: 99.9 %

Procedure:
A mixture of (4-trifluoromethoxyphenyl)cyclohexen-4-one ethyleneketal (43.3 g, 0.144 mol), ethanol (200 ml), ethyl acetate (50 ml) and Pa-C (2 g) was stirred at room temperature for 10 hours in hydrogen atmosphere (at that time, hydrogen (3.59 l) was consumed), filtering off the catalyst from the reaction solution, distilling off the solvent under reduced pressure, to obtain 4-(4-trifluoromethoxyphenyl)cyclohexanone ethyleneketal (43.5 g) (m.p. 41.2° C.), adding thereto formic acid (250 ml), heating the mixture under reflux for 2.5 hours, feeding the reaction substance into water, extracting with a mixed solvent of toluene (400 ml) with ethyl acetate (100 ml), twice washing the resulting orgnaic layer with water, drying over anhydrous MgSO4, filtering off anhydrous MgSO4, distilling off the solvent under reduced pressure and subjecting the resulting residue to column chromatography (silica gel, eluent: toluene), to obtain 4-(4-trifluoromethoxyphenyl)cyclohexanone (20.7 g). Yield: 47%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.CS(O[CH:20]([CH3:42])[CH2:21][O:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=O)=O>O>[I:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:20]([CH3:42])[CH2:21][O:22][C:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:10][CH:9]=1
Reactant: Oc1ccc(I)cc1
Reactant: CC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1ccc(I)cc1
Reaction time: 24 h
Yield: 46.1 %

Procedure:
To a solution of potassium carbonate (0.63 g, 4.5 mmol) in dimethylformaide (10 mL) was purged with nitrogen for 10 min at 75° C. 4-iodophenol (0.55 g, 2.5 mmol) was added to the mixture and the solution was purged with nitrogen for additional 10 min. To the reaction mixture 1-(trityloxy)propan-2-yl methanesulfonate (1.00 g, 2.53 mmol) was added and stirred for 24 hours at the same temperature. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL*3). The combined organic layer was dried over sodium sulfate and concentrated. The crude product was purified by combiflash silica gel chromatography (petroleum ether:ethyl acetate=10:1) to give the title compound (600 mg, 46%) as colorless oil.
Reaction SMILES: [BH4-].[Na+].[C:3]1([CH:9]([O:16][C:17]([C:19]2[N:24]3[C:25](=[O:38])[C@@H:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@H:23]3[S:22][CH2:21][C:20]=2[OH:39])=[O:18])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>CN(C)C=O.C(O)(=O)C>[C:3]1([CH:9]([O:16][C:17]([C@@H:19]2[N:24]3[C:25](=[O:38])[C@@H:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@H:23]3[S:22][CH2:21][CH:20]2[OH:39])=[O:18])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2[C@@H]1SCC(O)[C@@H]2C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
1.30 g of sodium borohydride are added in portions to a solution of 35.4 g of 3-hydroxy-7β-phenoxyacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester (crude product) in a mixture of 270 ml of dimethylformamide and 70 ml of glacial acetic acid in a stream of nitrogen while stirring and cooling with ice at approximately 15° to 20°. The reaction mixture is further stirred for one hour at room temperature, poured onto a mixture of ice and 2 N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed successively with 2 N hydrochloric acid, water, saturated, aqueous sodium bicarbonate solution and saturated, aqueous sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. The residue is substantially freed from dimethylformamide under a high vacuum and recrystallised from ethyl acetate and a little diethyl ether. The title compound is obtained which has a melting point of 167°-170°; Rf~0.47 (silica gel; toluene/ethyl acetate 1:1); [α]D20 =+88°± 1° (in chloroform, c=0.526%); IR spectrum (in CH2Cl2): Absorption bands up to 3580; 3410; 1780; 1740; 1695; 1600; 1518; 1494 cm-1.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:5]2=[N:6][C:7]=1[Cl:8].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[N:3]=[C:4]2[CH2:12][CH2:11][C:10](=[O:13])[N:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:5]2=[N:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)CCCCCCBr
Reactant: O=C1CCc2nc(Br)c(Cl)nc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCCN1C(=O)CCc2nc(Br)c(Cl)nc21
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of 2-bromo-3-chloro-7,8-dihydro-5H-pyrido[2,3-b]pyrazin-6-one (prepared according to the preparation procedures disclosed in PCT patent application PCT/EP2011/062028, Intermediate J) (3.9 g, 14.86 mmol) and ethyl 7-bromoheptanoate (7.05 g, 29.7 mmol) in DMF (75 ml) under a nitrogen atmosphere was treated with potassium carbonate (10.27 g, 74.3 mmol) and the resulting solution was stirred at room temperature for 4 days. The mixture was diluted with water and extracted with EtOAc (×2). The extracts were washed with water and brine, dried (MgSO4) and evaporated under vacuum. The crude product was purified by chromatography on silica eluting with 0-60% EtOAc in iso-hexane to afford the titled compound;
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=1[NH2:17]>>[Cl:1][C:2]1[N:11]=[C:10]([NH:17][C:16]2[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:15]=2[O:14][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(N)c(OC)c1
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: COc1ccc(Nc2nc(Cl)nc3ccccc23)c(OC)c1

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline and 2,4-dimethoxyaniline by a procedure similar to Example 28 (92% yield). 1H NMR (CDCl3): 8.59 (d, J=8.7 Hz, 1H), 8.22 (s, broad, 1H), 7.75-7.81 (m, 3H), 7.52 (ddd, J=8.4, 6.6 and 2.1 Hz, 1H), 6.52-6.59 (m, 2H), 3.95 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)[CH2:9]1)=O)(C)(C)C>C(O)=O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:17]2[CH2:18][CH2:19][N:14]([CH:10]3[CH2:9][NH:8][CH2:12][CH:11]3[OH:13])[CH2:15][CH2:16]2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C(N2CCN(Cc3ccc(Cl)cc3)CC2)C1
Solvent: O=CO
Product: OC1CNCC1N1CCN(Cc2ccc(Cl)cc2)CC1

Procedure:
The desired compound was prepared from 3-[4-(4-Chloro-benzyl)-piperazin-1-yl]4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester in a manner similar to that described in Example 161. 1H-NMR (300 MHz, DMSO, HCl salt): δ 2.80-3.60 (m, 12 H), 4.20-4.35 (m, 4 H), 7.51 (d, 2 H), 7.66 (d, 2 H). Retention Time (LC, method: Formic acid polar): 0.68 min. MS (M+H+): 296
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.[H-].[K+].[CH2:22]1OCCOCCOCCOCCOCCO[CH2:23]1.ICC>C1COCC1>[CH2:22]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][C:10]=2[CH3:12])[C:6]([CH:13]2[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]2)=[CH:7]1)[CH3:23]
Reactant: COc1cc(C)c2[nH]cc(C3CCN(C)CC3)c2c1
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [K+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCn1cc(C2CCN(C)CC2)c2cc(OC)cc(C)c21
Yield: 704.3 %

Procedure:
By a method similar to Preparation 26, using 5-methoxy-7-methyl-3-(1-methylpiperidin-4-yl)-1H-indole (5.81 mmole, 1.5 g) in THF (100 mL), 35% potassium hydride (5.81 mmole, 0.665 g), 18-crown-6 (0.58 mmole, 0.153 g), and iodoethane (5.81 mmole, 0.906 g, 0.464 mL) afforded 1.17 g (70%) of the title compound: mass spectrum (ion spray): m/z=287 (M+1); Calculated for C18H26N2O-0.1 H2O: C, 75.01; H, 9.16; N, 9.72. Found: C, 75.10; H, 9.01; N, 9.79.
Reaction SMILES: [N:1]([CH2:4][CH:5]([S:10]([OH:13])(=[O:12])=[O:11])[CH2:6][C:7]([OH:9])=[O:8])=[N+]=[N-]>[Pd].CO>[NH2:1][CH2:4][CH:5]([S:10]([OH:13])(=[O:11])=[O:12])[CH2:6][C:7]([OH:9])=[O:8]
Reactant: [N-]=[N+]=NCC(CC(=O)O)S(=O)(=O)O
Agent: [Pd]
Solvent: CO
Product: NCC(CC(=O)O)S(=O)(=O)O
Reaction time: 8 h
Yield: 95.1 %

Procedure:
In a 500 ml of hydrogenation bottle was added 4-azido-3-sulfobutanoic acid (3.00 g, 14.35 mmol), 150 ml of methanol and 0.32 g of Pd/C (10% Pd, 50% wet). After sucked out air, 30 psi of H2 was conducted, and the mixture was shaken overnight, filtered through celite, evaporated, and coevaporated with dry EtOH to afford about 2.50 g (95%) of 4-amino-3-sulfobutanoic acid. 1H NMR (CD3OD) 3.24 (m, 1H), 3.17 (m, 1H), 2.90 (dd, 1H, J=2.6, 16.5 Hz), 2.33 (dd, 1H, J=10.1, 16.5 Hz), ESI MS m/z− 181.60 (M−H). The resulted compound was unstable and was used directly without further purification.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([C:14](=[CH:20]OCC)[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:13])[CH2:10][CH2:11][CH3:12]>>[C:9]([C:14](=[CH:20][NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[F:1])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: CCCC(=O)C(=COCC)C(=O)OCC
Reactant: Nc1ccccc1F
Product: CCCC(=O)C(=CNc1ccccc1F)C(=O)OCC
Reaction time: 8 h
Yield: 58.4 %

Procedure:
2-Fluoroaniline (25 g, 0.23 mol) and ethyl 2-butyryl-3-ethoxyacrylate (48 g, 0.23 mol) were heated at 150° for 2 hours, then diluted with petroleum ether and left to stand overnight. Filtration and washing gave ethyl 2-butyryl-3-(2-fluorophenylamino)acrylate (37.5 g), m.p. 60°-62°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[C:3]=1[CH3:9].[OH-:10].[K+].O>C(O)COCCO>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([OH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: Cc1c(Cl)cccc1Cl
Agent: [K+]
Solvent: O
Solvent: OCCOCCO
Product: Cc1c(O)cccc1Cl

Procedure:
16.1 g (0.1 mol) of 2,6-dichlorotoluene and 19.8 g (0.3 mol) of potassium hydroxide (85%) are heated in 30 ml of diethylene glycol at a bath temperature of 190° C. for 18 hours. The water released by the reaction is distilled off. After cooling, the reaction mixture is stirred with 100 ml of water until a solution is obtained and extracted three times with 50 ml of dichloromethane. The aqueous phase is admixed with 35 ml of 30% hydrochloric acid and extracted three times with 70 ml of dichloromethane. The organic phases are dried over sodium sulphate and concentrated under reduced pressure. 3-Chloro-2-methylphenol is obtained as a solid (12.4 g, content by HPLC: 83%, 72% of theory).
Reaction SMILES: O.NN.O=C1C2C(=CC=CC=2)C(=O)[N:6]1[CH2:15][CH2:16][N:17]1[C@@H:22]([CH3:23])[CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][C@H:18]1[CH3:31]>CO>[NH2:6][CH2:15][CH2:16][N:17]1[C@@H:22]([CH3:23])[CH2:21][N:20]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:19][C@H:18]1[CH3:31]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1CCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1CCN
Temperature: 50 °C
Reaction time: 18 h
Yield: 67.5 %

Procedure:
Hydrazine hydrate (0.11 ml) was added to a solution of tert-butyl (cis)4-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3,5-dimethyl-1-piperazinecarboxylate (0.736 g) [see Preparation 6] in methanol (1.1 ml). The reaction mixture was then stirred at 50° C. for 18 hours, after which time the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and 10% citric acid. The aqueous layer was separated, basified with potassium carbonate, and the product extracted with tetrahydrofuran:ethyl acetate, 1:1, several times. The combined organic layers were dried over magnesium sulphate and the solvent removed under reduced pressure to afford tert-butyl (cis)-4-(2-aminoethyl)-3,5-dimethyl-1-piperazinecarboxylate (0.33 g) as a oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH2:7])=[O:6].C(O[CH:14](OCC)[N:15]([CH3:17])[CH3:16])C>>[Br:1][C:2]1[CH:3]=[C:4]([C:5](/[N:7]=[CH:14]/[N:15]([CH3:17])[CH3:16])=[O:6])[CH:8]=[CH:9][N:10]=1
Reactant: NC(=O)c1ccnc(Br)c1
Reactant: CCOC(OCC)N(C)C
Product: CN(C)/C=N/C(=O)c1ccnc(Br)c1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
2-bromo-isonicotinamide (406.2 mg, 2.021 mmol) and N,N-dimethylformamide diethyl acetal (0.48 ml, 2.80 mmol) were combined and heated to 120° C. A short path distillation apparatus was used to collect the ethanol that was liberated during the reaction. The reaction mixture was a light orange solution that slowly turned darker until it had become a dark amber solution. After 1.5 hours, the reaction mixture was cooled to room temperature. The reaction mixture solidified upon cooling and was placed under high vacuum overnight to give the title compound (507.4 mg) as an off-white solid.
Reaction SMILES: [CH:1]([C@@H:3]([NH:6][C:7](=[O:13])OC(C)(C)C)[CH2:4][CH3:5])=[O:2].Br[C:15]([F:22])([F:21])C(OCC)=O.S([O-])(O)(=O)=O.[K+]>O1CCCC1.[Zn]>[CH2:4]([C@@H:3]1[NH:6][C:7](=[O:13])[C:15]([F:22])([F:21])[C@@H:1]1[OH:2])[CH3:5]
Reactant: CC[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)C(F)(F)Br
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Zn]
Solvent: C1CCOC1
Product: CC[C@@H]1NC(=O)C(F)(F)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
tert-Butyl [(1S)-1-formylpropyl]carbamate (24.00 g) and ethyl bromodifluoroacetate (77.0 g) were dissolved in tetrahydrofuran (220 mL), and to a suspension of a zinc powder (25.4 g) in tetrahydrofuran (50 mL) was added dropwise the solution at room temperature. After heating under reflux for 1 hr, the mixture was cooled to room temperature, 1 mol/L aqueous potassium hydrogen sulfate solution (400 mL) was added, and the mixture was extracted with ethyl acetate. The extracted organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=10→40%), the obtained oil was dissolved in 4 mol/L hydrogen chloride/ethyl acetate solution (150 mL), and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (600 mL). Diisopropylethylamine (32.8 mL) was added, and the mixture was heated under reflux for 4 hr. The reaction solution was concentrated under reduced pressure, the residue was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate/hexane to give the title compound as a white powder (yield: 7.20 g, 54%).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[C:16]([CH2:18][CH2:19][Cl:20])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:21])=[N+]=[N-].Cl>CO.[Pd].C(O)C>[ClH:20].[NH2:1][CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[C:16]([CH2:18][CH2:19][Cl:20])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:21]
Reactant: [N-]=[N+]=NC[C@H]1O[C@@H](n2cc(CCCl)c(=O)[nH]c2=O)C[C@@H]1O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: NC[C@H]1O[C@@H](n2cc(CCCl)c(=O)[nH]c2=O)C[C@@H]1O
Reaction time: 2 h
Yield: 157.3 %

Procedure:
0.16 g of 5'-azido-2',5'-dideoxy-5-(2-chloroethyl)uridine was dissolved in 100 ml of methanol and 1.9 ml of a 0.27M solution of hydrogen chloride in methanol was added. A slurry of 25 mg of 5% palladium-on-charcoal catalyst in 10 ml of ethanol was added under a nitrogen atmosphere and the mixture was hydrogenated at room temperature and under atmospheric pressure for 2 hours. The catalyst was removed by filtration and the filtrate was evaporated to give a solid which, after crystallization from a mixture of 15 ml of methanol and 30 ml of diethyl ether, gave 0.13 g of 5'-amino-5-(2-chloroethyl)-2',5'-dideoxyuridine hydrochloride of melting point 229°-230° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[O:13][C:14]([CH3:21])=[C:15]([C:17]([O:19][CH3:20])=[O:18])[N:16]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>[Pd].CO>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:12]2[O:13][C:14]([CH3:21])=[C:15]([C:17]([O:19][CH3:20])=[O:18])[N:16]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1nc(-c2ccc([N+](=O)[O-])c(OC)c2)oc1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1nc(-c2ccc(N)c(OC)c2)oc1C
Yield: 100.9 %

Procedure:
The same operation as in Example (95b) was performed using methyl 2-(3-methoxy-4-nitrophenyl)-5-methyl-1,3-oxazole-4-carboxylate obtained in Example (105c) (0.75 g, 2.57 mmol), 10% Pd/C (0.2 g) and methanol (20 mL), to obtain 0.68 g of the title compound as a yellow solid (100%).
Reaction SMILES: [F:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl.CCN(C(C)C)C(C)C.[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:39])[C:27]2[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[C:30]([NH:36][CH3:37])=[CH:29][C:28]=2F)=[CH:21][C:20]=1[Cl:40]>CC#N>[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:39])[C:27]2[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[C:30]([NH:36][CH3:37])=[CH:29][C:28]=2[N:5]2[CH2:6][CH2:7][CH:2]([F:1])[CH2:3][CH2:4]2)=[CH:21][C:20]=1[Cl:40]
Reactant: FC1CCNCC1
Reactant: CNc1cc(F)c(C(=O)Nc2ccc(F)c(Cl)c2)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CNc1cc(N2CCC(F)CC2)c(C(=O)Nc2ccc(F)c(Cl)c2)cc1[N+](=O)[O-]
Reaction time: 6 h

Procedure:
A mixture of 4-fluoropiperidine×HCl (67 mg, 0.48 mmol), DIPEA (0.64 ml, 3.73 mmol), N-(4-fluoro-3-chloro-phenyl)-2-fluoro-4-methylamino-5-nitro-benzoic acid amide (150 mg, 0.44 mmol) and MeCN (5 mL) is stirred for 6 h at reflux. Then the mixture is concentrated, diluted with EtOAc, washed with water and concentrated.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CCCC)CCCC)CCC.[C:48]([OH:52])(=[O:51])[CH:49]=[CH2:50]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:12][C:9]1[CH:10]=[CH:11][C:2]([C:49](=[CH2:50])[C:48]([OH:52])=[O:51])=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=1
Reactant: COC(=O)c1cc(Cl)ccc1Br
Reactant: C=CC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=C(C(=O)O)c1ccc(Cl)cc1C(=O)OC
Temperature: 110 °C
Yield: 65.8 %

Procedure:
To a solution of methyl 2-bromo-5-chlorobenzoate (6.30 g), tri-o-tolylphosphine (P(o-tol)3) (770 mg), tri-n-butylamine (9.38 g) and acrylic acid (3.64 g) in toluene (20 mL) was added palladium acetate (284 mg) under nitrogen atmosphere, and the mixture was heated at 110° C. for 3 hours. The mixture was washed with 1N HCl, dried, filtered, and concentrated. The residue was purified by silica gel column chromatography, and the fractions containing the desired compound were combined, dissolved in ethyl acetate, and extracted with a saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was acidified with hydrochloric acid, extracted with ethyl acetate, and the organic layer was dried, filtered, and concentrated to give 2-(4-chloro-2-methoxycarbonylphenyl)acrylic acid (4.0 g, 66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([OH:15])=[O:14])[C:7](=[O:16])[CH2:6]2.[Cl:17][C:18]1[CH:19]=[N+:20]([O-:43])[CH:21]=[C:22]([Cl:42])[C:23]=1[CH2:24][C@@H:25]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:36])[F:35])=[C:29]([O:37][CH2:38][CH:39]2[CH2:41][CH2:40]2)[CH:28]=1)O.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:17][C:18]1[CH:19]=[N+:20]([O-:43])[CH:21]=[C:22]([Cl:42])[C:23]=1[CH2:24][C@@H:25]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:36])[F:35])=[C:29]([O:37][CH2:38][CH:39]2[CH2:41][CH2:40]2)[CH:28]=1)[O:14][C:13](=[O:15])[CH2:12][N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH2:6][C:7]1=[O:16]
Reactant: COc1ccc2c(c1)CC(=O)N2CC(=O)O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc2c(c1)CC(=O)N2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Yield: 26.4 %

Procedure:
To a solution of 2-(5-methoxy-2-oxoindolin-1-yl)acetic acid (200 mg, 0.904 mmol) in DCM (30 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (380 mg, 0.904 mmol), EDC (520 mg, 2.71 mmol) and DMAP (55.2 mg, 0.452 mmol) were added, and the mixture was reacted at room temperature overnight. The solvent was evaporated, and the resulting crude was partitioned between DCM (20 ml) and a 1N HCl (20 ml), and the desired compound was extracted with ethyl acetate (3×20 ml). The combined organic layers were dried over sodium sulfate and the solvent was removed. The crude was purified by flash chromatography on silica gel (DCM:MeOH 98:2) recovering the title compound (149.2 mg, 0.239 mmol, 27% yield). MS/ESI+ 623.12 [MH]+; [αD]=+19.12 c=0.5 in DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.45 (s, 2H), 7.18 (d, 1H), 7.06 (d, 1H), 6.92-6.98 (m, 2H), 7.07 (t, 1H), 6.76 (dd, 1H), 6.64 (d, 1H), 6.02 (dd, 1H), 4.54 (d, 1H), 4.46 (d, 1H), 3.91 (d, 2H), 3.74 (s, 3H), 3.59 (s, 2H), 3.40 (dd, 1H), 3.21 (dd, 1H), 1.03-1.41 (m, 1H), 0.50-0.70 (m, 2H), 0.21-0.50 (m, 2H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][Cl:22]>CN(C)C=O.C(OCC)(=O)C>[Cl:22][CH2:21][CH2:20][CH2:19][N:4]1[C:3](=[O:11])[CH2:2][O:1][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]1=2
Reactant: O=C1COc2ccccc2N1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1COc2ccccc2N1CCCCl
Temperature: 60 °C
Reaction time: 60 h

Procedure:
To a solution of 2H-1,4-benzoxazin-3(4H)-one (1.0 g, 6.7 mmol) and potassium carbonate (1.4 g, 10.05 mmol) in N,N-dimethylformamide (20 mL), was added 1-bromo-3-chloropropane (1.99 mL, 20.1 mmol, d=1.6). After stirring at 60° C. for 60 hours, the reaction mixture was diluted with ethyl acetate (100 mL), washed with dilute citric acid, water and brine. The organic phase was dried over MgSO4 and concentrated to the title compound (1.46 g, 97%); 1H NMR (DMSO-d6): δ 1.99-2.03 (m, 2H), 3.71 (t, 2H, J=6.4 Hz), 4.00-4.04 (m, 2H), 4.63 (s, 2H), 7.00-7.01 (m, 2H), 7.03-7.09 (m, 1H), 7.22 (d, 1H, J=7.6 Hz); MS for C11H12ClNO2 m/z 225.96 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1>C(O)C.O=[Pt]=O.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(OCCCl)cc1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: ClCCl
Product: Nc1ccc(OCCCl)cc1
Temperature: 0 °C

Procedure:
36 g (0.178 Mol) of 1-(2-Chloro-ethoxy)-4-nitro-benzene is dissolved in 360 mL of ethanol and subjected to catalytic hydration at rt using PtO2 (1.5 g) as catalyst. The resulting suspension is diluted with CH2Cl2, filtered, and concentrated to approx. 150 mL. After cooling to 0° C. the crystals are filtered off, washed and dried at 60° C. under vacuum to obtain 4-(2-chloro-ethoxy)-phenylamine. Title compound: m.p.: 87-91° C.; ES-MS: 172 [M+H]+; single peak at tR=2.73 min (System 1).