Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1([OH:18])[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1.[ClH:24].C(O)C>C(O)C>[ClH:24].[F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1([OH:18])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(Cc2ccc(F)cc2F)CC1
Agent: Cl
Solvent: CCO
Product: OC1(Cc2ccc(F)cc2F)CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-(2,4-difluorobenzyl)-4-hydroxypiperidine-1-carboxylate (3.7 g) in ethanol (30 mL) was added 2.0 M HCl/ethanol solution (28 mL), and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the obtained solid was recrystallized from ethyl acetate/diisopropyl ether to give the title compound (2.9 g).
Reaction SMILES: Cl[CH2:2][C:3]([F:10])([F:9])[CH2:4][CH2:5][C:6]([OH:8])=[O:7].Cl.[BrH:12]>O1CCOCC1.C(O)(=O)C>[Br:12][CH2:2][C:3]([F:10])([F:9])[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: Br
Reactant: O=C(O)CCC(F)(F)CCl
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=C(O)CCC(F)(F)CBr

Procedure:
A solution of the product from Step 2 (14.2 g, 57.9 mmol) in a 5:1 methanol/H2O solvent mixture (240 mL) was stirred as lithium hydroxide mono-hydrate (7.29 g, 174 mmol) was added. After stirring at room temperature for 2 h, the reaction volume was concentrated and the remainder was partitioned between dichloromethane (300 mL) and 4N HCl (100 mL). The organic phase was separated, dried over sodium sulfate and concentrated to afford 8.60 g (68%) of the product as a white solid. This product contains 33% of the 5-chloro adduct. 1H NMR (400 MHz, Chloroform-d) δ 3.67 (t, 0.6H), 3.53 (t, 1.4H), 2.62 (t, 2H), 2.43-2.28 (m, 2H). 5-Chloro-4,4-difluoro-pentanoic acid can be prepared in an analogous fashion by substituting HCl in dioxane for the HBr in acetic acid in Step 1.
Reaction SMILES: C1([Si:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([Cl:9])[Cl:8])C=CC=CC=1.[Cl:16][SiH](Cl)Cl>[Cl-].[Al+3].[Cl-].[Cl-]>[C:10]1([Si:7]([Cl:8])([Cl:9])[Cl:16])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: Cl[Si](Cl)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: Cl[Si](Cl)(Cl)c1ccccc1
Yield: 116.5 %

Procedure:
380 g of diphenyldichlorosilane, 22.5 g of anhydrous aluminium chloride and 2.3 g of anhydrous alumina (specific surface area : 0.1 m2 /g) are placed in a flask. 477 g of trichlorosilane are run in over the course of 6 hours 50 minutes, whilst keeping the reaction mixture at 70°C and distilling the dichlorosilane. A fraction weighing 76 g, containing 74% of dichlorosilane, is obtained. 370 g of phenyltrichlorosilane are obtained on distilling the mixture remaining in the flask.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:7]=[C:6]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[C:28]([O:35][CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH:27]=2)[C:3]=1[C:4]#[N:5].Cl[Sn]Cl>CN(C=O)C>[NH2:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:7]=[C:6]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[C:28]([O:35][CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH:27]=2)[C:3]=1[C:4]#[N:5]
Reactant: COc1ccc(COc2ccccc2-c2cc(-c3ccc([N+](=O)[O-])c(OCCN4CCCCC4)c3)c(C#N)c(N)n2)cc1
Agent: Cl[Sn]Cl
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccccc2-c2cc(-c3ccc(N)c(OCCN4CCCCC4)c3)c(C#N)c(N)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-amino-6-{2-[(4-methoxybenzyl)-oxy]phenyl}-4-{4-nitro-3-[2-(1-piperidinyl)ethoxy]-phenyl}-nicotinonitrile, SnCl2 and DMF was stirred at room temperature overnight. The usual work-up and column chromatography gave 2-amino-4-{4-amino-3-[2-(1-piperidinyl)ethoxy]phenyl}-6-{2-[(4-methoxybenzyl)oxy]-phenyl}nicotinonitrile.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6](C)=[CH:5][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C@@H:16]([N:18]3[CH2:23][CH2:22][C@:21]([CH2:30][C:31]([OH:34])([CH3:33])[CH3:32])([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:20][C:19]3=[O:35])[CH3:17])=[CH:12][CH:11]=2)=[N:3]1.ClC1C=CC(=O)N(C[CH:44]2[CH2:46][CH2:45]2)N=1>>[CH:44]1([CH2:1][N:2]2[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:10]3[CH:11]=[CH:12][C:13]([C@@H:16]([N:18]4[CH2:23][CH2:22][C@:21]([CH2:30][C:31]([OH:34])([CH3:33])[CH3:32])([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[O:20][C:19]4=[O:35])[CH3:17])=[CH:14][CH:15]=3)=[N:3]2)[CH2:46][CH2:45]1
Reactant: O=c1ccc(Cl)nn1CC1CC1
Reactant: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)nn(C)c1=O
Product: C[C@@H](c1ccc(-c2ccc(=O)n(CC3CC3)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 3-{(S)-1-[4-(1,5-dimethyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one and 6-chloro-2-(cyclopropylmethyl)pyridazin-3(2H)-one following a procedure analogous to that described in Example 17. Mass spectrum (ESI+): m/z=502 [M+H]+
Reaction SMILES: [Na].[CH3:2][CH:3]([OH:7])[CH2:4][CH:5]=[CH2:6].[C:8](OC)(=[O:12])[C:9]([CH3:11])=[CH2:10]>CO>[C:8]([O:7][CH:3]([CH2:4][CH:5]=[CH2:6])[CH3:2])(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: C=CCC(C)O
Reactant: C=C(C)C(=O)OC
Agent: [Na]
Solvent: CO
Product: C=CCC(C)OC(=O)C(=C)C
Temperature: 100 °C

Procedure:
Sodium metal (0.2 g) was dissolved in anhydrous methanol (3 g) and to this solution 4-penten-2-ol (18.5 g) was added followed by the addition of methyl methacrylate (50 g). The resulting mixture was stirred and heated until the methanol started to distill. The distilled methanol was collected at 64-70° C. After the removal of methanol was complete, the temperature was increased and at about 100° C. methyl methacrylate began to distill. At this moment, the reaction mixture was cooled to room temperature and was divided between dilute sulfuric acid (1N, 250 ml) and methylene dichloride (150 ml). The organic phase was then separated and washed with water and dried. Remaining solvents were removed and the residue was then fractionated under vacuum. Pure 4-penten-2-yl methacrylate was collected at 65-68° C./25 mmHg. Yield 17.5 g.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.CCOC(C)=O>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccn2)c(Cl)c1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1ccc(OCc2ccccn2)c(Cl)c1
Yield: 45.2 %

Procedure:
2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8 g, 30.2 mmol, 1 equiv) and iron (8.44 g, 151.1 mmol, 5 equiv) were mixed in acetic acid (100 mL) and EtOAc (50 mL) and were stirred at rt overnight. The reaction mixture was filtered through a pad of Celite®. The filtrate was concentrated in vacuo and neutralized with saturated Na2CO3 solution. The solution was extracted with EtOAc and the organic layer was washed with brine and concentrated in vacuo. The resulting crude material was purified by flash chromatography eluting with EtOAc/hexane (3:7) to give 3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamine (3.2 g, 52%) as a white solid. 1H-NMR (CDCl3-d) δ 5.18 (s, 2H), 6.50 (dd, 1H), 6.76 (d, 1H), 6.80 (d, 1H), 7.22 (m, 1H), 7.64 (d, 1H), 7.73 (td, 1H), 8.55 (m, 1H); LCMS RT=0.89 min, [M+H]+=235.1.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])=[CH:6][C:5]([CH3:20])=[CH:4][N:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1.CC1C=CC(C)=CC=1>[CH3:20][C:5]1[CH:6]=[C:7]2[N:8]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:16]([O-:18])=[O:17])[S:22][C:2]2=[N:3][CH:4]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cc1cnc(Cl)c(NC(=O)c2ccccc2[N+](=O)[O-])c1
Solvent: Cc1ccc(C)cc1
Solvent: c1ccncc1
Product: Cc1cnc2sc(-c3ccccc3[N+](=O)[O-])nc2c1
Temperature: 140 °C
Reaction time: 20 h
Yield: 75.4 %

Procedure:
A mixture of N-(2-chloro-5-methylpyridin-3-yl)-2-nitrobenzamide (5.0 g, 17.1 mmol) and P2S5 (7.6 g, 34.2 mmol) in pyridine (50 mL) and p-xylene (200 mL) was stirred at 140° C. for 20 h. The hot solution was transferred to another flask and the solvent was removed in vacuo. The residue was purified by recrystallization from EtOH to afford 6-methyl-2-(2-nitrophenyl)thiazolo[5,4-b]pyridine as a yellow solid (3.5 g, yield: 75%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12]C)=[O:11])[CH:3]=1.[OH-].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([OH:12])=[O:11])[CH:3]=1
Reactant: COC(=O)c1cc(Cl)c(Cl)c(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(Cl)c(Cl)c(Cl)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 94.3 %

Procedure:
Methyl 4,5,6-trichloropyridine-2-carboxylate (10.11 g, 42 mmol) was suspended in dioxane (200 mL) and water (200 mL). To this mixture was added 1 N NaOH (42 mL, 42 mmol), and the reaction mixture was stirred at 25° C. After 72 h, 2 N NaOH (15 mL, 30 mmol) was added to drive the reaction to completion. The dioxane was removed by rotary evaporation, and the aqueous residue was acidified with concentrated hydrochloric acid. The precipitate was collected by suction filtration, washed with water and dried to provide 4,5,6-trichloropyridine-2-carboxylic acid (8.92 g, 39.6 mmol), mp 115-120° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([C@H:11]1[CH2:19][CH2:18][CH2:17][C@H:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C@@H:15]([O:29][CH2:30][CH:31]=[CH2:32])[C@H:14]([CH3:33])[O:13][C:12]1=[O:34])[CH2:8][O:9][CH3:10])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6](=[O:35])[N:7]([C@H:11]1[CH2:19][CH2:18][CH2:17][C@H:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C@@H:15]([O:29][CH2:30][CH2:31][CH3:32])[C@H:14]([CH3:33])[O:13][C:12]1=[O:34])[CH2:8][O:9][CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCO[C@@H]1[C@@H](Cc2ccc(OC)cc2)CCC[C@H](N(COC)C(=O)OC(C)(C)C)C(=O)O[C@H]1C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCO[C@@H]1[C@@H](Cc2ccc(OC)cc2)CCC[C@H](N(COC)C(=O)OC(C)(C)C)C(=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A vial was charged with 5 wt % Pd/C (26.0 mg, 0.012 mmol) and a solution of tert-butyl((3S,7R,8R,9S)-8-(allyloxy)-7-(4-methoxybenzyl)-9-methyl-2-oxooxonan-3-yl)(methoxymethyl)carbamate (200 mg, 0.407 mmol) in EtOAc (1 mL). The vial was evacuated and backfilled with H2 (3×) and then stirred vigorously under one atmosphere of H2 (balloon) at room temperature for 15 h. The reaction mixture was filtered through a plug of Celite® and concentrated to the title compound as a colorless oil (168 mg, 84%) IR (neat) 3368, 2973, 2936, 2877, 1746, 1705, 1511, 1454, 1367, 1175 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.12-7.03 (m, 2H), 6.87-6.77 (m, 2H), 5.04-4.67 (m, 2H), 4.21-4.09 (m, 1H), 3.78 (s, 3H), 3.71 (dtd, J=8.6, 6.8, 1.9 Hz, 1H), 3.50 (dtd, J=8.4, 6.6, 1.7 Hz, 1H), 3.34-3.25 (m, 3H), 3.12 (td, J=9.3, 3.6 Hz, 1H), 3.07-2.98 (m, 1H), 2.27 (ddd, J=13.4, 11.7, 6.2 Hz, 1H), 2.07 (s, 2H), 1.76 (s, 1H), 1.71-1.54 (m, 4H), 1.55-1.33 (m, 14H), 0.97 (td, J=7.4, 1.0 Hz, 3H), 0.81 (s, 1H); 13C NMR (101 MHz, CDCl3) δ 173.30, 157.80, 132.75, 129.69, 113.73, 99.98, 84.02, 83.99, 81.11, 75.59, 75.52, 55.25, 55.23, 46.20, 35.86, 35.82, 28.32, 26.56, 23.59, 19.21, 18.19, 18.12, 10.75; HRMS-ESI (m/z) ([M]+) calcd for C27H43NO7, 493.3040; found, 493.3018.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27]Cl)[CH2:21][CH2:20]1>>[O:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[O:5][C:4](=[O:12])[C:3]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:21][CH2:20]1
Reactant: O=c1oc2ccccc2c(O)c1-c1ccccc1
Reactant: CC(C)(CCl)CN1CCOCC1
Product: CC(C)(COc1c(-c2ccccc2)c(=O)oc2ccccc12)CN1CCOCC1
Yield: 87.2 %

Procedure:
Prepared according to the method of Example 8 from 4-hydroxy-3-phenyl-coumarin and 3-morpholino-2,2-dimethyl-1-chloropropane. By recrystallisation from ethanol, a solid melting at 167° C. is obtained. Yield 87.2%.
Reaction SMILES: [C:1]1([CH:7]([N:9]2[CH2:12][CH:11]([CH2:13][CH2:14][OH:15])[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([O:15][CH2:14][CH2:13][CH:11]2[CH2:12][N:9]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:8])[CH2:10]2)=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(c1ccccc1)N1CC(CCO)C1
Product: CC(c1ccccc1)N1CC(CCOc2ccc([N+](=O)[O-])cc2)C1

Procedure:
The title compound is prepared according to the procedures of Example 3 from 1-(1-phenylethyl)-3-azetidine ethanol and 4-nitrophenol.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[CH:2].[C:10]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12][CH2:11]1>C(Cl)Cl>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:10](=[O:17])[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:5][CH:4]=1)#[CH:2]
Reactant: O=C1CCCC(=O)O1
Reactant: C#Cc1ccc(N)cc1
Solvent: ClCCl
Product: C#Cc1ccc(NC(=O)CCCC(=O)O)cc1
Reaction time: 1 h

Procedure:
To a solution of 4-ethynylaniline (0.99 g, 8.5 mmol) in CH2Cl2(100 ml) is added glutaric anhydride (1.06 g, 9.30 mmol). After 1 h, the resulting slurry is concentrated by rotary evaporation and the crude mixture is purified by silica column chromatography (10% methanol/5% TEA/CH2Cl2).
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:8]1[S:12](=[O:14])(=[O:13])[O:11][CH2:10][CH2:9]1>>[CH2:1]([NH:7][CH2:10][CH2:9][CH2:8][S:12]([OH:14])(=[O:13])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=S1(=O)CCCO1
Reactant: CCCCCCN
Product: CCCCCCNCCCS(=O)(=O)O

Procedure:
In the manner of previous Examples n-hexylamine was reacted with propanesultone to yield the 3-hexylamino propylsulfonic acid, mp
Reaction SMILES: O.[NH2:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1.[CH3:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:10]=1[C:11](Cl)=[O:12]>O1CCCC1.O>[CH3:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:10]=1[C:11]([NH:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1)=[O:12]
Reactant: Cc1cccc([N+](=O)[O-])c1C(=O)Cl
Reactant: Nc1nnn[nH]1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc([N+](=O)[O-])c1C(=O)Nc1nnn[nH]1
Reaction time: 16 h

Procedure:
To a warm solution of 28 g of 5-aminotetrazole monohydrate in 300 ml of tetrahydrofuran and 15 ml of water was added 26.7 g of 2-methyl-6-nitrobenzoyl chloride in 50 ml of tetrahydrofuran. The solution was allowed to stand for 16 hours, the solvent was evaporated and the residue was treated with water. The solid obtained was separated by filtration, slurried with ether and again separated by filtration to give 2-methyl-6-nitro-N-(1H-tetrazol-5-yl)benzamide melting at about 230°-232° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=S)=[N:8][CH:9]=[C:10]([Cl:12])[CH:11]=1.[NH3:29]>>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[NH:29])=[N:8][CH:9]=[C:10]([Cl:12])[CH:11]=1
Reactant: N
Reactant: Fc1cccc(Cl)c1COc1cc(Cl)cnc1NC(=S)Nc1ccc(Cl)cc1
Product: N=C(Nc1ccc(Cl)cc1)Nc1ncc(Cl)cc1OCc1c(F)cccc1Cl

Procedure:
A mixture of yellow men:uric oxide (0.36 g, 0.0017 mol), N-[3-(2-chloro-6-fluorobenzyloxy)-5-chloropyrid-2-yl]-N'-4-chlorophenylthiourea (0.64 g, 0.0014 mol)and methanolic ammonia solution (20 ml) was stirred for 1 day at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent followed by recrystallisation from ethanol gave the desired product. Yield 0.09 g (15%), m.p. 162°-163 ° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][C:6]#[N:7].[H-].[Na+].[C:13](=O)([O:17]CC)[O:14][CH2:15][CH3:16]>C1COCC1>[CH2:15]([O:14][C:13](=[O:17])[CH:5]([C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=1)[C:6]#[N:7])[CH3:16]
Reactant: CCOC(=O)OCC
Reactant: N#CCc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 68 %

Procedure:
step 1—A solution 3-chlorobenzyl cyanide (10 g, 66 mmol) dissolved in diethyl carbonate (80 mL) was added over 15 min to a suspension of NaH (8.7 g, 0.218 mol, 60% dispersion in oil) in THF (70 mL) cooled to 0° C. The resulting mixture was stirred at RT for 12 h, heated at reflux for 14 h then cooled to RT and quenched with H2O. The reaction mixture was partitioned between Et2O and H2O and the aqueous layer was adjusted to pH 3 with 2M aqueous HCl and thrice back-extracted with Et2O. The combined organic layers were washed with water, brine, dried (Na2SO4), filtered and evaporated to afford 10.1 g (68% yield) of (3-chloro-phenyl)-cyano-acetic acid ethyl ester which was used in the next step without purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:25])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][OH:24])=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[CH:26]1([NH:29][C:30]([C:32]2[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=2)=[O:31])[CH2:28][CH2:27]1>>[CH:26]1([NH:29][C:30](=[O:31])[C:32]2[CH:39]=[CH:38][C:35]([C:36]3[NH:10][C:9]4[CH:8]=[CH:7][C:6]([NH:13][C:14](=[O:25])[C:15]5[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][OH:24])=[CH:17][CH:16]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:34][CH:33]=2)[CH2:27][CH2:28]1
Reactant: O=Cc1ccc(C(=O)NC2CC2)cc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(OCCO)cc1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(C(=O)NC4CC4)cc3)nc2c1)c1ccc(OCCO)cc1

Procedure:
Compound 237 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-(2-hydroxyethoxy)benzamide and 4-cyclopropylaminocarbonylbenzaldehyde. [M+H]+ calcd for C26H24N4O4: 457.19; found: 457.51.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[CH3:16][C:17]1[S:21][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:19][C:18]=1[CH2:28][CH2:29]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OCC)(=O)C>[CH3:16][C:17]1[S:21][C:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[N:19][C:18]=1[CH2:28][CH2:29][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Reactant: Cc1sc(-c2ccccc2)nc1CCO
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(OCCc3nc(-c4ccccc4)sc3C)ccc2[nH]1
Reaction time: 48 h
Yield: 53 %

Procedure:
A solution of ethyl 5(hydroxy)-1H-indole-2-carboxylate (991 mg, 4.83 mmol) and 2-(5-methyl-2-phenyl-1,3-thiazol-4-yl)ethanol (1.06 g, 4.83 mmol) in tetrahydrofuran (30 +5 mL rinse) was added to a stirred mixture of triphenylphosphine (1.3 g, 4.9 mmol) and 1,1′-(azodicarbonyl)dipiperidine (1.2 g, 4.9 mmol) in tetrahydrofuran (10 mL). The reaction was stirred for 48 h and then diluted with ethyl acetate (200 mL). This solution was washed successively with water, 10% hydrochloric acid, and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Flash chromatography of the residue over silica gel using 25% ethyl acetate/hexane gave 1.04 g (53%) of the desired product. The product had: 1H NMR (300 MHz, acetone-D6) □ 10.40-10.55 (br s, 1 H), 7.89-7.95 (m, 2 H), 7.38-7.49 (m, 4 H), 7.19 (d, 1 H), 7.06-7.09 (m, 1 H), 6.95 (dd, 1 H), 4.30-4.40 (m, 4 H), 3.20 (t, 2 H), 2.51 (s, 3 H), 1.35 (t, 3 H); mass spectrometry gave MH+=407.1 (calc'd exact mass for C23H22N2O3S=406.14).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]([C:12]1[N:17]=[C:16]2[O:18][C:19]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[C:20]([C:21](=[O:24])[NH:22][CH3:23])[C:15]2=[CH:14][C:13]=1[C:32]1[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=1)[C:35]([O:37]C(C)(C)C)=[O:36])([CH2:10][CH3:11])[CH3:9]>C(Cl)Cl>[CH:8]([C:12]1[N:17]=[C:16]2[O:18][C:19]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[C:20]([C:21](=[O:24])[NH:22][CH3:23])[C:15]2=[CH:14][C:13]=1[C:32]1[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=1)[C:35]([OH:37])=[O:36])([CH2:10][CH3:11])[CH3:9]
Reactant: CCC(C)c1nc2oc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1-c1cccc(C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)c1nc2oc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1-c1cccc(C(=O)O)c1
Reaction time: 2 h
Yield: 93.6 %

Procedure:
TFA (0.90 ml, 12 mmol) was added to a stirring solution of tert-butyl 3-(6-(sec-butyl)-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)benzoate (118 mg, 0.235 mmol) in DCM (2.3 ml) at rt. The reaction was allowed to stir for 2 h and then was concentrated to dryness azeotroping with toluene 2×. The resulting solid was triturated with DCM to give 3-(6-(sec-butyl)-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)benzoic acid (98 mg, 0.22 mmol, 93% yield) consistent by LCMS. LC-MS retention time: 1.84 min; m/z (MH+): 447. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][C:14]2[C:15]([NH:25][CH2:26][CH2:27][CH2:28][OH:29])=[C:16]([CH:21]=[CH:22][C:23]=2[Cl:24])[C:17]([O:19][CH3:20])=[O:18])=S)=[C:6]([CH3:30])[CH:5]=1)(=[O:3])[NH2:2].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>O1CCCC1.C(=O)([O-])O.[Na+]>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:25]([CH2:26][CH2:27][CH2:28][OH:29])[C:15]3[C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=[C:23]([Cl:24])[C:14]=3[N:13]=2)=[C:6]([CH3:30])[CH:5]=1)(=[O:3])[NH2:2]
Reactant: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ccc(C(N)=O)cc2C)c1NCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cl)c2nc(Nc3ccc(C(N)=O)cc3C)n(CCCO)c12
Temperature: 50 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
A mixture of the resulting thiourea (2.10 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (981 mg, 5.12 mmol), and triethylamine (0.72 mL) in tetrahydrofuran (60 mL) was stirred at 50° C. for 2 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with ethyl acetate to give the title compound as a colorless powder (1.30 g, 3.12 mmol, 39% in 2 steps).