Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][CH:3]1[C:7]2[C:8]([O:12]COC)=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][O:4]1>CO.ClCCl>[CH3:2][CH:3]1[C:7]2[C:8]([OH:12])=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][O:4]1
Reactant: COCOc1cccc2c1C(C)OC2
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC1OCc2cccc(O)c21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 123.2 %

Procedure:
In a 8 ml vial 1-methyl-7-{[(methyloxy)methyl]oxy}-1,3-dihydro-2-benzofuran (Intermediate 97, 25.2 mg) was dissolved in methanol (1 ml) to give a colourless solution. A solution of HCl (2M/H2O) (0.259 ml, 0.519 mmol) was added. The reaction mixture was shaken at 80° C. After 30 minutes, the reaction mixture was diluted with 10 ml of dichloromethane. The phases were separated through a phase separator cartridge. The organic phase was mixed with the fraction obtained before and evaporated under vacuum to afford a residue which was purified by silica gel chromatography (Biotage SP1 system, 10 g-SNAP Silica column) with Cyclohexane/EtOAc as eluents (from 100/0 to 3/1 in 10 CV; then 3/1 for 5 CV; then from 3/1 to 1:1 in 5 CV; then 1:1 for 5 CV). The collected fractions afforded the title compound (24 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14]([C:16]2[C:17]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:24][C:18]=3[S:19][C:20]=2N(C)C)=[O:15])[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[N:36]1([CH2:41][CH2:42][O:43][C:44]2[CH:49]=[CH:48][C:47](Br)=[CH:46][C:45]=2[O:51][CH3:52])[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:14]([C:16]2[C:17]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:24][C:18]=3[S:19][C:20]=2[C:47]2[CH:48]=[CH:49][C:44]([O:43][CH2:42][CH2:41][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[C:45]([O:51][CH3:52])[CH:46]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: Cc1cc(C(=O)c2c(N(C)C)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Reactant: COc1cc(Br)ccc1OCCN1CCCC1
Product: COc1cc(-c2sc3cc(OCc4ccccc4)ccc3c2C(=O)c2ccc(CN3CCCC3)c(C)c2)ccc1OCCN1CCCC1
Yield: 30 %

Procedure:
The title compound was prepared from 6-benzyloxy-2-(dimethylamino)benzo[b]thiophen-3-yl 3-methyl-4-[(1-pyrrolidinyl)methyl]phenyl ketone (Example 124, Part C) and 4-bromo-2-methoxyphenyl 2-(1-pyrrolidinyl)ethyl ether (Part A) in 30% yield after PrepLC (SiO2; gradient of 80:15:5 to 70:25:5 hexanes-THF-TEA) by essentially following the procedure detailed in Example 123, Part A.
Reaction SMILES: C(O)(C)C.Cl[C:6]1[C:7]2[C:14]3[CH2:15][CH2:16][C:17]4([CH2:22][C:13]=3[S:12][C:8]=2[N:9]=[CH:10][N:11]=1)[O:21][CH2:20][CH2:19][O:18]4.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=1)[NH2:27].Cl>O1CCOCC1>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:6]2[C:7]3[C:14]4[CH2:15][CH2:16][C:17]5([CH2:22][C:13]=4[S:12][C:8]=3[N:9]=[CH:10][N:11]=2)[O:21][CH2:20][CH2:19][O:18]5)[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=1
Reactant: Cc1cccc(COc2ccc(N)cc2Cl)n1
Reactant: Clc1ncnc2sc3c(c12)CCC1(C3)OCCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Cc1cccc(COc2ccc(Nc3ncnc4sc5c(c34)CCC3(C5)OCCO3)cc2Cl)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To isopropanol (80 mL) was sequentially added 4-chloro-5,8-dihydro-6H-spiro[1-benzothieno[2,3-d]pyrimidine-7,2′-[1,3]dioxolane] (5.5 g, 19.4 mmol), 3-chloro-4-[(6-methylpyridin-2-yl)methoxy]aniline (4.61 g, 18.5 mmol), and 4N HCl in dioxane (0.8 mL). The suspension was stirred with heating to 80° C., upon which time the contents turn brown and homogeneous. After 8 h, the heterogeneous mixture was removed from heating, and allowed to cool to rt. The resultant precipitate was collected by filtration as a light-brown solid (5.67 g, 81%), which was used without further purification. 1H-NMR (DMSO-d6) δ 8.35 (s, 1H), 8.16 (s, 1H), 7.78 (d, 1H), 7.73 (d, 1H), 7.51 (dd, 1H), 7.34 (d, 1H), 7.21 (m, 1H), 7.19 (d, 1H), 5.21 (s, 2H), 3.97 (s, 4H), 3.26 (t, 2H), 3.01 (s, 2H), 2.48 (s, 3H), 1.95 (t, 2H); LCMS RT=2.78 min; [M+H]+=495.2.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20](O)=[O:21])[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:26]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.O[NH:49][C:50](=[NH:52])[CH3:51]>CN(C=O)C.O>[CH3:51][C:50]1[N:52]=[C:20]([C:19]2[CH:18]=[C:17]([N:14]3[CH2:13][C@H:12]4[N:8]([CH2:9][CH2:10][CH2:11]4)[C:7]4[N:26]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[C:15]3=[O:16])[CH:25]=[CH:24][CH:23]=2)[O:21][N:49]=1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(=O)O)c1)C2=O
Reactant: CC(=N)NO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nc(C)no3)c1)C2=O
Temperature: 100 °C
Reaction time: 6 h
Yield: 91.4 %

Procedure:
(S)-3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzoic acid (180 mg, 0.49 mmol) obtained in Step 1 of Example 56 was suspended in DMF (3.0 mL), and the mixture was stirred at 100° C. for 6 hours after adding 1-hydroxybenzotriazole (200 mg, 1.46 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (280 mg, 1.46 mmol), and N-hydroxyacetamidine (108 mg, 1.46 mmol). Thereafter, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give (S)-5-[3-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (183 mg, 91%).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][F:20])=[CH:13][CH:12]=1)(=[O:10])=[O:9].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(OCC)(=O)C.[Pd]>[CH3:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17]/[CH:18]=[CH:19]\[F:20])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(C#CCF)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(C/C=C\F)cc1
Yield: 99.3 %

Procedure:
cis-hydrogenation using Lindlar catalyst and pyridine: Stir a mixture of 533 mg, 2.51 mmoles of the title compound of Example 1 (recrystallized from dichloromethane-hexane), 211 mg, 2.67 mmoles of pyridine and 127 mg of Lindlar catalyst (palladium on calcium carbonate, poisoned with lead (obtained from Aldrich) in 25 mL of ethyl acetate under hydrogen at atomospheric pressure at 26° C. for 1 hr until the theoretical amount of hydrogen (62 mL) is consumed. Remove the catalyst by filtration and wash it with ethyl acetate. Wash the ethyl acetate solution successively with ice-cold 4% HCl solution, saturated NaHCO3 solution and water, and dry over anhydrous MgSO4. Evaporate solvent under vacuum to give the title compound as an oil (534 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][NH:14]2)=[O:9].Br[CH2:20][CH2:21][CH2:22][Cl:23]>>[Cl:23][CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][NH:14]2)=[O:9]
Reactant: ClCCCBr
Reactant: O=C(c1ccccc1O)c1cccc2[nH]ccc12
Product: O=C(c1ccccc1OCCCCl)c1cccc2[nH]ccc12

Procedure:
Using the procedure of Step E of Example 1, 10.9 g of the product of Step D and 18.17 ml of 1-bromo-3-chloro propane were reacted to obtain after chromatography on silica (eluant: methylene chloride - hexane (75-25)), 14.4 g of the desired product melting at 94° C., which was used as is for the following step.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:35]=[CH:34][C:15]([O:16][C:17]2[C:18]([CH:23]3[CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]3)=[N:19][CH:20]=[CH:21][N:22]=2)=[CH:14][CH:13]=1)=[O:11].FC(F)(F)C(O)=O>C(Cl)Cl>[NH:25]1[CH2:26][CH:23]([C:18]2[C:17]([O:16][C:15]3[CH:34]=[CH:35][C:12]([C:10]([C:2]4[NH:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=4)=[O:11])=[CH:13][CH:14]=3)=[N:22][CH:21]=[CH:20][N:19]=2)[CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CC(c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(Oc2nccnc2C2CNC2)cc1)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 3-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)azetidine-1-carboxylate (175 mg, 0.371 mmol) in CH2Cl2 (1 mL) is added 2,2,2-trifluoroacetic acid (1.0 mL). The reaction was stirred at rt 1 h. The solution was concentrated and CH2Cl2 (5 mL) and saturated NaHCO3 (0.5 mL) was added. MgSO4 was added to remove water and the solution filtered and concentrated to give the crude amine as a dark green oil which was carried on to the next step without purification. (Note: An insoluble solid crashed out during the extraction, which later was identified as the desired crude amine product, which is sparingly soluble in CH2Cl2, but soluble in THF. The insoluble solid from the extraction was dissolved in THF, dried (MgSO4), concentrated, and combined with the material from aqueous extraction and carried on into the next step.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH2:12][CH3:13])[C:7]=2[C:6](=[O:14])[NH:5][C:4]1=[O:15])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][CH2:24][CH2:25][CH:26]=[CH:27][CH3:28]>CN(C)C=O>[CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH2:12][CH3:13])[C:7]=2[C:6](=[O:14])[N:5]([CH2:28][CH2:27][CH2:26][CH:25]=[CH:24][CH3:23])[C:4]1=[O:15])[CH3:2]
Reactant: CCn1cnc2c1c(=O)[nH]c(=O)n2CC
Reactant: CC=CCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC=CCCCn1c(=O)c2c(ncn2CC)n(CC)c1=O
Yield: 94.7 %

Procedure:
20.8 g (0.1 mole) of 3,7-diethylxanthine, 15.2 g (0.11 mole) of potassium carbonate and 13.0 g (0.11 mole) of 1-chloro-4-hexene in 600 ml of dimethylformamide were stirred at 110° C. for 18 hours. After cooling down, the mixture was filtered, the filtrate was evaporated under reduced pressure and the residue was taken up in chloroform. The unreacted 3,7-diethylxanthine was removed by extracting with 1N sodium hydroxide solution by shaking, the organic phase was washed to neutrality with water, dried over sodium sulfate and the solvent was distilled off in a rotary evaporator. After drying the solid residue from evaporation, 27.5 g (94.7% of theory) of crude 3,7-diethyl-1-(4-hexenyl)xanthine were obtained, ##STR29## which, after dissolving in 350 ml of chloroform and adding 23.1 g (0.114 mole) of 3-chloroperbenzoic acid (85% pure), was stirred under a nitrogen atmosphere at room temperature for 48 hours. The mixture was then initially extracted by shaking with 10% strength sodium dithionite solution until the iodine-starch reaction disappeared, and then with 10% strength sodium bicarbonate solution, and the solution was washed with water until neutral and free of salt, dried and evaporated under reduced pressure. 29.0 g (100% of theory) of crude 3,7-diethyl-1-(4,5-epoxyhexyl)xanthine were obtained ##STR30## which, after being taken up in a solvent mixture composed of 150 ml of tetrahydrofuran and 100 ml of water and addition of 0.46 ml of perchloric acid (70% strength), was stirred at room temperature for 90 hours. The mixture was then neutralized with saturated sodium bicarbonate solution, the solvent was distilled off under reduced pressure and the residue was chromatographed on silica gel with chloroform as the mobile phase. This produced 26.4 g (86% of theory) of a crystalline product, which was recrystallized from ethyl acetate/petroleum ether, and which was almost pure by thin-layer chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[Na+].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>O>[C:13]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cccc(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.7 %

Procedure:
To a solution of 1.37 g of 3-aminobenzoic acid and 0.4 g of sodium hydroxide in 50 ml of water, 1.41 g of benzoyl chloride and a solution containing 0.4 g of sodium hydroxide in 5 ml of water were simultaneously added dropwise, in an ice bath, and the mixture was stirred at room temperature for 6 hours. The reaction solution was adjusted to pH 1 by addition of 1N hydrochloric acid, and thus obtained solid was collected by filtration to give 1.92 g (yield 80%) of the title compound as a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2].C([Li])CCC.[C:15]1(=O)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1.Cl>O1CCCC1>[CH2:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)([CH3:3])[CH3:2])=[CH:16]1
Reactant: CC(C)c1ccccn1
Reactant: O=C1CCc2ccccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C1=CCc2ccccc21)c1ccccn1

Procedure:
A solution of 10.8 g (0.09 mol) of 2-isopropylpyridine in 47 ml of tetrahydrofuran was cooled to −20° C. and 62.5 ml of n-butyllithium (1.6M in hexane, 0.11 mol) were subsequently added while stirring. The mixture was allowed to come to room temperature and was stirred for a further one hour. A solution of 15.84 g (0.12 mol) of 1-indanone in 12 ml of tetrahydrofuran was then added at such a rate that the temperature remained at 25° C. The mixture was stirred for a further 12 hours and hydrolyzed with 200 ml of dilute hydrochloric acid. The organic phase was separated off, the aqueous phase was extracted once with diethyl ether, the aqueous phase was subsequently neutralized with aqueous ammonia solution and was extracted three times with 100 ml each time of chloroform. The organic phases were combined, dried over magnesium sulfate, the magnesium sulfate was filtered off and the solvent was distilled off. This gave 16.6 g (77%) of 2-[1H-inden-3-yl)-1-methylethyl]pyridine.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.O>C1COCC1>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:13][CH2:12][CH2:11][CH2:10][CH2:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCCCCCCBr
Reactant: OCCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: BrCCCCCCOCCCCc1ccccc1
Yield: 48 %

Procedure:
NaH (46% dispersion in oil; 6.5 g) was added portionwise to a solution of 4-phenyl-1-butanol (15.0 g) and 1,6-dibromohexane (48.8 g) in THF (200 ml) under nitrogen. The resulting suspension was refluxed for 27 h and treated with H2O (80 ml). The mixture was extracted with ER (2×200 ml) and the dried extract was evaporated to leave an orange oil. The oil was purified on a column of silica (800 ml) [A] to give a yellow oil which on distillation gave the title compound as a colourless oil (15.0 g) b.p. 90°-95°/0.1 mmHg.
Reaction SMILES: [CH2:1]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>C(Cl)(Cl)Cl>[CH2:1]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[O:13])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CCCCCCc1ccc(C(=O)N2CCOCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 7 h
Yield: 87.7 %

Procedure:
The compound ([5]-(53)-75) (7.60 g) prepared in Example 61 was dissolved in anhydrous chloroform (152 ml). Then, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.37 g), 1-hydroxybenzotriazole (4.48 g), and morpholine (6.31 g) were added to the solution. The reaction mixture was stirred at room temperature for 7 hours. After the reaction was completed, chloroform was added. The solution was washed with 0.5N HCl aqueous solution, 0.5N NaOH aqueous solution, and distilled water. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Kieselgel 60=150 g, hexane/ethyl acetate=1/1) to obtain the above-captioned compound ([5]-(54)-75) (8.50 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[I:12].[NH4+].[Cl-]>C(O)C.O.[Fe]>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][C:3]=1[I:12]
Reactant: Nc1nc(Cl)c(I)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc(I)c(Cl)nc1N
Yield: 97.1 %

Procedure:
To a solution of 6-chloro-3-nitropyridin-2-amine (630 mg, 3.63 mmol) in ethanol (11 mL) was add I2 (920 mg, 3.62 mmol) and Ag2SO4 (1132 mg, 3.63 mmol).). The resulting solution was stirred overnight at room temperature and dissolved in water (100 mL), then extracted with ethyl acetate (3×80 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated under vacuum to produce 6-chloro-5-iodo-3-nitropyridin-2-amine as a yellow solid (640 mg, 59%). Next, to a solution of 6-chloro-5-iodo-3-nitropyridin-2-amine (640 mg, 2.14 mmol) in ethanol (40 ml) and water (10 ml) was added Fe powder (1.93 g, 34.46 mmol) and NH4Cl (887 mg, 16.58 mmol). The resulting solution was heated to reflux for 4 h and then concentrated. The residue was dissolved in water (100 mL) and extracted with ethyl acetate (3×80 ml). The combined organic layers was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column with 33% ethyl acetate in petroleum ether to produce 6-chloro-5-iodopyridine-2,3-diamine as a brown solid (560 mg, 97%). The mixture of 6-chloro-5-iodopyridine-2,3-diamine (100 mg, 0.37 mmol), (2,3-dichlorophenyl)boronic acid (147.3 mg, 0.77 mmol), Pd(Ph3P)4 (42.9 mg, 0.04 mmol) and sodium carbonate (118.2 mg, 1.12 mmol) in water (5 mL) and dioxane (15 mL) was heated to reflux overnight. Then the resulting solution was quenched with water (100 mL) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column with 50% ethyl acetate in petroleum ether to produce 6-chloro-5-(2,3-dichlorophenyl)pyridine-2,3-diamine as a brown solid (80 mg, 75%). Finally, the solution of 6-chloro-5-(2,3-dichlorophenyl)pyridine-2,3-diamine (80 mg, 0.28 mmol) in trifluoroacetic acid (10 mL) and hydrochloric acid (conc., 2 mL) was heated to reflux overnight. Then the resulting mixture was quenched with water (100 mL), adjusted pH to 8 with sodium carbonate and extracted with ethyl acetate (3×80 mL). The combined organic layers was dried over anhydrous magnesium sulfate and concentrated to give a residue, which was purified by a silica gel column with 50% ethyl acetate in petroleum ether to produce 5-chloro-6-(2,3-dichlorophenyl)-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyridine. Trifluoroacetic acid as a off-white solid (2 mg, 2%).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17]Br>CC(C)=O>[C:1]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:17][CH2:16]1)#[N:2]
Reactant: BrCCBr
Reactant: CCOC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(C#N)CC1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
To a solution of ethyl cyanoacetate (11.8 g) in acetone (83.0 mL), potassium carbonate (43.1 g) and 1,2-dibromoethane (39.2 g) were added and the mixture was refluxed for 12 hours. After being cooled to room temperature, the reaction mixture was filtered through Celite (registered trademark). The filtrate was concentrated under reduced pressure and further dried under reduced pressure with heating to give ethyl 1-cyanocyclopropanecarboxylate as a red oil (14.2 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[C:30]([N:13]1[CH2:14][CH2:15][CH:10]([CH:9]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:11][CH2:12]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Fc1ccc(NC(c2ccc(F)cc2)C2CCNCC2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCC(C(Nc2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
A solution of N,α-bis(4-fluorophenyl)-4-piperidinemethanamine (3.21 g, 0.0106 mol), triethylamine (2.5 g, 0.025 mol), and benzoyl chloride (1.70 g, 0.012 mol) in 400 mL of methylene chloride was stirred 16 h at room temperature. The reaction was concentrated to dryness and dissolved in chloroform. The chloroform layer was extracted successively with water, 1N sulfuric acid, and 5% sodium hydroxide. The chloroform layer was dried (Na2SO4) and filtered. The chloroform was removed to give a fluffy-white residue. This material was dissolved in methylene chloride and chromatographed by flash chromatography on silica gel. Elution was accomplished using methylene chloride, 1% acetone-methylene chloride, 2% acetone-methylene chloride, and 4% acetone-methylene chloride. Fractions of similar purity were combined, and solvents removed to give a fluffy-white residue. This material was triturated with isopropyl ether and chilled in a freezer. A white solid was isolated and dried, 16 h at 78° C. This furnished 1.40 g (32.5%) of white crystalline solid, mp 157°-158° C.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2OCC[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.Cl.C(=O)([O-])O.[Na+]>CO>[CH2:1]([S:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CSc2ccc(C3OCCO3)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=Cc1ccc(SCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a solution of 2-(4-benzylsulfanyl-phenyl)-[1,3]dioxolane (1.06 g, 3.89 mmol) described in Manufacturing Example 205-1-1 in methanol (5 mL) and tetrahydrofuran (5 mL) was added 1 N hydrochloric acid (4.16 mL), which was stirred for 30 minutes at room temperature. The mixture was cooled to 0° C. and neutralized with a saturated sodium hydrogencarbonate aqueous solution, and then extracted with ethyl acetate. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (840 mg). The title compound was used in the following reaction without any further purification.