Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:13])=O>>[Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: O=C(O)c1ccncc1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccncc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 3-chloroisonicotinic acid (413 mg, 2.62 mmol) was added thionyl chloride (5 mL, 68.5 mmol). The reaction mixture was stirred at room temperature for about 20 hours. The solution was concentrated under reduced pressure and the residue was dried under high vacuum for 1 hour to give 3-chloro-isonicotinoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[N+:10]([O-])=O.C([O-])=O.[NH4+].C1(C)C=CC=CC=1>[Fe].O>[NH2:10][C:3]1[CH:4]=[C:5]([CH2:8][OH:9])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])c1cc(CO)ccc1Cl
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1cc(CO)ccc1Cl
Yield: 85 %

Procedure:
A 100 mL flask was charged with (4-chloro-3-nitrophenyl)methanol (commercially available from Acros; 1.0 g, 5.5 mmol), ammonium formate (1.4 g, 22 mmol), and iron powder (1.2 g, 22 mmol). Toluene (15 mL) and water (15 mL) were added to the flask and the mixture was heated to reflux for 4 hours, after which time, the mixture was filtered through a plug of Celite. The supernatant was washed with ethyl acetate (3×50 ml). The combined organic solution was washed with water (100 ml), saturated sodium chloride solution (100 ml), dried over anhydrous sodium sulfate and filtered. The organic solvent was removed on a rotary evaporator under reduced pressure to yield (3-amino-4-chlorophenyl)methanol (0.74 g, 85% yield). The material was used without further purification. 1H-NMR (400 MHz, CDCl3) δ 6.88 (d, 1H), 6.56 (d, 1H), 6.40 (s, 1H), 5.85 (bs, 2H), 5.39 (bs, 1H), 5.85 (bs, 1H), 4.79 (s, 2H): MS (EI): 158 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([C:25]([O:27][CH3:28])=[O:26])[C:18](=[CH:23][CH:24]=1)[C:19]([O:21][CH3:22])=[O:20])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([C:25]([O:27][CH3:28])=[O:26])[C:18](=[CH:23][CH:24]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1C(=O)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(OC[C@@H]2CCCN2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 18.4 %

Procedure:
To a solution of dimethyl (S)-4-[1-(tert-butoxycarbonyl)-2-pyrrolidinylmethoxy]phthalate (5.75 g, 14.62 mmol) in CH2Cl2 (25 mL) was added TFA (20 mL), and the resulting mixture was stirred for 50 min at room temp. The resulting mixture was concentrated in vacuo and made basic with sat. NaHCO3. The mix was extracted with CH2Cl2, washed with brine, dried over MgSO4, and evaporated off in vacuo. The residue was purified by column chromatography on silica-gel with CHCl3—MeOH (50:1, v/v) as eluent to give 790 mg (18%) dimethyl (S)-4-(2-pyrrolidinylmethoxy)phthalate as a brown oil. 1H-NMR (CDCl3) δ1.48-1.57 (m, 1 H), 1.72-1.84 (m, 2 H), 1.89-1.98 (m, 2 H), 2.91-3.03 (m, 2 H), 3.48-3.54 (m, 1 H), 3.82-3.97 (m, total 8 H), 6.98 (dd, 1 H, J=2.4, 8.8 Hz), 7.06 (d, 1 H, J=2.4 Hz), 7.78 (d, 1 H, J=8.8 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][CH2:18][C:19]1[C:27]2[C:22](=[N:23][C:24]([C:41]3[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=3)=[C:25]([C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)[C:26]=2[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[NH:21][N:20]=1>>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:26]2[C:25]([C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)=[C:24]([C:41]3[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=3)[N:23]=[C:22]3[NH:21][N:20]=[C:19]([CH2:18][NH:17][C:14]([CH:11]4[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]4)=[O:16])[C:27]=23)=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NCc1n[nH]c2nc(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)c12
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCc2n[nH]c3nc(-c4ccc(F)cc4)c(-c4ccncc4)c(-c4ccc(F)cc4)c23)CC1
Yield: 26 %

Procedure:
Following a similar procedure to that described in example 48, but using 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid instead of 2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]acetic acid and 3-aminomethyl-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (obtained in example 68) instead of morpholine, the title compound was obtained (yield: 26%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([NH2:19])[CH3:18])=[CH:13][CH:12]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][CH:17]([C:14]2[CH:15]=[CH:16][C:11]([OH:10])=[CH:12][CH:13]=2)[CH3:18])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: CC(N)c1ccc(O)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Product: CC(Nc1nc(Cl)ncc1F)c1ccc(O)cc1

Procedure:
In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine was reacted with 1-(4-hydroxyphenyl)ethylamine to provide (±)-2-chloro-5-fluoro-N4-[1-(4-hydroxyphenyl)ethyl]-4-pyrimidineamine. 1H NMR (CDCl3): δ 7.88 (d, 1H, J=2.3 Hz), 7.50–7.47 (dd, 2H, J=1.7 and 8.7 Hz), 7.26–7.23 (dd, J=8.7 and 1.7 Hz), 5.35–5.28 (m, 2H), 1.59 (d, 3H, J=7.0 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@@H:14]([OH:21])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)c2ccccc21
Solvent: CO
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC[C@H](O)c2ccccc21
Reaction time: 0.25 h
Yield: 393.6 %

Procedure:
To a mixture of 0.5 mL of (R)-2-methyl-CES-oxazaborolidine solution and 3 mL of dichloromethane was added dropwise 0.07 mL of 1.0M borane-dimethylsulfide complex at 25° C., and the mixture was stirred at the same temperature for 15 minutes. To the solution was added dropwise a solution of 141 mg of 1-benzyloxycarbonyl-4-oxo-1,2,3,4-tetrahydroquinoline in 2.5 mL of dichloromethane over about 10 minutes. Furthermore, to the reaction solution were added 0.07 mL of 1.0M borane-dimethylsulfide complex and a solution of 141 mg of 1-benzyloxycarbonyl-4-oxo-1,2,3,4-tetrahydroquinoline in 2.5 mL of dichloromethane alternately with total 4 times. To the reaction solution was added dropwise 1 mL of methanol, and the reaction solution was concentrated. To the resulting residue were added 10 mL of dichloromethane and 10 mL of phthalate buffer (pH4.0), and the aqueous layer was removed, and then water was added. The organic layer was separated, dried over magnesium sulfate, and then filtered, and the filtrate was concentrated. The resulting residue was purified by column chromatography on silica gel (solvent; n-hexan/ethyl acetate=4/1) to give 559 mg of (4S)-1-benzyloxycarbonyl-4-hydroxy-1,2,3,4-tetrahydroquinoline (yield: 99%, optical purity: 96% ee).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH:5]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:17].C(O)(=[O:20])C.S(=O)(=O)(O)O>O>[O:17]([C:6]12[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=[CH:16][C:5]1=[CH:4][CH:3]=[CH:2][O:1]2)[OH:20]
Reactant: CC(=O)O
Reactant: O=C1CCCCCCCCCCC1CCCO
Agent: O=S(=O)(O)O
Solvent: O
Product: OOC12C=CC=CC=CC=CC=CC1=CC=CO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.5 %

Procedure:
A 4-neck flask equipped with mechanical stirring, an inlet funnel, a thermometer, a condenser and kept under nitrogen, was charged with 30 g (125 mmol) of 2-(3-hydroxypropyl)-1-cyclododecanone and 137.5 g (2.29 mol) of glacial acetic acid. The mixture was stirred at room temperature until it became homogeneous. A cooled mixture of water (12.5 g) and a 50% aqueous solution of sulphuric acid (12.5 g) was then added. The reaction mixture was cooled to 0° C. and then 10 ml of 70% oxygenated water were added thereto dropwise over 15 min; the temperature rose to 7° C. Once the introduction was completed, stirring was continued for 15 min at 0° C. The formed precipitate was filtered, washed with water and then with diluted aqueous NaHCO3. 62.0 G of wet product were thus obtained which, after drying, provided 25.6 g (yield 80%) of 14a-hydroperoxy-cyclododeca[b]-pyran which was used in the following step. M. p.: 104°-106° C.
Reaction SMILES: [Cl-].C[SiH](C)C.[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Br)=[CH:9][CH:8]=1.[Cl:15][C:16]1[CH:21]=[C:20](Cl)[N:19]=[CH:18][N:17]=1.O>O1CCCC1.BrC(Br)C.[Zn]>[Cl:15][C:16]1[CH:21]=[C:20]([CH2:11][C:10]2[CH:13]=[CH:14][C:7]([F:6])=[CH:8][CH:9]=2)[N:19]=[CH:18][N:17]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Clc1cc(Cl)ncn1
Agent: CC(Br)Br
Agent: C[SiH](C)C
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(Cc2cc(Cl)ncn2)cc1
Reaction time: 0.33 h
Yield: 32.2 %

Procedure:
In 10 ml of tetrahydrofuran was suspended 1.3 g of zinc (powder), to which dibromoethane (2 drops) was added. The mixture was heated under reflux for 5 minutes, to which trimethylsilane chloride was added. The mixture was further heated under reflux for 5 minutes, to which a solution of 1.9 g of 4-fluorobenzyl bromide dissolved in 20 ml of tetrahydrofuran was slowly added with heating under reflux, followed by stirring for 20 minutes. (The solution thus obtained is referred to as solution Q). In 10 ml of tetrahydrofuran were suspended 1.5 g of 4,6-dichloropyrimidine and 0.1 g of dichlorobistriphenylphosphine palladium, to which the above solution Q was added, followed by heating under reflux for 3 hours and further stirring at room temperature for 12 hours. The reaction mixture was then poured into water and extracted three times with ethyl acetate. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.72 g of 4-chloro-6-(4-fluorobenzyl)pyrimidine.
Reaction SMILES: CS(O[C@H:6]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])(=O)=O.[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C>[N:22]([C@@H:6]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](OS(C)(=O)=O)c1ccncc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H](N=[N+]=[N-])c1ccncc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
(R)-2-(tert-Butyldimethylsilyloxy)-1-(pyridin-4-yl)ethyl methanesulfonate was taken in DMF, and sodium azide (61.6 mg, 0.947 mmol) was added. The reaction mixture was warmed to 40° C., and stirred overnight. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give the title compound as a colorless oil (58 mg). LCMS m/z=279.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:19]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:18]=[CH:17][N:16]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:28]=1.ClCCl.[I-].C(OC([N:40]1[CH2:43][CH:42]([Zn+])[CH2:41]1)=O)(C)(C)C.Cl>CN(C)C(=O)C.[Cu]I>[NH:40]1[CH2:43][CH:42]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[S:12][C:13]([C:15]5[N:19]([C:20]6[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=6[F:27])[N:18]=[CH:17][N:16]=5)=[CH:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:28]=2)[CH2:41]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2ccc(Br)cc2OCC3)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CC([Zn+])C1
Agent: [Cu]I
Agent: Cl
Agent: [I-]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2ccc(C4CNC4)cc2OCC3)c(F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 8.1 %

Procedure:
5-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-1-(2,4-difluorophenyl)-1H-1,2,4-triazole (300 mg, 0.6 mmol) was dissolved in N,N-dimethyacetamide and purged with nitrogen. Added [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (30 mg, 0.04 mmol) and copper(I)iodide (10 mg, 0.08 mmol). Bubbled in nitrogen for 10 minutes. Added (1-(tert-butoxycarbonyl)azetidin-3-yl)zinc(II) iodide (230 mg, 0.65 mmol) in 2.3 mL DMA. Heated at 80° C. overnight. Complete reaction was confirmed by LCMS. Diluted reaction mixture with 1 M HCl and extracted the t-Boc protected intermediate, tert-butyl 3-(2-(1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)azetidine-1-carboxylate, with ethyl acetate. Dried over magnesium sulfate and concentrated in vacuo. Purified by flash chromatography (0 to 50% ethyl acetate in hexanes). Concentrated in vacuo and re-dissolved the residue in 10 mL 1,4-dioxane. Added 5 mL 4 N HCl in dioxane and let stir for 2 hours. Complete deprotection was confirmed by LCMS. Concentrated in vacuo purified by HPLC to give 419 (21.1 mg, 7% yield, M=1 437.1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH4+:15].[OH-]>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH2:15])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1cc(-c2ccccc2)c(Cl)nn1
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1cc(-c2ccccc2)c(Cl)nn1
Temperature: 140 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
3,6-dichloro-4-phenylpyridazine (J. Med. Chem. 2005, 48, 7089; 5.93 g, 26.3 mmol) was divided into 6 microwave tubes, and concentrated NH4OH (7 mL) was added to each. After sealing, each was heated at 140° C. for 1 h. The microwave tubes were uncapped, the precipitates were filtered and washed with cold water. The precipitates from all reactions were combined, and Et2O (150 mL) was added. After stirring overnight, the remaining solid was filtered, rinsed with Et2O and dried to give 6-chloro-5-phenylpyridazin-3-amine (3.06 g, 56%)
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[N:13][C:14]([C:16]([OH:18])=O)=[CH:15][C:10]=3[N:9]=[CH:8]2)=[CH:4][CH:3]=1.Cl.[F:22][C:23]1[C:31]([F:32])=[C:30]([F:33])[C:29]([F:34])=[C:28]([F:35])[C:24]=1[CH2:25][O:26][NH2:27]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[N:13][C:14]([C:16]([NH:27][O:26][CH2:25][C:24]4[C:28]([F:35])=[C:29]([F:34])[C:30]([F:33])=[C:31]([F:32])[C:23]=4[F:22])=[O:18])=[CH:15][C:10]=3[N:9]=[CH:8]2)=[CH:19][CH:20]=1
Reactant: NOCc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(O)c1cc2ncn(Cc3ccc(F)cc3)c2cn1
Agent: Cl
Product: O=C(NOCc1c(F)c(F)c(F)c(F)c1F)c1cc2ncn(Cc3ccc(F)cc3)c2cn1

Procedure:
The title compound was prepared by coupling of 3-(4-fluorobenzyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid and N-[(2,3,4,5,6-pentafluorobenzyl)oxy]amine hydrochloride under the same conditions as those in step (c) of example 1. 1H NMR (300 MHz, MeOH-d4) δ; 8.69 (s, 1H), 8.52 (s, 1H), 8.28 (s, 1H), 7.33–7.32 (m, 2H), 7.07–7.02 (m, 2H), 5.56 (s, 2H), 5.09 (s, 2H). LCMS (API-ES, M+H+): 467.0. HRMS calcd for C21H13F6N4O2 (M+H) 467.0943. found 467.0942. HPLC: >80% purity.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1.CC(C)([O-])C.[K+].F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[N:23]1[C:27](=[O:28])[N:26]([CH3:29])[N:25]=[N:24]1>C1COCC1>[O:4]1[CH2:5][CH2:6][C@@H:2]([O:1][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[N:23]2[C:27](=[O:28])[N:26]([CH3:29])[N:25]=[N:24]2)[CH2:3]1
Reactant: Cn1nnn(-c2cc([N+](=O)[O-])ccc2F)c1=O
Reactant: O[C@@H]1CCOC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1nnn(-c2cc([N+](=O)[O-])ccc2O[C@@H]2CCOC2)c1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 94.1 %

Procedure:
(R)-(−)-3-Hydroxytetrahydrofuran (440 mg, 5 mmol, 2 equiv) in THF (15 ml) under argon gas, was cooled to 0° C. Potassium tert-butoxide (617 mg, 5.5 mmol, 2.2 equiv) was added in one portion, and the reaction mixture was stirred for 20 minutes at 0° C. Then 1-(2-fluoro-5-nitrophenyl)-4-methyl-1H-tetrazol-5(4H)-one (Described in: WO 2011/068898. 598 mg, 2.5 mmol, 1 equiv) was added in one portion, and the reaction mixture was stirred for 10 minutes at 0° C. and allowed to warm up to ambient temperature over 2 hours. The reaction mixture was concentrated, and the residue was taken in DCM and water. The layers were separated, and the organic layer was washed with water (×2), dried over Na2SO4, filtered, and concentrated to provide 1-(2-((R)-tetrahydrofuran-3-yloxy)-5-nitrophenyl)-4-methyl-1H-tetrazol-5(4H)-one (723 mg, 94%) as a yellow solid that was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=2)=[O:12])=[C:6]([O:21][CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH:5]=1.[OH-].[Li+].Cl>CO>[CH3:27][N:25]([CH3:26])[CH2:24][CH2:23][CH2:22][O:21][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[NH:10][C:11]([NH:13][C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)=[O:12])[C:3]([OH:28])=[O:2]
Reactant: COC(=O)c1ccc(NC(=O)Nc2cnc(C)cn2)c(OCCCN(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1cnc(NC(=O)Nc2ccc(C(=O)O)cc2OCCCN(C)C)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 52 %

Procedure:
To a stirred solution of 3-(3-dimethylamino-propoxy)-4-[3-(5-methyl-pyrazin-2-yl)-ureido]-benzoic acid methyl ester (1.0 gm; 3.3 mmol) in methanol (25 mL) was added lithium hydroxide (5 mL of a 2M aqueous solution). The reaction was heated to 60 degrees and stirred for 12 hours. The reaction was allowed to cool to room temperature and the pH was adjusted to 5.5 with 1N hydrochloric acid. A precipitate formed which was filtered and dried under reduced pressure to yield the desired product as a tan solid (52% yield). 1H-NMR (400 MHz, d6-DMSO) δ8.62 (br s, 1H), 8.39 (d, 1H, 8.21 (s, 1H), 7.59 (d, 1H), 7.43 (s, 1H), 4.15 (t, 2H), 2.42 (m, 5H), 2.18 (s, 6H), 2.01 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:14][N:15]=2)=[O:9])[N:6]=1.[CH2:19]([C:21](I)(CC)[C:22]([O-])=[O:23])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH:16]([C:13]1[S:12][C:11]([NH:10][C:8](=[O:9])[CH2:7][C:5]2[N:6]=[C:2]([N:1]3[CH2:20][CH2:19][CH2:21][C:22]3=[O:23])[S:3][CH:4]=2)=[N:15][CH:14]=1)([CH3:18])[CH3:17]
Reactant: CCC(I)(CC)C(=O)[O-]
Reactant: CC(C)c1cnc(NC(=O)Cc2csc(N)n2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)c1cnc(NC(=O)Cc2csc(N3CCCC3=O)n2)s1
Yield: 30 %

Procedure:
A mixture of 2.8 g (0.01 mol) of 2-(2-amino-1,3-thiazol-4-yl)-N-(5-isopropyl-1,3-thiazol-2-yl)acetamide, 4.84 g (0.02 mol) of ethyl-iodobutyrate and 2.76 g (0.02 mol) of potassium carbonate in 50 ml of absolute ethanol was stirred under reflux for 5 hours. The mixture was cooled and filtered, and the salts were washed with two 20 ml portions of ethanol. The ethanol was removed at reduced pressure and the residue was dissolved in 100 ml of CH2Cl2. The solution was washed with 30 ml of water, dried, and the solvent was evaporated. The residue was purified by chromatography on silica gel, using CH2Cl2:MeOH 95:5 as eluent, to give the title compound in 30% yield (1.05 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:28])[C:17]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:18])=[CH:11][C:10]=1[F:29])C1C=CC=CC=1.Br>C(O)(=O)C>[F:29][C:10]1[CH:11]=[C:12]([NH:15][C:16](=[O:28])[C:17]([NH:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:18])[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: O=C(NCCc1ccccc1)C(=O)Nc1ccc(OCc2ccccc2)c(F)c1
Agent: Br
Solvent: CC(=O)O
Product: O=C(NCCc1ccccc1)C(=O)Nc1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(4-benzyloxy-3-fluorophenyl)-N′-(2-phenylethyl)ethanediamide (40 g, 100 mmol) and 38% hydrobromic acid in acetic acid (250 mL) was stirred at room temperature overnight. The resulting solid was filtered, washed with water and dried to give N-(3-fluoro-4-hydroxyphenyl)-N′-(2-phenylethyl)ethanediamide as a slightly yellow solid (30.6 g, 99% yield). 1H NMR (400 MHz, d6-DMSO): δ 10.60 (s, 1H), 9.02 (t, 1H), 7.70 (d, 1H), 7.47 (d, 1H), 7.32-7.20 (m, 3H), 6.91 (t, 1H), 3.43 (m, 2H), 2.81 (m, 2H); 13C NMR (100 MHz, d6-DMSO): δ 160.5, 158.8, 152.0, 149.6, 142.2, 139.8, 130.3, 129.3, 129.0, 126.8, 118.1, 117.4, 109.6, 109.3 IR (cm−1): 3279, 1653, 1518, 1456, 1279, 1190, 742, 696, 584; LC/MS (M+H 303).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.[NH:10]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11]1.[OH-].[K+]>O1CCCC1.CO.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].CC(P(C(C)(C)C)C1N(C2C(C3C=CC=CC=3)=NN(C3C=CC=CC=3)C=2C2C=CC=CC=2)N=CC=1)(C)C>[CH3:9][O:8][C:4]1[N:3]=[C:2]([N:10]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11]2)[CH:7]=[CH:6][CH:5]=1
Reactant: O[C@H]1CCNC1
Reactant: COc1cccc(Cl)n1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccnn1-c1c(-c2ccccc2)nn(-c2ccccc2)c1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(N2CC[C@H](O)C2)n1
Temperature: 70 °C
Reaction time: 18 h
Yield: 226.5 %

Procedure:
To a solution of 2-chloro-6-methoxypyridine (1.966 g, 3.750 mmol) and commercially available (3S)-pyrrolidin-3-ol (1.437 g, 16.50 mmol) in tetrahydrofuran/methanol (137 mL/6.7 mL), was added Pd2(dba)3 (62.2 mg, 0.0688 mmol), BippyPhos (139.2 mg, 0.2750 mmol) and potassium hydroxide (1.16 g, 20.6 mmol, 88% pellets). The reaction was then was purged with nitrogen for 2 minutes and stirred at 70° C. for 18 hours. The reaction was filtered, quenched with saturated ammonium chloride solution, adjusted to pH=7˜8 with 1N hydrochloric acid and extracted with dichloromethane (100 mL*2) and ethyl acetate (100 mL*3). The combined organic phase was washed with saturated brine, dried over sodium sulfate and evaporated in vacuo. The residue was then purified by silica gel chromatography with ethyl acetate/petroleum ether, 0-25% to give the title compound (1.65 g, 62%) as a yellow gum that was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12](Br)Br)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.CC(C)=[O:17]>O.[N+]([O-])([O-])=O.[Ag+]>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]=[O:17])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Brc1ccc(C(Br)Br)c2ncccc12
Reactant: CC(C)=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: O=Cc1ccc(Br)c2cccnc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 5-Bromo-8-(dibromomethyl)quinoline (75 g, 0.197 mol) in Acetone (400 ml), Water (100 ml) was added Silvernitrate (75 g) at 0° C. in lots for 10 min and this reaction mixture was stirred at RT for 6 h. The reaction completion was confirmed by TLC. After completion of reaction the reaction mixture was filtered and the filterate was extracted with MTBE (1000 ml). The organic layer was washed with 10% NaHCO3 solution water, brine and the organic layer was dried over sodium sulphate and concentrated to afford the title compound as off white solid (15 g, 32% yield). 1H NMR (DMSO-d6 400 MHz): δ 11.272-11.27 (s, 1H), 9.17-9.15 (dd, J=4.2, 5.8 Hz, 1H), 8.64-8.62 (dd, J=8.6, 10.3 Hz, 1H), 8.17-8.15 (d, J=7.84, 1H), 8.09-8.07 (d, J=7.88 Hz, 1H), 7.85-7.82 (dd, J=8.64, 12.84 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=3)=[N:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:27]([CH3:26])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:20][CH:19]=3)=[N:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNc1ccccc1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccc(Cl)cc1
Product: CN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccc(Cl)cc2)cc1)c1ccccc1
Yield: 76 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from 4-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzenesulfonamide, and N-methyl-aniline, the title compound was isolated as a yellow solid in 76% yield (96% purity by HPLC).