Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C@@H:12]([C:13](OC)=[O:14])[C@@H:11]([C:17](O)=[O:18])[N:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>C(O)(C)C.ClCCCl>[CH2:20]([N:10]1[C@H:11]2[CH2:17][O:18][C:13](=[O:14])[C@H:12]2[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)[C@H]1[C@@H](C(=O)O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCCl
Product: O=C1OC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
A solution of (4S,5R)-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid (mp., 146°-150° C., [α]36525 =-27.6° at c=1 in DMF, 3.68 g) in isopropanol (10 ml) and 1,2-dichloroethane (60 ml) was added dropwise to a mixture of sodium borohydride (760 mg) and isopropanol (20 ml) at 5°-10° C. over a period of 15 minutes. The obtained mixture was allowed to warm up to room temperature and to react at the same temperature for 20 hours. Then, 1N hydrochloric acid (50 ml) was added to the reaction mixture. The mixture was stirred at 55°-60° C. for 30 minutes. Aqueous layer was separated from organic layer and extracted once with 1,2-dichloroethane (50 ml). The organic layers were combined, washed successively with water, 5% aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (3aS,6aR)-1,3-dibenzylhexahydro-1H-furo[3,4-d]imidazole-2,4-dione (3.12 g). M.P., 116°-117° C. [α]D25 =+61.0° (c=1, CHCl3).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3].CCN(CC)CC.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:16][CH:13]1[CH2:14][CH2:15][N:10]([C:7]2[N:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][N:6]=2)[CH2:11][CH2:12]1)(=[O:27])=[O:26]
Reactant: CCCc1cnc(N2CCC(O)CC2)nc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1cnc(N2CCC(OS(C)(=O)=O)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To a stirring solution of 1-(5-propylpyrimidin-2-yl)piperidin-4-ol (9.2 g, 41.6 mmol), Et3N (12.85 mL, 91 mmol, Aldrich) in CH2Cl2 (80 mL) at 0° C. was added a solution of Methanesulfonyl chloride (3.54 mL, 45.7 mmol, Acros) in CH2Cl2 (20 mL) dropwise. The reaction mixture was stirred at room temperature for 1 h and washed with 1N HCl in H2O, saturated NaHCO3 in H2O and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to yield 11.7 g of the desired product as an off-white solid. MS (ESI) 300 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]2[NH:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1.[OH-].[Na+].[H][H]>[Pd].O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[NH:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:15][CH:16]=1
Reactant: [H][H]
Reactant: COc1ccc(C=C2NC(=O)NC2=O)cc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(CC2NC(=O)NC2=O)cc1

Procedure:
5-p-Methoxybenzylidene hydantoin, 171.5 g., in 680 ml. of water, 63 g. of 50% sodium hydroxide solution and 6 g. of 20% palladium-on-carbon is shaken under a hydrogen atmosphere at a pressure of 51.5 psi. for about one and a half hours until the hydrogen pressure no longer diminishes. The reaction is vented and the mixture filtered to separate the catalyst. The filtrate is cooled and taken to pH 2 with concentrated hydrochloric acid. The solid is separated by filtration, washed with water and dried at 50° C. in a vacuum oven yielding the above named compound, mp. 177°-179° C.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:14]([CH3:27])[C:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[Cl:26])=[O:16])[CH2:11][CH:12]=[CH2:13])(C(C)(C)C)(C)C.Cl>CO>[Cl:26][C:20]1[C:21]([F:25])=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][NH:17][C:15](=[O:16])[N:14]([C@@H:10]([CH2:11][CH:12]=[CH2:13])[CH2:9][OH:8])[CH3:27]
Reactant: C=CC[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)NCc1cccc(F)c1Cl
Agent: Cl
Solvent: CO
Product: C=CC[C@@H](CO)N(C)C(=O)NCc1cccc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
To a solution of (S)-1-(1-(tert-butyldimethylsilyloxy)pent-4-en-2-yl)-3-(2-chloro-3-fluorobenzyl)-1-methylurea (5.80 g, 10.8 mmol) in MeOH (50 mL) was added HCl (1N, 32.0 mL). The resulting solution was stirred at RT for 30 min. The mixture was partially concentrated and filtered. The filtrate was purified on RP-HPLC using a mixture of acetonitrile and water to give (S)-3-(2-chloro-3-fluorobenzyl)-1-(1-hydroxypent-4-en-2-yl)-1-methylurea (2.0 g, 77%) as a white solid, which was used without further purification. LRMS (M+H+) m/z 301.2.
Reaction SMILES: Br.[CH:2]([NH:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][NH:15][CH3:16])=[CH:9][CH:8]=1)([CH3:4])[CH3:3].O.C(=O)([O-])[O-].[K+].[K+].C(Cl)[Cl:26]>>[ClH:26].[CH:2]([NH:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][NH:15][CH3:16])=[CH:9][CH:8]=1)([CH3:4])[CH3:3]
Reactant: ClCCl
Agent: Br
Agent: CNNCc1ccc(C(=O)NC(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: O
Product: Cl

Procedure:
87.5 g. of 4-[(2-methyl-hydrazino)-methyl]-benzoic acid isopropylamide hydrobromide (obtained according to Example 3) were dissolved in 550 ml. of water. To this solution, there were added 1000 ml. of methylene chloride and, while cooling with ice and stirring under nitrogen atmosphere, 1200 g. of potassium carbonate portionwise. The methylene chloride layer was separated and the aqueous slurry extracted 3 times with 500 ml. of methylene chloride in a nitrogen atmosphere. The united methylene chloride extracts were concentrated in vacuo. The residue was dissolved under nitrogen in 100 ml. of methanol and treated, while cooling with ice, with 40 ml. of a 45% methanolic hydrochloric solution, which induces immediate crystallization. The crystals were filtered off and recrystallized from methanol, yielding 4-[(2-methyl-hydrazino)-methyl]-benzoic acid isopropylamide hydrochloride melting at 223°-226°.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4]([CH2:14][CH2:15][CH3:16])=[CH:5][C:6](=[O:13])[O:7]2.[N+](C1C=CC=CC=1)([O-])=O.[C:26](OC(=O)C)(=[O:28])[CH3:27].Cl>ClCCCl>[OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]([C:26](=[O:28])[CH3:27])=[C:8]2[C:3]=1[C:4]([CH2:14][CH2:15][CH3:16])=[CH:5][C:6](=[O:13])[O:7]2
Reactant: CCCc1cc(=O)oc2cc(O)cc(O)c12
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: O=[N+]([O-])c1ccccc1
Solvent: ClCCCl
Product: CCCc1cc(=O)oc2c(C(C)=O)c(O)cc(O)c12
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 12.2 %

Procedure:
To a mixture of 5,7-dihydroxy-4-propyl-coumarin (2.06 g 9.36 mmol) and anhydrous AICI3 (2.53 g, 18.7 mmol) was added 1,2-dichloroethane (120 mL). The resulting suspension was heated to 75° C. with vigorous stirring. After 30 minutes of stirring, a brown slurry was obtained, then nitrobenzene was introduced into the mixture resulting in an orange colored solution. A solution of anhydrous AICI3 (2.53 g, 18.7 mmol) and acetic anhydride (0.88 μL, 9.36 mmol) in 1,2-dichloroethane (40 mL) was added dropwise over a period of 1-2 hours. After addition, the mixture was allowed to stir at 75° C. for another two hours and subsequently cooled to room temperature. The resulting mixture was poured into ice and 1N HCl. The precipitated product was filtered and then taken into ethyl acetate and the aqueous solution was extracted throughly with ethyl acetate (3×100 mL). The combined ethyl acetate extracts were dried over Na2SO4 and the solvent was removed under reduced pressure. The resulting solid was purified by column chromatography (1:1 hexane/ethyl acetate) yielding 5,7-dihydroxy-8-acetyl-4-propyl-coumarin (0.30 g, 12%): mp. 221-224° C.; 1H NMR (DMSO-d6) δ 0.94 (t, 3H), 1.58 (sextet, 2H), 2.66 (s, 3H) 2.87 (t, 2H), 6.01 (s, 1H), 6.29 (s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:2]1.CCN(CC)CC.C(OCl)(C)(C)C.[CH3:36][C:37]([CH3:49])=[CH:38][CH2:39]B1C2CCCC1CCC2>C1COCC1>[CH3:36][C:37]([C:2]1[NH:1][C:9]2[C:4]([C:3]=1[CH2:10][CH2:11][N:12]1[C:13](=[O:22])[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]1=[O:21])=[CH:5][CH:6]=[CH:7][CH:8]=2)([CH3:49])[CH:38]=[CH2:39]
Reactant: CC(C)=CCB1C2CCCC1CCC2
Reactant: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccccc12
Agent: CC(C)(C)OCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(C)(C)c1[nH]c2ccccc2c1CCN1C(=O)c2ccccc2C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-[2-(1H-indol-3-yl)ethyl]-1H-isoindole-1,3(2H)-dione (3.77 g, 13.0 mmol) in dry THF (0.13 L) under argon was added NEt3 (1.84 mL, 13.0 mmol). This mixture was cooled to −78° C., and neat t-BuOCl (1.54 mL, 13.0 mmol) was added. The reaction mixture was stirred for 30 min at −78° C. A solution of 9-(3-methyl-2-butenyl)-9-bora-bicyclo[3.3.1]nonane (40 mmol) in hexanes was added. The reaction mixture was stirred for 6 h at −78° C. It was quenched with 1 M aq HCl, and permitted to warm to rt overnight. The reaction mixture was extracted with CH2Cl2. The CH2Cl2 extracts were dried, filtered, and concentrated to give an oil. The oil was purified by silica chromatography to give the title compound: TLC Rf=0.36 (CH2Cl2); MS (ESI+) m/z 381.2, 359.2; 1H NMR (300 MHz, CDCl3) δ 7.91 (1H), 7.88-7.69 (5H), 7.29 (1H), 7.10 (2H), 6.18 (1H), 5.25 (2H), 3.95 (2H), 3.16 (2H), 1.61 (6H).
Reaction SMILES: [C:1]([OH:15])(=[O:14])[CH2:2][CH2:3][NH:4][C:5](=[O:13])[C@@H:6]([C:8]([CH2:11][OH:12])([CH3:10])[CH3:9])[OH:7].CC1(C)C(O)C(=O)OC1.C=O.[C-]#N>>[C:1]([OH:15])(=[O:14])[CH2:2][CH2:3][NH:4][C:5](=[O:13])[C@H:6]([C:8]([CH2:11][OH:12])([CH3:10])[CH3:9])[OH:7]
Reactant: CC(C)(CO)[C@@H](O)C(=O)NCCC(=O)O
Agent: C=O
Agent: CC1(C)COC(=O)C1O
Agent: [C-]#N
Product: CC(C)(CO)[C@H](O)C(=O)NCCC(=O)O

Procedure:
Pantothenic acid can be prepared by chemical synthesis, or biotechnologically by fermentation of suitable microorganisms in suitable nutrient solutions. In the chemical synthesis, DL-pantolactone is an important precursor. It is prepared in a multi-stage process from formaldehyde, isobutylaldehyde and cyanide, and in further process steps, the racemic mixture is separated, D-pantolactone is subjected to a condensation reaction with β-alanine, and D-pantothenic acid is obtained in this way.
Reaction SMILES: C(OC([N:8](CC1C=CC(OC)=CC=1)[C:9]1[S:10][CH:11]=[C:12]([CH:14]([O:20][CH:21]([CH3:23])[CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1)=O)(C)(C)C>C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[S:10][CH:11]=[C:12]([CH:14]([O:20][CH:21]([CH3:22])[CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1
Reactant: CCOC(=O)C(OC(C)C)c1csc(N(Cc2ccc(OC)cc2)C(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(OC(C)C)c1csc(N)n1
Yield: 75 %

Procedure:
Ethyl 2-[2-[tert-butoxycarbonyl-[(4-methoxyphenyl)methyl]amino]thiazol-4-yl]-2-isopropoxy-acetate (0.55 g, 1.2 mmol) was dissolved in TFA (7 mL). The reaction mixture was refluxed for 5 hours. TFA was removed under reduced pressure. The residue was diluted with water (10 mL) and ethyl acetate (15 mL) and basified with sodium bicarbonate. The organic layer was separated and aqueous layer was again extracted with ethyl acetate (15 mL). The combined organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to obtain crude product which was purified by silica gel column chromatography using 20% ethyl acetate in hexane to provide ethyl 2-(2-aminothiazol-4-yl)-2-isopropoxy-acetate (0.22 g).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:18]([CH3:19])[C:17](=[O:20])[CH:16]3[CH2:21][CH2:22][CH2:23][N:15]3[CH2:14][C:13]=2[CH:24]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[N:18]([CH3:19])[C:17](=[O:20])[CH:16]3[CH2:21][CH2:22][CH2:23][N:15]3[CH2:14][C:13]=2[CH:24]=1
Reactant: [H][H]
Reactant: CN1C(=O)C2CCCN2Cc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CCO
Product: CN1C(=O)C2CCCN2Cc2cc(O)ccc21

Procedure:
A mixture of 6.44 g. of 7-benzyloxy-1,2,3,5,10,11a- hexahydro-10-methyl-11H-pyrrolo[2,1-c] [1,4]benzodiazepin-11- one, 200 ml. of ethanol and 1.0 g. of 10% palladium-on-carbon catalyst is shaken in a Parr hydrogenator under about 3 atmospheric of hydrogen pressure until the theoretical amount of hydrogen is absorbed. The catalyst is filtered off and the mother liquor is concentrated to remove the solvent. The residue is purified by partition chromatography on a diatomaceous earth column using a heptane/methyl cellosolve solvent system to yield pure 1,2,3,5,10,11a-hexahydro-7-hydroxy- 10-methyl-11H-pyrrolo[2,1-c] [1,4]benzodiazepin-11-one.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1.S(=O)(=O)(O)O.[OH-].[Na+]>C(O)(=O)C>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH:21]=[CH:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc(C(=O)C=Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C
Yield: 66.9 %

Procedure:
30 g of p-nitrobenzaldehyde was reacted with 30 g of p-methoxyacetophenone in 200 ml of acetic acid in the presence of 34 ml of sulfuric acid at room temperature for 1 day, and the reaction mixture was poured into 1 liter of ice-water. After neutralizing the mixture with 48 g of NaOH, cyrstals formed were collected by filtration, and recrystallized from acetoneacetonitrile (0.2 liter/1.3 liter) to obtain 37.6 g of the desired compound. m.p. 171°-173° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1N.N(OCCCCC)=O.[I:21]I>C(Cl)(Cl)Cl.C(Cl)Cl>[CH3:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[I:21]
Reactant: II
Reactant: Cc1cc(C(F)(F)F)ccc1N
Agent: CCCCCON=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)ccc1I

Procedure:
To a solution of 2-methyl-4-trifluoromethyl aniline (Step A) (2.2 g, 12.6 mmol) in chloroform (20 ml) at room temperature were added n-pentyl nitrite (2.2 g, 18.9 mmol) and iodine (6.38 g, 25.1 mmol). The mixture was heated to reflux for 1 h. The mixture was diluted with methylene chloride (50 ml). The solution was washed with saturated aqueous sodium thiosulfate, brine and dried over sodium sulfate. The title compound was obtained after flash column using hexane as the eluant.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.Br[CH2:7][CH2:8][CH2:9][CH2:10][Cl:11].[OH-].[Na+].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[Cl:11][CH2:10][CH2:9][CH2:8][CH2:7][N:1]1[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: ClCCCCBr
Reactant: c1c[nH]nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: ClCCCCn1ccnn1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Triazole (0.41 ml), 1-bromo-4-chlorobutane (0.93 ml), tetrabutylammonium iodide (10 mg), and a 3 M aqueous sodium hydroxide solution (1 ml) were dissolved in acetone (10 ml), and the solution was stirred at 50° C. for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography by development with chloroform to give an intermediate (1-(4-chlorobutyl)-1H-1,2,3-triazole, 314 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[CH3:9])=[CH:4][C:3]=1[F:12].C([Li])CCC.CN([CH:21]=[O:22])C>C1COCC1>[F:10][C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:21]=[O:22])=[C:3]([F:12])[CH:4]=1)([F:11])[CH3:9]
Reactant: CC(F)(F)c1ccc(Br)c(F)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(F)(F)c1ccc(C=O)c(F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
To a solution of 1-bromo-4-(1,1-difluoroethyl)-2-fluorobenzene (2.1 g, 8.79 mmol) in THF (30.3 mL) was added n-butyllithium (1.6M in hexanes, 5.60 mL) over ˜20 min at −78° C. The mixture was stirred for 30 min at −78° C. and DMF (1.02 mL, 13.18 mmol) was added dropwise over ˜4 min. Stirring was continued for 1 hr, the mixture was diluted/quenched with 1N aqueous HCl/MeOH (2/1, 15 mL) and allowed to warm to room temperature. The reaction mixture was diluted further with water (50 mL) and extracted with diethylether (2×50 mL). The combined organic layers were washed with 1N aqueous sodium hydroxide solution (50 mL) and brine (100 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography [SiO2, 40 g, heptane/ethyl acetate] providing 4-(1,1-difluoroethyl)-2-fluorobenzaldehyde (699 mg) as a dark yellow, volatile oil, which was contaminated with 1-bromo-4-(1,1-difluoroethyl)-2-fluorobenzene. 1H NMR (400 Mhz, CDCl3) δ ppm 10.40 (s, 1H), 7.95 (t, J=7.4 Hz, 1H), 7.39-7.47 (m, 2H), 7.35 (d, J=10.6 Hz, 1H), 1.94 (t, J=18.2 Hz, 4H) 7.73 (dd, J=7.2, 8.1 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[F:10][C:11]1([F:15])[CH2:14][NH:13][CH2:12]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:13]2[CH2:14][C:11]([F:15])([F:10])[CH2:12]2)=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: FC1(F)CNC1
Agent: Cl
Product: FC1(F)CN(c2ncc(Br)cn2)C1

Procedure:
The title compound was prepared following a procedure analogous to that described for Intermediate 27 using 5-bromo-2-chloropyrimidine and 3,3-difluoroazetidine hydrogen chloride salt. LC (method 5): tR=1.57 min; Mass spectrum (ESI+): m/z=250/252 (Br) [M+H]+.
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][C:29]=1[F:30])[C:12]([C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1)=[O:13].CO>C1COCC1.CCOC(C)=O>[Cl:8][C:9]1[CH:10]=[C:11]([C@H:12]([OH:13])[C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:15]2)[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2ccc(F)c(Cl)c2)C1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](O)c2ccc(F)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
To a solution of 1 M R-CBS-oxazaborolidine in toluene (13.8 mL, 13.8 mmol, 0.15 eq) and 10 M BH3 in THF (9.2 mL, 92.4 mmol, 1.0 eq) at −15° C. under nitrogen was added dropwise a solution of (R)-tert-butyl 3-(3-chloro-4-fluorobenzoyl)piperidine-1-carboxylate (31.5 g, 92.4 mmol) in anhydrous THF (300 mL). After addition, the reaction mixture was stirred for 1 hr at rt. Methanol (200 mL) was added dropwise carefully at 0° C. The solvent was removed under reduced pressure to provide the crude product. The crude product was dissolved in EtOAc till the alcohol was just dissolved (about 5 mL/1 g), the solvent was removed on the rotary evaporator until a few crystals appeared. To the above solution was added petroleum ether (about 300 mL) under stirring, which was allowed to stir at rt for 2 hr and then filtered, the crystals were washed with petroleum ether and re-crystallized 6 times to afford the (R)-tert-butyl 3-((R)-(3-chloro-4-fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (10 g, 32%, 93% e.e.). 1H NMR (CD3OD, 400 MHZ) δ 7.44 (d, 1H), 7.25 (d, 1H), 7.20 (t, 1H), 4.34 (d, 1H), 4.20 (s, 1H), 3.93 (d, 1H), 2.68 (m, 2H), 1.62 (m, 2H), 1.41 (s, 9H), 1.32 (m, 2H), 1.21 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[CH:9][C:10](=O)[C:3]=12.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl>C(O)C>[ClH:24].[NH:22]([N:23]=[C:10]1[C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:9]1)[C:19]([NH2:21])=[NH:20]
Reactant: N=C(N)NN
Reactant: Cc1ccccc1C1=CC(=O)c2c(C)ccnc21
Agent: Cl
Solvent: CCO
Product: Cc1ccccc1C1=CC(=NNC(=N)N)c2c(C)ccnc21
Yield: 71.8 %

Procedure:
A mixture of 4-methyl-7-(2-methylphenyl)-5-oxo-cyclopenta[2,1-b]pyridine (48 mg), aminoguanidine hydrochloride (25 mg) and concentrated hydrochloric acid (40 mg) in ethanol (1 ml) was refluxed for 2 hours. The reaction solution was cooled, and precipitated crystals were filtered, washed with ethanol and dried to give 5-guanidinoimino-4-methyl-7-(2-methylphenyl)cyclopenta[2,1-b]pyridine hydrochloride (Compound 91) (48 mg) as yellow crystals.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[F:25])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:25][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:15]=1[O:14][CH2:13][CH:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc(OCC2CCCN2C(=O)OC(C)(C)C)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(OCC2CCCN2)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.5 %

Procedure:
To a stirred solution of methyl 4-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl ]methoxy-3-fluorobenzoate (323.0 mg, 0.914 mmol) in CH2Cl2 (6.5 mL) was added TFA (1.3 mL) at 0° C., and the mixture was stirred 1.5 hr at room temp. The solvent was removed under a reduced pressure and the residue was made basic by the addition of 1 N NaOH. The mixture was extracted with CHCl3. The extract was washed with brine, dried over Na2SO4, and concentrated under a reduced pressure to afford 174.8 mg (76%) methyl 3-fluoro4-(2-pyrrolidinyl)methoxybenzoate as a brownish oil. 1H-NMR (400 MHz, CDCl3) δ 1.54–1.63 (m, 1H), 1.76–2.02 (m, 3H), 2.93–3.07 (m, 2H), 3.57 (ddd, J=4.9, 6.9, 14.3 Hz, 1H), 3.89 (s, 3H), 3.97 (dd, J=6.8, 9.3 Hz, 1H), 4.04 (dd, J=5.0, 8.8 Hz, 1H), 6.98 (t, J=17.6 Hz, 1H), 7.73 (dd, J=2.0, 11.7 Hz, 1H), 7.78 (dt, J=2.0, 8.8 Hz, 1H); MS (FAB) m/z 253 (M++1).
Reaction SMILES: C([O:3][P:4]([CH:9]=[CH:10][CH:11]1[CH:15]([OH:16])[CH:14]([OH:17])[CH:13]([N:18]2[CH:26]=[N:25][C:24]3[C:23](=[O:27])[NH:22][C:21]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])=[N:20][C:19]2=3)[O:12]1)(=[O:8])[O:5]CC)C.C(NC1NC(=O)C2N=CN(C3OC(C=CP(O)(O)=O)C(OC(=O)C4C=CC=CC=4)C3OC)C=2N=1)(=O)C(C)C>>[OH:16][CH:15]1[CH:14]([OH:17])[CH:13]([N:18]2[CH:26]=[N:25][C:24]3[C:23](=[O:27])[NH:22][C:21]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])=[N:20][C:19]2=3)[O:12][CH:11]1[CH:10]=[CH:9][P:4](=[O:3])([OH:5])[OH:8]
Reactant: CCOP(=O)(C=CC1OC(n2cnc3c(=O)[nH]c(NC(=O)C(C)C)nc32)C(O)C1O)OCC
Agent: COC1C(OC(=O)c2ccccc2)C(C=CP(=O)(O)O)OC1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21
Product: CC(C)C(=O)Nc1nc2c(ncn2C2OC(C=CP(=O)(O)O)C(O)C2O)c(=O)[nH]1
Yield: 66.6 %

Procedure:
Compound 18.5 (400 mg, 67% yield) was synthesized from compound 18.4 (680 mg, 1.4 mmol) using the procedure described for the preparation of compound 16.8.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([CH2:11][NH2:12])[N:10]=[C:4]2[CH:3]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([CH2:11][NH:12][S:21]([CH3:20])(=[O:23])=[O:22])[N:10]=[C:4]2[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCc1cn2ccc(Br)cc2n1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCc1cn2ccc(Br)cc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.2 %

Procedure:
To a stirred solution of C-(7-Bromo-imidazo[1,2-a]pyridin-2-yl)-methylamine (310 mg, 1.371 mmol) in CH2Cl2 (5 mL) is added triethyl amine (0.23 mL), 1.64 mmol) followed by methane sulfonyl chloride (0.112 mL, 1.371 mmol) at 0° C. then stirred at room temperature for 2 hours. The reaction mixture is diluted with water and extracted with CH2Cl2. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by column chromatography eluting in 2% methanol:CH2Cl2 to afford the title compound (130 mg). 1H-NMR (400 MHz, DMSO-d6) δ: 2.91 (s, 3H), 4.25 (d, J=6.08 Hz, 2H), 7.04-7.06 (dd, J1=1.88 Hz, J2=7.24 Hz, 1H), 7.58 (t, J=6.12 Hz, 1H), 7.81 (d, J=0.88 Hz, 1H), 7.89 (s, 1H), 8.51 (d, J=7.04 Hz, 1H). LC-MS (m/z): [M+H]=306.0.