Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15](=[O:21])[CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH2:10][CH2:9]2)=[C:4]([F:28])[CH:3]=1.[N:29]([C:32]1[C:33]([CH3:38])=[N:34][O:35][C:36]=1[CH3:37])=[C:30]=[O:31]>ClCCCl>[CH3:38][C:33]1[C:32]([NH:29][C:30](=[O:31])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][CH:11]([N:14]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:15](=[O:21])[CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH2:10][CH2:9]3)=[C:4]([F:28])[CH:3]=2)=[C:36]([CH3:37])[O:35][N:34]=1
Reactant: CCC(CC)C(=O)N(c1ccccc1)C1CCN(c2ccc(N)cc2F)CC1
Reactant: Cc1noc(C)c1N=C=O
Solvent: ClCCCl
Product: CCC(CC)C(=O)N(c1ccccc1)C1CCN(c2ccc(NC(=O)Nc3c(C)noc3C)cc2F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.8 %

Procedure:
A mixture of N-[1-(4-amino-2-fluoro-phenyl)-piperidin-4-yl]-2-ethyl-N-phenyl-butyramide (0.30 mmol) and 4-isocyanato-3,5-dimethyl-isoxazole (1.0 mmol) in DCE (10 mL) was stirred at rt for 16 h. The mixture was concentrated and the residue was purified by PTLC to give the title compound (56 mg, 36%). MS (ESI): mass calcd. for C29H36FN5O3, 521.28. m/z found, 522.4 [M+H]+. 1H NMR (CDCl3): 8.00-7.82 (br s, NH), 7.55-7.41 (m, 4H), 7.20-7.11 (m, 2H), 7.10-6.95 (br s, NH), 6.94-6.75 (m, 2H), 4.90-4.72 (m, 1H), 3.40-3.22 (m, 2H), 2.66-2.57 (m, 2H), 2.33 (s, 3H), 2.24 (s, 3H), 2.09-2.00 (m, 1H), 1.94-1.85 (m, 2H).1.70-1.58 (m, 2H), 1.57-1.45 (m, 2H), 1.42-1.30 (m, 2H), 0.85 (t, J=7.2, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18]CC3C=CC=CC=3)[CH:11]=2)=[CH:4][N:3]=1.[ClH:26].[H][H]>CO.[Pd]>[ClH:26].[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([OH:18])[CH:11]=2)=[CH:4][N:3]=1
Reactant: COc1ccc(Cc2cnc(N)nc2N)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc(Cc2cnc(N)nc2N)cc1O

Procedure:
A solution of 55 g (0.15 mole) of 2,4-diamino-5-(3-benzyloxy-4-methoxybenzyl)pyrimidine from the preceding step in 2500 ml of methanol and 20 ml of concentrated hydrochloric acid is hydrogenated at about 2.5 to 3.0 atm. in the presence of 4 g of 10% Palladium-on-charcoal catalyst. After the uptake of hydrogen has stopped (3.5 hr.) the catalyst is filtered and the filtrate concentrated in vacuo to 250 ml. The crystalline product weighs 41.5 g (90%), m.p. 230°-32°.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:16]/[CH:17]=[CH:18]/[C:19]#[C:20][C:21]([CH3:24])([CH3:23])[CH3:22]>C1COCC1.CN(C=O)C>[CH3:22][C:21]([CH3:24])([CH3:23])[C:20]#[C:19]/[CH:18]=[CH:17]/[CH2:16][O:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)C#C/C=C/CBr
Reactant: OCc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)C#C/C=C/COCc1cccc2ccccc12
Reaction time: 1 h

Procedure:
5 g of 1-(Hydroxymethyl)naphthalin are in THF are treated at room temperature with 900 mg of 80% NaH (dissolved in mineral oil) and stirred until the evolution of gas ceases (ca. 1 hr.). A solution of 6.36 g of (E)-1-bromo-6,6-di-methyl-2-hepten-4-ine in DMF are added dropwise and the reaction mixture stirred overnight at room temperature.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([CH:18]=O)=[C:14]([OH:20])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+]>C1COCC1>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([OH:20])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2ccc(C=O)c(O)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc2oc(C(=O)OC(C)(C)C)c(C)c2c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.1 %

Procedure:
To 5-formyl-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester (430 mg, 1.56 mmol) was added 8 mL of THF, and sodium cyanoborohydride (117 mg, 1.87 mmol) was added in one portion. The solution was stirred at room temperature for 1 h and then placed in a 65° C. oil bath overnight. The solvent was removed under vacuum and water was added. The mixture was extracted with ethyl acetate. Removal of the solvent gave the crude product, which was purified by column chromatography to give 70 mg of 4-hydroxy-3,5-dimethyl-benzofuran-2-carboxylic acid tert-butyl ester as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[N:13](C(=O)C)[C:12]3[CH:24]=[CH:25][CH:26]=[CH:27][C:11]=3[S:10]2)=[CH:5][CH:4]=1.C(NCC)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[NH:13][C:12]3[CH:24]=[CH:25][CH:26]=[CH:27][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2Sc3ccccc3N(C(C)=O)C(=O)C2OC(C)=O)cc1
Solvent: ClC(Cl)Cl
Solvent: CCNCC
Product: COc1ccc(C2Sc3ccccc3NC(=O)C2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
7-(1). 2-(4'-Methoxyphenyl)-3-acetoxy-5-acetyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one [Compound (VII)] (1.93 g) and diethylamine (0.44 g) are added to chloroform (20 ml), and the mixture is stirred at room temperature for one hour. After distilling off chloroform, water is added to the residue, and the precipitated crystals are separated by filtration, washed with water and dried to give the title compound (II) (1.63 g, 94.8%), m.p. 198°-200° C.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].FC(F)(F)C1C=C(O)C=CC=1.[Cl:23][C:24]1[CH:25]=[C:26]([OH:31])[CH:27]=[CH:28][C:29]=1[F:30]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][C:29]=1[F:30])[O:31][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Oc1ccc(F)c(Cl)c1
Reactant: O=C(O)c1cc(F)cnc1Cl
Agent: Oc1cccc(C(F)(F)F)c1
Product: O=C(O)c1cc(F)cnc1Oc1ccc(F)c(Cl)c1

Procedure:
2-(3-Chloro-4-fluoro-phenoxy)-5-fluoro-nicotinic acid was prepared in analogy to Example 1, Step 1, replacing 2-chloro-nicotinic acid with 2-chloro-5-fluoro-nicotinic acid ([CAS RN 38186-88-8]) and 3-trifluoromethyl-phenol with 3-chloro-4-fluoro-phenol ([CAS RN 2613-23-2]). 1H NMR (400 MHz, DMSO): δ7.16-7.19 (m, 1H), 7.44-7.48 (m, 2H), 8.19 (dd, J=8.1 Hz, J=3.2 Hz, 1H), 8.35 (d, J=3.2 Hz, 1H), 13.60 (s, 1H). 19F NMR (376.5 MHz, DMSO): −121.6, −134.8. MS (ISN): 283.8 [M−H]−.
Reaction SMILES: [CH2:1]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[Na+:13].CC(O)C.[C:18](=[S:20])=[S:19]>>[CH2:7]([N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:18](=[S:19])[S-:20])[CH2:8][CH2:9][CH2:10][CH3:11].[Na+:13]
Reactant: S=C=S
Reactant: CCCCCNCCCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCCCCN(CCCCC)C(=S)[S-]

Procedure:
To a 250 mL 3-neck round bottom reaction flask equipped with an overhead stirrer, a thermocouple probe, a reflux condenser, a Claisen adapter, and a 25 mL addition funnel, 30.0 g (0.19 mol) of diamyl amine, 15.3 g of a 50 weight percent NaOH solution (0.19 mol NaOH) and 100 mL reagent 2-propanol was added. 12.5 mL (0.21 mol) carbon disulfide was charged to the addition funnel. Carbon disulfide was added over a half-hour period. The reaction temperature was maintained at 25°-30° C. The product was post-reacted at 25° C. for 1 hour.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[C:12]1(/[CH:18]=[CH:19]\[C:20](O)=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:20](=[O:21])/[CH:19]=[CH:18]\[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:4]2
Reactant: O=C(O)/C=C\c1ccccc1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(/C=C\c1ccccc1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride, and Z-3-phenylpropenoic acid; MS (ES+) 257 (MH+).
Reaction SMILES: S(Cl)(C)(=O)=O.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[CH2:20]O)=[CH:11][CH:10]=1)([O-:8])=[O:7].C(N(CC)CC)C.[Cl-:29].[Na+]>CN(C=O)C>[Cl:29][CH2:20][CH:16]1[CH2:17][CH2:18][CH2:19][N:15]1[C:12]1[CH:13]=[CH:14][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(N2CCCC2CO)cc1
Reactant: [Cl-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CCCC2CCl)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 882.2 %

Procedure:
27.9 ml (0.36 mol) of mesyl chloride were added dropwise to a solution of [1-(4-nitrophenyl)pyrrolidin-2-yl]methanol (66.7 g, 0.03 mol), 300 ml of anhydrous DMF and 58.5 ml (0.42 mol) of anhydrous triethylamine, cooled in an ice bath. The temperature was allowed to rise to 20° C. over one hour with stirring. 35.2 g (0.6 mol) of sodium chloride were added and the mixture was heated at 100° C. for one hour. The reaction medium was poured into 1.4 l of ice-water. The precipitate was filtered off, washed with water, dried and recrystallized from isopropanol. 63.7 g of a yellow powder (1) were thus obtained.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>C(#N)C>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[N:11]=2)[C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8]1)[CH3:13]
Reactant: C1CCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCCC3)nc21
Yield: 88.6 %

Procedure:
A mixture containing 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (1.0 g), pyrrolidine (1.31 g), and acetonitrile (80 ml) was heated under reflux for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure. The residue was mixed with 5% hydrochloric acid (25 ml) and the mixture was heated on a steam-bath for several minutes and then cooled. The resulting precipitate was collected, washed with water, and recrystallized from chloroform-ethyl acetate to give 1.0 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-pyrrolidinyl)-1,8-naphthyridine-3-carboxylic acid, m.p. 299°-300° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9])[CH3:2].[H-].[Na+].Cl[C:13]1[C:17]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[N:16][S:15][N:14]=1.O>O1CCCC1>[CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][C:13]1[C:17]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[N:16][S:15][N:14]=1)[CH3:2]
Reactant: CCOCCOCCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOCCOCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(2-ethoxyethoxy)ethanol (1.21 g, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [CH:1]([S:4]([CH2:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[N:9]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:34]>O1CCOCC1>[CH:1]([S:4]([CH2:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:33](=[O:34])[O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:24][CH:25]=2)[N:9]=1)(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)Cc1cc(N2CCOCC2)nc(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)Cc1cc(N2CCOCC2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
(4-{4-[(Isopropylsulfonyl)methyl]-6-morpholin-4-ylpyrimidin-2-yl}phenyl)amine (1.5 g, 3.98 mmol) was dissolved in dioxane (10 mL). Sodium bicarbonate (503 mg, 5.98 mmol) was added, followed by phenyl chloroformate (0.502 mL, 3.98 mmol) and the reaction stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the resultant oil partitioned between 10 mL DCM and 10 mL water. The organic phase was dried over magnesium sulphate, filtered and concentrated in vacuo. The cream solid obtained was chromatographed on silica, eluting with 0-50% ethyl acetate in DCM, to give the desired material as a white solid (1.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][N:17]=1)[C:5]([O:7]C1C=CC=C(C)C=1)=O.[C:18]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:19]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)=O.Cl>C(OCC)(=O)C.O>[C:18]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:19]([S:24]([NH:27][C:5](=[O:7])[C:4]2[CH:15]=[CH:16][N:17]=[C:2]([Cl:1])[CH:3]=2)(=[O:26])=[O:25])=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cccc(OC(=O)c2ccnc(Cl)c2)c1
Reactant: NS(=O)(=O)c1ccccc1-c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NS(=O)(=O)c1ccccc1-c1ccccc1)c1ccnc(Cl)c1
Yield: 42.9 %

Procedure:
2.4 g (0.01 mol ) of 3-methylphenyl 2-chloroisonicotinate, 2.3 g (0.01 mol) of 2-biphenylsulfonamide and 1.4 g (0.01 mol) of anhydrous potassium carbonate were melted under agitation at 120° to 130° C. When the generation of gaseous carbon dioxide came to an end after 30 min to 1 hr., 50 ml of water were added and, then concentrated hydrochloric acid dropwise added to acidify. The organic layer obtained by extraction with ethyl acetate was dried and then concentrated to precipitate crude crystals, which were recrystallized to 1.6 g (yield: 42.9%) of N-(2-biphenylsulfonyl)-2-chloroisonicotinamide as white crystals.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Br:8][C:9]1[CH:36]=[CH:35][C:12]([CH2:13][N:14]2[CH:22]=[C:21]3[C:16]([N:17](CC4C=CC(OC)=CC=4)[C:18](=[O:25])[N:19]([CH3:24])[C:20]3=[O:23])=[N:15]2)=[CH:11][CH:10]=1.C(S(O)(=O)=O)(F)(F)F>C(Cl)Cl>[Br:8][C:9]1[CH:36]=[CH:35][C:12]([CH2:13][N:14]2[CH:22]=[C:21]3[C:16]([NH:17][C:18](=[O:25])[N:19]([CH3:24])[C:20]3=[O:23])=[N:15]2)=[CH:11][CH:10]=1
Reactant: COc1ccc(Cn2c(=O)n(C)c(=O)c3cn(Cc4ccc(Br)cc4)nc32)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(=O)[nH]c2nn(Cc3ccc(Br)cc3)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
TFA (500 mL) is slowly added into a suspension of 2-(4-bromobenzyl)-7-(4-methoxybenzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (226 g, 496 mmol) in methylene chloride (320 mL), and then TFMSA (160 mL) is added slowly. The reaction mixture is stirred at room temperature overnight. Solvents are removed under reduced pressure. The obtained residue is treated with water (4 L) and ethyl acetate (2 L), stirred at room temperature for 30 min, and then filtered. The filter cake is thoroughly washed with water to remove residual acids, followed by washing with ethyl acetate. The obtained white solids are dried in a heated oven to give 159 g of product (yield: 96%). MS (ESI) m/z 335.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)=[N:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.ClC(OCC)=O.[N-:34]=[N+:35]=[N-:36].[Na+]>CC(C)=O.O>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([N:34]=[N+:35]=[N-:36])=[O:17])=[CH:14][CH:13]=2)=[N:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCc1ccc(-c2ccc(C(=O)O)cc2)nc1
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: CCCCCc1ccc(-c2ccc(C(=O)N=[N+]=[N-])cc2)nc1
Yield: 93.7 %

Procedure:
A solution of 2.1 g of p-(5-pentyl-2-pyridyl)benzoic acid in 80 ml of acetone was cooled to 2° C. while stirring and gassing with nitrogen and treated dropwise within 10 minutes with a solution of 2.16 ml of triethylamine in 15 ml of acetone. The reaction mixture was then treated dropwise at 1°-2° C. within 10 minutes with a solution of 1.86 ml of ethyl chloroformate in 8 ml of acetone and stirred at this temperature for a further 30 minutes. Subsequently, a solution of 1.38 g of sodium azide in 8 ml of water was added dropwise to the reaction mixture at 1°-2° C. within 10 minutes and the resulting mixture was stirred for a further 1 hour in an ice-bath. Thereafter, the reaction mixture was poured into 200 ml of water and extracted with diethyl ether. The organic phase was washed with water, dried over sodium sulphate, filtered and freed from solvent. Purification of the resulting light yellowish crystals (2.1 g) by chromatography on 120 g of silica gel with 1 l of methylene chloride gave 2.15 g of p-(5-pentyl-2-pyridyl)benzoic acid azide as a light yellowish paste.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:23])[C:5]([N:8]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:9]([C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[N:6][CH:7]=1.[O:24]1[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]1.[H-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:23])[C:5]([N:8]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:31][CH2:30][CH:27]3[CH2:28][CH2:29][O:24][CH2:25][CH2:26]3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[N:6][CH:7]=1
Reactant: Cc1cc(Cl)cnc1N(CC(C)C)S(=O)(=O)c1ccc(F)cc1
Reactant: OCC1CCOCC1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(Cl)cnc1N(CC(C)C)S(=O)(=O)c1ccc(OCC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
N-(5-chloro-3-methylpyridin-2-yl)-4-fluoro-N-isobutylbenzenesulfonamide (200.5 mg, 0.562 mmol) was dissolved in dimethyl sulfoxide DMSO (2 mL) and to this solution was added (tetrahydro-2H-pyran-4-yl)methanol (98 mg, 0.84 mmol) and sodium hydride (33 mg, 0.84 mmol, 60% wt in mineral oil). The reaction was left to stir overnight at room temperature, under nitrogen. The reaction was concentrated under a stream of nitrogen, then the crude product was extracted to the organic phase of an aqueous work up between ethyl acetate and water. The organic phase was passed through a hydrophobic frit and concentrated in vacuo to give the title compound (224 mg). LCMS (2 min, formic) Rt 1.42 min, m/z (ES+) 453 (M+H).
Reaction SMILES: [Br:1][C:2]12[S:10][CH:3]1[CH:4]=[CH:5][C:6]1([Cl:9])S[CH:7]12.[BH4-].[Na+].CO.Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[SH:10]
Reactant: ClC12C=CC3SC3(Br)C1S2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Sc1ccc(Cl)cc1Br
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-bromo-4-chlorobenzene disulfide (3.8 g, 8.5 mmol) in THF (30 mL) was treated with NaBH4 (0.83 g, 22.0 mmol). The mixture was refluxed for a while and treated with MeOH (2 mL); heating was resumed for 0.5 hours. Mixture was cooled to 23° C., acidified with HCl (3N) and extracted with Et2O. The Et2O extracts were dried over MgSO4, filtered, and the filtrate was concentrated in vacuo to afford the title compound which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C@@H:10]1[N:14]2[CH:15]=[N:16][CH:17]=[C:13]2[C:12]([OH:31])([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C3CCCCO3)[CH:19]=2)[CH2:11]1)[C:5]#[N:6].Cl.CCOCC>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C@@H:10]1[N:14]2[CH:15]=[N:16][CH:17]=[C:13]2[C@@:12]([OH:31])([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=2)[CH2:11]1)[C:5]#[N:6]
Reactant: N#Cc1ccc([C@H]2CC(O)(c3cccc(OC4CCCCO4)c3)c3cncn32)c(F)c1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: N#Cc1ccc([C@H]2C[C@](O)(c3cccc(O)c3)c3cncn32)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.1 %

Procedure:
To a solution of 3-fluoro-4-((5R)-7-hydroxy-7-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile (1.87 g, 4.46 mmol) in anhydrous MeOH (372 ml) was added a 2M solution of hydrochloric acid in ether (9.59 ml, 19.18 mmol) at room temperature. The crude was stirred at room temperature for 2 hrs. The crude was concentrated and quenched with saturated NaHCO3. The crude was diluted in CH2Cl2 and the organic layer was washed with water, brine, dried over MgSO4, filtered, and concentrated. The crude was purified via HPLC 20%-100% MeCN/H2O to provide 510 mg of the entitled product as the major diastereomer. MS 336.0 (M+H); LCMS condition A, retention time 0.96 min. 1H NMR (400 MHz, CDCl3) δ ppm 2.90 (d, 1H), 3.22 (dd, 1H), 5.65 (d, 1H), 6.65-6.72 (m, 2H), 6.90 (s, 1H), 7.02-7.09 (m, 2H), 7.15-7.21 (m, 2H), 7.24 (s, 1H), 7.32 (dd, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[C:16]([O:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[C:17]([CH3:25])[CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.O1CCOCC1>[CH3:33][O:32][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][O:26][C:16]1[C:15]([N:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]2)=[C:24]2[C:19]([CH:20]=[CH:21][CH:22]=[N:23]2)=[CH:18][C:17]=1[CH3:25]
Reactant: COC(=O)CCCOc1c(C)cc2cccnc2c1N1CCCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)CCCOc1c(C)cc2cccnc2c1N1CCCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
The product from step 1 was dissolved in MeOH (18.8 mL) and HCl was added (4M in dioxane, 18.8 mL, 75.2 mmol). The reaction was stirred at room temperature for 2 h, then concentrated. CH2Cl2 was added and this solution was washed with sat. aq. NaHCO3, then brine. The organic was dried over MgSO4, filtered, and concentrated to give the product (1.30 g, 96% yield) as an oil.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C@H:32]([C:41](C2C=CC=CC=2)(C2C=CC=CC=2)[O:42][SiH2]C(C)(C)C)[CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[C:28](=[O:60])[C@@H:27]1[CH3:61])=[O:25])([CH3:22])([CH3:21])[CH3:20]>O1CCCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C@H:32]([CH2:41][OH:42])[CH2:33][CH2:34][N:35]2[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]2)[C:28](=[O:60])[C@@H:27]1[CH3:61])=[O:25])([CH3:20])([CH3:22])[CH3:21]
Reactant: C[C@H]1C(=O)N([C@@H](CCN2CCCCC2)C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)CCN1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H]1C(=O)N([C@H](CO)CCN2CCCCC2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
Tetrabutylammonium fluoride solution (1 M in tetrahydrofuran, 0.14 mL, 0.14 mmol) was added at room temperature to a solution of (S)-4-[(S)-1-(tert-butyl-diphenyl-silanyloxymethyl)-3-piperidin-1-yl-propyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (75 mg, 0.12 mmol) in tetrahydrofuran (1 mL), then after 16 h another portion of tetrabutylammonium fluoride solution (1 M in tetrahydrofuran, 20 μL, 20 μmol) was added. The reaction mixture was stirred at room temperature for another 60 min, then evaporated. Chromatography (SiO2; dichloromethane dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (42 mg, 92%). Colorless gum, MS (ISP)=370.3 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([O:16][CH3:17])[CH:4]=1.[C-:18]#[N:19].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[C:18]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([O:16][CH3:17])[CH:4]=1)#[N:19]
Reactant: [C-]#N
Reactant: COc1cc(CCl)ccc1Sc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CC#N)ccc1Sc1ccccc1
Temperature: 30 °C
Reaction time: 14 h

Procedure:
Thus obtained 1-chloromethyl-3-methoxy-4-phenylthiobenzene was dissolved in 200 ml of N,N-dimethylformamide, and 7.34 g of finely ground sodium cyanide was added and stirred for 14 hours at 30° C. To the reaction mixture, 300 ml of saturated brine and 300 ml of ice water were added, and the mixture was extracted with ethyl acetate (300 ml×3). The extract was washed with saturated brine (200 ml×3), and dried with anhydrous sodium sulfate, and 1-cyanomethyl-3-methoxy-4-phenylthiobenzene was obtained.