Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C@H:18]2[CH2:22][CH2:21][C@H:20]([C:23]3[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=3)[O:19]2)[CH:5]=[C:6]([S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])[C:7]=1[O:8][CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:42][CH2:43][CH2:44][N:45]1[C:49](=[O:50])[C:48]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:47]2[C:46]1=[O:55]>CC(C)=O>[C:46]1(=[O:55])[N:45]([CH2:44][CH2:43][CH2:42][O:1][C:2]2[CH:3]=[C:4]([C@H:18]3[CH2:22][CH2:21][C@H:20]([C:23]4[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=4)[O:19]3)[CH:5]=[C:6]([S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])[C:7]=2[O:8][CH2:9][CH2:10][CH3:11])[C:49](=[O:50])[C:48]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:47]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1c(OCCCN2C(=O)c3ccccc3C2=O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CCC
Temperature: 25 °C
Yield: 64 %

Procedure:
To a solution of (±)-trans-2-(3-hydroxy-4-propoxy-5-propylsulfonylphenyl)-5-(3,4,5-trimethoxyphenyl) tetrahydrofuran (2.80 g, 5.66 mol) in acetone (40 ml) were added potassium carbonate (1.01 g, 7.36 mol) and N-(3-bromopropyl) pthalimide (2.06 g, 8.50 mmol). The reaction mixture was refluxed for 16 h. The reaction mixture was cooled to room temperature and acetone was removed, water was added and extracted with ethyl acetate (120 ml), dried (Na2SO4), filtered and concentrated. The crude product was purified on silica gel column using Ethyl acetate:light petroleum (2:5) to give (±)-trans-2-[3-(3-pthalimidopropoxy)-4-propoxy-5-propylsulfonyl phenyl]-5-(3,4,5-trimethoxyphenyl) tetrahydrofuran as solid (3.71 g, 94%). TLC: Ethyl acetate:light petroleum (2:1), Rf=0.5 ; m.p. 195-196° C. 1H NMR (CDCl3, 200 MHz): δ 1.05 (t, J=7.14 Hz, 3H), 1.08 (t, J=6.66 Hz, 3H), 1.68-2.06 (m, 6H), 2.2-2.3 (m, 2H), 2.4-2.55 (m, 2H), 3.35 (m, 2H), 3.83 (s, 3H), 3.9 (s, 6H), 3.95 (t, J=6.6 Hz, 2H), 4.15 (t, J=6.13 Hz, 4H), 5.2 (m, 2H), 6.58 (s, 2H), 7.23 (d, J=1.5 Hz, 1H), 7.45 (d, J=1.51 Hz, 1H), 7.7 (m, 2H), 7.85 (m, 2H); IR (neat): 3010, 2975, 1775, 1715, 1600, 1490, 1380 cm−1 FAB Mass: 681(M+); HRMS: calculated. 681.260769; found. 681.265005.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:32]=[CH:31][C:15]3[N:16]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:18][C:14]=3[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:35][O:36][C:37](=[O:40])[CH2:38]Br.O>CN(C)C=O>[CH3:35][O:36][C:37](=[O:40])[CH2:38][N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[C:12]1[CH:32]=[CH:31][C:15]2[N:16]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:18][C:14]=2[CH:13]=1
Reactant: O=S(=O)(Nc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)c1ccc(Cl)cc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN(c1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
100 mg of 4-chloro-N-(1,2-diphenyl-1H-benzimidazol-5-yl)benzenesulfonamide was suspended in 0.5 ml of N,N-dimethylformamide, mixed with 8 mg of sodium hydride and stirred for 30 minutes at 20° C. 50 mg of bromoacetic acid methyl ester was added, allowed to stir for 15 hours, mixed with water, extracted three times with ethyl acetate, the extracts were dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was chromatographed on silica gel.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:28][CH3:29])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH:36]1(N)C[CH2:37]1>C1COCC1>[C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:28][CH:29]5[CH2:37][CH2:36]5)[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CNc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4)c(F)cc3C)c(=O)n(C)c2n1
Reactant: NC1CC1
Solvent: C1CCOC1
Product: Cc1cc(F)c(NC(=O)Nc2cnn(C(C)(C)C)c2)cc1-c1cc2cnc(NC3CC3)nc2n(C)c1=O
Yield: 63.2 %

Procedure:
Using general method E, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea from Example 109 (0.081 g, 0.16 mmol) and cyclopropanamine (0.027 g, 0.48 mmol) were combined in THF (1 mL) to provide 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(5-(2-(cyclopropylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluoro-4-methylphenyl)urea as a white solid (0.051 g, 64% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.64 (s, 1H), 8.60 (brs, 1H), 8.40 (d, J=1.6 Hz, 1H), 8.06-8.04 (m, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.77 (s, 1H), 7.66 (s, 1H), 7.36 (s, 1H), 7.10 (d, J=12.4 Hz, 1H), 3.61-3.54 (m, 3H), 2.78-2.83 (m, 1H), 2.05 (s, 3H), 1.45 (s, 9H), 0.725 (brs, 2H), 0.55-0.53 (m, 2H); (ESI) m/z: 505.2 (M+H+).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C@H:14]([CH2:26][O:27][CH3:28])[CH2:15][CH2:16][N:17]2[CH2:24][CH2:23][C:20]3([CH2:22][CH2:21]3)[C@H:19]([OH:25])[CH2:18]2)[C:10](=[O:29])[C@@H:9]1[CH3:30])=[O:7])(C)(C)C.Cl.[Cl:32][C:33]1[CH:34]=[C:35]([N:40]=C=O)[CH:36]=[CH:37][C:38]=1[F:39]>O1CCOCC1>[Cl:32][C:33]1[CH:34]=[C:35]([NH:40][C:6]([N:8]2[CH2:13][CH2:12][N:11]([C@H:14]([CH2:26][O:27][CH3:28])[CH2:15][CH2:16][N:17]3[CH2:24][CH2:23][C:20]4([CH2:22][CH2:21]4)[C@H:19]([OH:25])[CH2:18]3)[C:10](=[O:29])[C@@H:9]2[CH3:30])=[O:7])[CH:36]=[CH:37][C:38]=1[F:39]
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Reactant: COC[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: COC[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(C(=O)Nc2ccc(F)c(Cl)c2)[C@@H](C)C1=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 95.1 %

Procedure:
A solution of (S)-4-[(S)-3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-1-methoxymethyl-propyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (intermediate 23; 47 mg, 0.11 mmol) in 1,4-dioxane (0.5 mL) was cooled to 0° C. and treated with hydrogen chloride solution (4 M in 1,4-dioxane, 0.28 mL, 1.1 mmol) The ice bath was removed, the reaction mixture stirred for 4 h, then 4-methylmorpholine (112 mg, 1.1 l mmol) and N,N-dimethylformamide (1 mL) were added. To this reaction mixture was added 3-chloro-4-fluorophenyl isocyanate (19 mg 0.11 mmol), then after 16 h the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was saturated with sodium chloride and extracted with ethyl acetate. The combined organic phases were dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; dichloromethane/methanol/25% aq. ammonia solution gradient 98:2:0.25 to 90:10:0.25) furnished the title compound (52 mg, 95%). Light yellow gum, MS (ISP)=497.3 (M+H)+.
Reaction SMILES: [N:1]1([C:8]2[N:13]=[C:12](Cl)[N:11]=[C:10]([NH:15][C@@H:16]3[CH2:21][CH2:20][C@H:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]3)[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][NH2:26].Cl>CC#N.O>[N:1]1([C:8]2[N:13]=[C:12]([NH:26][CH3:25])[N:11]=[C:10]([NH:15][C@@H:16]3[CH2:21][CH2:20][C@H:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]3)[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN
Reactant: O=C(O)[C@H]1CC[C@@H](Nc2nc(Cl)nc(N3CCCCCC3)n2)CC1
Agent: Cl
Solvent: CC#N
Solvent: O
Product: CNc1nc(N[C@H]2CC[C@@H](C(=O)O)CC2)nc(N2CCCCCC2)n1
Temperature: 80 °C

Procedure:
To the solution of crude cis-4-(4-(azepan-1-yl)-6-chloro-1,3,5-triazin-2-ylamino)cyclohexanecarboxylic acid (0.77 mmol) in CH3CN/H2O (1/1, 20 ml) was added methylamine (0.4 ml, 6 equivalents). The reaction mixture was heated at 80° C. overnight. The reaction solution was acidified with 6N HCl. The solution was condensed to give the crude product, which was further purified by RP-HPLC (Luna 5μ C8(2), 100×21 mm, 15-60% CH3CN/H2O, 0.1% TFA, 17 min) to give the product (29 mg). MS (ES+): m/e 349.33 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([OH:32])=O)[O:24][C:25]=1[CH3:26])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:19])([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1)[CH3:2].Cl.CN.[CH3:39][N:40]1CCOCC1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-]>CN(C=O)C.CCOCC>[CH2:1]([N:3]([CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH:40][CH3:39])=[O:32])[O:24][C:25]=1[CH3:26])[C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:19])([C:11]([F:14])([F:12])[F:13])[C:15]([F:18])([F:16])[F:17])=[CH:8][CH:9]=1)[CH3:2]
Reactant: CN1CCOCC1
Reactant: CCN(Cc1nc(-c2cccc(C(=O)O)c2)oc1C)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCN(Cc1nc(-c2cccc(C(=O)NC)c2)oc1C)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 6 h
Yield: 82.5 %

Procedure:
A solution of 22 mg (0.04 mmol) of 3-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzoic acid (example 32) in 1 mL of DMF was treated with 9 mg (0.13 mmol) of methylamine hydrochloride and 0.03 mL (0.26 mmol) of 4-methylmorpholine and cooled to 00. After addition of 12 mg (0.06 mmol) of EDCI and 1 mg (0.001 mmol) of HOBT the mixture was allowed to reach RT, stirred for 6 hours and distributed between Et2O and a saturated aqueous solution of NH4Cl. The combined organic phases were dried over Na2SO4 and evaporated. Column chromatography on silica gel with EtOAc gave 17 mg (75%) of 3-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-N-methyl-benzamide, colorless gum, MS: 516 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH2:22][C:23]([OH:25])=O)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[CH2:26]([NH:33][CH2:34][CH3:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:22][C:23]([N:33]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:34][CH3:35])=[O:25])=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc(N)nc2)cc1
Reactant: CCNCc1ccccc1
Product: CCN(Cc1ccccc1)C(=O)CN(c1ccc(N)nc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(6-amino-pyridin-3-yl)-(4-tert-butyl-benzenesulfonyl)-amino]-acetic acid with benzyl-ethyl-amine
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][N:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.CC(C)([O-])C.[K+].F[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([N+:27]([O-:29])=[O:28])=[CH:19][CH:18]=1>CS(C)=O>[N+:27]([C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]([N:1]2[C:5]3[CH:6]=[CH:7][N:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)=[CH:18][CH:19]=1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1ccc(F)c2ccccc12
Reactant: c1cc2nc[nH]c2cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(-n2cnc3cnccc32)c2ccccc12
Temperature: 60 °C

Procedure:
5-Aza-benzimidazole (312 mg, 2.62 mmol, 1 equiv.) in 5 mL anhydrous DMSO was treated with potassium tert-butoxide (294 mg, 2.62 mmol, 1.0 equiv.) at room temperature. When the mixture was completely homogeneous, 4-fluoro-1-nitro-naphthalene (500 mg, 2.62 mmol, 1 equiv.) was added in one portion and the mixture was heated to 60° C. for 0.5 h. The reaction was allowed to cool, then quenched with dilute aqueous NaHCO3 solution. The product was extracted with a mixture of EtOAc, THF and acetone. The organic extracts were washed with water and brine, then dried (Na2SO4), filtered and the solvents removed in vacuo. 1H NMR revealed a 1:1 ratio of regioisomers. The products were purified by column chromatography on SiO2 using EtOAc/MeOH eluent mixtures. 1-(4-Nitro-naphthalen-1-yl)-1H-imidazo[5,4-c]pyridine was isolated at high Rf and 1-(4-nitro-naphthalen-1-yl)-1H-imidazo[4,5-c]pyridine at lower Rf, and overlapping fractions were in between. The overall yield was 357 mg (47%). Each nitro-naphthalene from above (˜100 mg, 0.4 mmol) was separately dissolved in 10 mL EtOAc and 5 mL of MeOH. Ammonium formate was then added (100 mg, 1.6 mmol or 4 equiv.) and 10% palladium-on-carbon (˜60 mg). The mixture was stirred for 0.5 h at 50° C., then allowed to cool, filtered through diatomaceous earth and the solvents were removed in vacuo to afford ˜80 mg of each naphthyl-amine 5a and 5b, which could be coupled with anilines or pyrazolamines to form ureas by the procedures described in Examples 2-4 above.
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[C:16]([CH2:19][NH:20][C@H:21]([C:25]([OH:27])=[O:26])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][C:5]1=2)#[N:2].[C:28](Cl)(=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32]>ClCCl.C(N(C(C)C)CC)(C)C>[C:1]([CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[C:16]([CH2:19][N:20]([C:28](=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32])[C@H:21]([C:25]([OH:27])=[O:26])[CH:22]([CH3:23])[CH3:24])[CH:17]=[CH:18][C:5]1=2)#[N:2]
Reactant: CCCCC(=O)Cl
Reactant: CC(C)[C@H](NCc1ccc2c(c1)CCc1ccccc1N2CC#N)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(=O)N(Cc1ccc2c(c1)CCc1ccccc1N2CC#N)[C@H](C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
Compound 40-b (1.2 g) was dissolved in a mixture of 30 ml of dichloromethane and 0.6 ml of diisopropylethylamine, and 0.4 ml of valeryl chloride was added to the solution under ice cooling, followed by stirring at room temperature for 5 hours. Then, ice was added thereto, and the mixture was stirred for some time. The mixture was diluted with dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: hexane/ethyl acetate (5/1)] to give 1.4 g (96%) of the product as a yellow oily substance.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH:10]=[C:11]2[N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[CH2:3]1.O.NN.C(O)(=O)C>CCO>[OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[CH2:3]1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(n3cncn3)=CC[C@@H]12
Agent: NN
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2n1cncn1
Temperature: 80 °C
Reaction time: 6 h
Yield: 74.4 %

Procedure:
A mixture of Compound 6 (200 mg, 0.590 mmol), hydrazine hydrate (0.57 ml, 1.77 mmol), and acetic acid (0.35 ml) in EtOH (20 ml) was heated at 80° C. while a stream of air was passed through the solution for 6 h. The reaction mixture was concentrated to about 10 ml and after cooling, it was diluted with EtOAc (30 ml) followed by washing with saturated aqueous NaHCO3 (10 ml×2), and brine (10 ml×2), dried (Na2SO4) and concentrated to give a crude product (190 mg). This was purified by FCC (silica gel, CH2Cl2/EtOH, (30:1)) to give the Compound 8 (150 mg, 10-74.6%), mp 246-248° C. 1H NMR (300 MHz, CDCl3): δ 0.56 (3H, s, 18-Me), 1.01 (3H, s, 19-Me), 3.53 (1H, m, 3α-H), 4.19 (1H, t, J 9.6 Hz, 17a-H), 5.37 (1H, d, J=5.2 Hz, 6-H), 7.93 (1H, s, 3′-H) and 8.10 (1H, s, 5′-H). Analysis calculated for C21H31ON3: C, 73.85; H, 9.16; N, 12.31. Found: C, 73.75; H, 9.40; N, 12.28.
Reaction SMILES: [C:1]([C:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[S:5][C:4]=1[NH:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[N:2]>N1C=CC=CC=1>[C:1]([C:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH:7]([C:4]([CH2:3][CH3:1])=[S:5])[C:6]=2[S:5][C:4]=1[NH:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[N:2]
Reactant: N#Cc1c(NC(=O)c2ccccc2)sc2c1CCNC2
Solvent: c1ccncc1
Product: CCC(=S)C1NCCc2c1sc(NC(=O)c1ccccc1)c2C#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
100 mg of N-(3-cyano4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-benzamide (compound B2) and 57 mg of ethylchlorothioformiate are dissolved in 2 ml of pyridine. After stirring for 3 hours at room temperature, the solvent is removed and the remaining residue recristallized from ethanol to obtain the desired product.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]1[CH:31]=[CH:30][C:23]([C:24]([CH2:26][CH2:27][CH2:28]I)=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(C(C)=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([CH2:26][CH2:27][CH2:28][N:10]2[CH2:9][CH2:8][C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)=[O:25])=[CH:30][CH:31]=1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Reactant: O=C(CCCI)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: O=C(CCCN1CCC(c2ccccc2)(c2ccccc2)CC1)c1ccc(F)cc1

Procedure:
6.1 g. of 4,4 -diphenylpiperidine are heated to boiling with 6.2 g. of 3-(p-fluorobenzoyl)propyl iodide and 5.3 g of anhydrous sodium carbonate in 30 cc. of methyl ethyl ketone for 8 hours while stirring. After cooling, the precipitated salt is filtered off and the filtrate is evaporated to dryness. The residue is dissolved in water and the aqueous solution is rendered alkaline by the addition of sodium hydroxide solution. The resulting base is recovered by repeated extraction with ether. The combined ether extracts are dried over potassium carbonate, the ether is distilled off, and the residue is recrystallized from ethanol with the addition of activated charcoal. Thereby, 9 g. of 1-[3-(p-fluorobenzoyl)-propyl]-4,4-diphenylpiperidine of the melting point 107° to 108° C. are obtained. On adding fumaric acid to its solution in ether, the fumarate of the melting point 195° to 197° C. is obtained.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](O)=[O:18]>C1COCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]
Reactant: O=C(O)CCCCCCCCCCCCCCCBr
Solvent: C1CCOC1
Product: OCCCCCCCCCCCCCCCCBr
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
Under inert atmosphere 10 ml of BH3. THF complex (1.0 M THF solution) were added to 30 ml THF solution of 2.15 gr (6.41 mmole) of 16-bromohexadecanoic acid at -20° C. Reaction mixture was stirred at this temperature for 2 hrs and then additional 1 hr at RT. After that time the resulted mixture was poured, with stirring, into a vessel containing 200 ml of ice/saturated sodium bicarbonate aqueous solution. Organic compounds were extracted with 3×200 ml of ether. The ether fractions were combined and dried over sodium sulfate. After removal of ether material was dissolved in minimum amount of dicloromethane and purified by silica gel chromatography (100% dicloromethane as eluent). 1.92 gr (93% yield) of the desired product were obtained.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:16][C@H:15]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[O:14][C:13]3=[O:22])=[CH:8][C:7]=2[F:23])[CH2:2]1.Cl[C:25]1[N:34]=[C:33]2[C:28]([C:29](=[O:41])[C:30]([C:38]([OH:40])=[O:39])=[CH:31][N:32]2[CH:35]2[CH2:37][CH2:36]2)=[CH:27][C:26]=1[F:42].C[Si](C)(C)Cl.C(N(CC)CC)C>CN1CCCC1=O>[C:19]([NH:18][CH2:17][CH:15]1[O:14][C:13](=[O:22])[N:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH:3]3[CH2:4][N:1]([C:25]4[N:34]=[C:33]5[C:28]([C:29](=[O:41])[C:30]([C:38]([OH:40])=[O:39])=[CH:31][N:32]5[CH:35]5[CH2:37][CH2:36]5)=[CH:27][C:26]=4[F:42])[CH2:2]3)=[C:7]([F:23])[CH:8]=2)[CH2:16]1)(=[O:21])[CH3:20]
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OC3CNC3)c(F)c2)C(=O)O1
Agent: C[Si](C)(C)Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(=O)NCC1CN(c2ccc(OC3CN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)C3)c(F)c2)C(=O)O1
Temperature: 150 °C
Reaction time: 0.12 h

Procedure:
A suspension of 100 mg N-{(5S)-3-[4-(Azetidin-3-yloxy)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-yl methyl}-acetamide (MW: 323.32, 0.31 mmol), 73 mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-Naphthyridine-3-carboxylic acid (MW: 282.66, 0.25 mmol), 0.066 ml trimethylchlorosilane (MW: 108.64, d=0.859, 0.51 mmol) and 0.108 ml triethylamine (MW: 101.19, d=0.726, 0.77 mmol) in 2 ml N-methyl-pyrrolidin-2-one was heated under stirring in a micro wave oven at 150° C. for 7 min. The N-methyl-pyrrolidin-2-one was evaporated, the residue was purified by chromatography. Yield: 55 mg, 30%. MS: 570.5 (M+H)+, Method ESI+. Molecular Weight=570
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH2:16]([O:20][CH2:21][CH2:22][CH2:23][NH2:24])[CH:17]([CH3:19])[CH3:18].O>CC(C)=O>[CH3:18][CH:17]([CH3:19])[CH2:16][O:20][CH2:21][CH2:22][CH2:23][NH:24][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9]
Reactant: CC(C)COCCCN
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Solvent: O
Solvent: CC(C)=O
Product: CC(C)COCCCNC(c1ccccc1)C(O)c1ccccc1
Temperature: 140 °C
Reaction time: 18 h
Yield: 29.4 %

Procedure:
A mixture of trans-stilbene oxide (91.96 g, 0.10 mole) and 3-isobutoxy-1-propylamine (3.93 g, 0.030 mole) was heated at 140° C. for 5 hrs. After standing at ambient temperature for 18 hrs the mixture was dissolved in acetone (20 ml) and the solution poured into water (120 ml). A solid formed rapidly which was collected by filtration and dried under ambient conditions to obtain 2.89 g (88%) of the desired product. Recrystallization from tolueneisooctone gave 2.44 g of an off-white solid, m.p. 90°-92° C.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[Cl:5][C:6]1[N:11]=[C:10](Cl)[C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][N:7]=1.FC(F)(F)C(O)=O>>[Cl:5][C:6]1[N:11]=[C:10]([O:4][CH2:1][C:2]#[CH:3])[C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: C#CCO
Solvent: O=C(O)C(F)(F)F
Product: C#CCOc1nc(Cl)ncc1C(F)(F)F
Temperature: 0 °C
Reaction time: 6 h

Procedure:
3.97 ml (68.2 mmol) Prop-2-yn-1-ol are slowly added to 3.40 g (15.6 mmol) of 2,4-Dichloro-5-trifluoromethyl-pyrimidine at 0° C. under a nitrogen atmosphere. 0.79 ml Trifluoro-acetic acid are added dropwise and the batch is stirred for 6 hours at 0° C. The batch is poured on ice and extracted with ethyl acetate (3×). The combined organic phases are washed with water, dried (Na2SO4), filtered and concentrated by evaporation. The remaining residue is purified by chromatography (hexane/ethyl acetate 95:5). 591 mg (2.5 mmol, corresponding to 16% of theory) of the product is obtained.