Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:17][C:18](=[O:20])[CH3:19])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([F:16])[CH2:12][CH2:11]1.[CH3:21][C:22]([CH3:27])([CH3:26])[C:23](Cl)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:22]([C:27]1[N:8]([CH2:9][CH:10]2[CH2:11][CH2:12][CH:13]([F:16])[CH2:14][CH2:15]2)[C:7]2[CH:6]=[CH:5][C:4]([NH:17][C:18](=[O:20])[CH3:19])=[CH:3][C:2]=2[N:1]=1)([CH3:26])([CH3:23])[CH3:21]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(=O)Nc1ccc(NCC2CCC(F)CC2)c(N)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCC(F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(3-Amino-4-{[(4-fluorocyclohexyl)methyl]amino}phenyl)acetamide (300 mg, 1.07 mmol) and DMAP (25 mg, 0.214 mmol) were dissolved in 10 mL of DCM. Trimethylacetyl chloride (0.145 mL, 1.18 mmol) was added dropwise and the solution was stirred at rt for 1 h. The solution was washed with aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The residue was dissolved in 5 mL of AcOH and was heated at 150° C. for 2.5 h using a Personal Chemistry microwave apparatus. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by silica gel flash chromatography using 2:1/acetone:hexanes as eluent. Yield: 196 mg (53%). 1HNMR (400 MHz, CHLOROFORM-D) δ 1.14-1.25 (m, 2 H), 1.37-1.45 (m, 1 H), 1.43-1.51 (m, 1 H), 1.54-1.57 (m, 9 H), 1.70-1.78 (m, 2 H), 1.70-1.77 (m, 1 H), 2.02-2.08 (m, 1 H), 2.10-2.17 (m, 1 H), 2.19-2.21 (m, 3 H), 4.12-4.19 (m, 2 H), 4.53 (m, 0.3 H), 4.73 (m, 0.3 H), 4.78 (m, 0.2 H), 4.90 (m, 0.2 H), 7.21-7.29 (m, 1 H), 7.30 (s, 1 H), 7.50-7.57 (m, 1 H), 7.64-7.67 (m, 1 H).
Reaction SMILES: C(OC1C=C(C=CC=1C)CN1CCC(NC2C=C(C=CN=2)C#N)CC1)C.Cl.Cl.[NH:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:36]2[CH:37]=[C:38]([CH:41]=[CH:42][N:43]=2)[C:39]#[N:40])[CH2:31][CH2:30]1.[CH2:44]([O:46][C:47]1[CH:48]=[C:49]([CH:52]=[C:53]([O:56][CH2:57][CH3:58])[C:54]=1[F:55])[CH:50]=O)[CH3:45]>>[CH2:44]([O:46][C:47]1[CH:48]=[C:49]([CH:52]=[C:53]([O:56][CH2:57][CH3:58])[C:54]=1[F:55])[CH2:50][N:29]1[CH2:30][CH2:31][CH:32]([NH:35][C:36]2[CH:37]=[C:38]([CH:41]=[CH:42][N:43]=2)[C:39]#[N:40])[CH2:33][CH2:34]1)[CH3:45]
Reactant: CCOc1cc(C=O)cc(OCC)c1F
Reactant: N#Cc1ccnc(NC2CCNCC2)c1
Agent: CCOc1cc(CN2CCC(Nc3cc(C#N)ccn3)CC2)ccc1C
Agent: Cl
Product: CCOc1cc(CN2CCC(Nc3cc(C#N)ccn3)CC2)cc(OCC)c1F

Procedure:
The title compound was prepared in analogy to the synthesis of 2-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-isonicotinonitrile (example 189) from 2-(piperidin-4-ylamino)-isonicotinonitrile dihydrochloride (intermediate B15) and 3,5-diethoxy-4-fluoro-benzaldehyde (intermediate E5) in a yield of 4.3 mg (6%). MS (ISP): 399.3 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[CH2:9]([O:16][CH:17](O)[CH3:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[CH2:9]([O:16][CH2:17][CH2:18][O:8][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]1=[O:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(O)OCc1ccccc1
Reactant: O=C1CCCCC1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: O=C1CCCCC1OCCOCc1ccccc1
Reaction time: 10 h
Yield: 67.1 %

Procedure:
A mixture of dimeric 2-hydroxycyclohexanone (13.7 g), 2 benzyloxyethanol (20 g) and p-toluensulphonic acid (2 g) were dissolved in xylene (500 ml) in a round bottom flask fitted with a Dean Stark apparatus and reluxed for 10 hrs. The resulting solution was cooled, washed with sodium hydrogen carbonate (3×50 ml) dried and concentrated under reduced pressure. The crude oil was then purified by flash chromatography using cyclohexane/ethyl acetate 60/40 as eluant yielding 20 g of the title compound (Rf=0.5).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:13])=[N:9][CH:10]=[CH:11][CH:12]=1)(=O)=O.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18].C(N(CC)CC)C>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:13][C:8]1[C:7]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: Cc1ncccc1OS(=O)(=O)C(F)(F)F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ncccc1C#C[Si](C)(C)C
Reaction time: 3 h
Yield: 84.1 %

Procedure:
First, 2-methylpyridin-3-yl trifluoromethanesulfonate (34.3 g, 142 mmol), trimethylsilylacetylene (30 ml, 212 mmol), bis(triphenylphosphine)palladium (II) chloride (10.0 g, 14.2 mmol), and copper (I) iodide (2.75 g, 14.4 mmol) were dissolved in N,N-dimethyl formamide (150 ml). Thereafter, triethylamine (43 ml, 309 mmol) was added in a nitrogen atmosphere at room temperature to the mixture. The mixture was then stirred for 3 hours (exothermic reaction took place). The reaction mixture was separated by ethyl acetate and a saturated aqueous ammonium chloride solution and insoluble substance was removed by filtration. The organic layer of the filtrate was washed twice with a saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtrated and concentrated to obtain the title compound (22.6 g, yield: 84.1%) as brown oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:15]=[C:14](Br)[S:13][C:12]=1Br.C([Li])CCC.[CH:23](N1CCCCC1)=[O:24].C1C[O:34][CH2:33]C1>CCCCCC>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:15]=[C:14]([CH:33]=[O:34])[S:13][C:12]=1[CH:23]=[O:24]
Reactant: Brc1cc(-c2ccc3ccccc3c2)c(Br)s1
Reactant: O=CN1CCCCC1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: O=Cc1cc(-c2ccc3ccccc3c2)c(C=O)s1
Reaction time: 0.5 h

Procedure:
See Reaction Scheme 434 in FIG. 4E. A solution of 0.01 mole of 3-naphth-2-yl-2,5-dibromothiophene (prepared as described in Example 10) may be prepared in about 10 milliliters of anhydrous THF and cooled using a dry ice/acetone bath under an inert atmosphere. About 0.021 mole of n-butyllithium in hexane may be added, and the mixture may be stirred for about 30 minutes. Next, about 0.021 mole of 1-formyl piperidine may be added, and the mixture may be stirred and allowed to rise to room temperature over about 12 hours. The reaction mixture may be washed with aqueous ammonium chloride, and the organic layer may be dried and evaporated to form a residue. The residue may be purified via silica gel chromatography to give 3-(naphthalen-2-yl)thiophene-2,5-dicarbaldehyde.
Reaction SMILES: [CH2:1]([CH:8]1[O:12][C:11](=[O:13])[CH:10]=[C:9]1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][CH:16]([CH3:19])[CH:17]=O.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][CH2:30][NH:31][C:32](=[O:34])[CH3:33])=[CH:21]1>>[CH2:1]([CH:8]1[O:12][C:11](=[O:13])[C:10]([CH:17]([C:21]2[NH:20][C:28]3[C:23]([C:22]=2[CH2:29][CH2:30][NH:31][C:32](=[O:34])[CH3:33])=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:16]([CH3:19])[CH3:15])=[C:9]1[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C=O
Reactant: O=C1C=C(O)C(Cc2ccccc2)O1
Reactant: CC(=O)NCCc1c[nH]c2ccccc12
Product: CC(=O)NCCc1c(C(C2=C(O)C(Cc3ccccc3)OC2=O)C(C)C)[nH]c2ccccc12

Procedure:
Using general procedure C, 5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) was reacted with 2-methyl-propionaldehyde and N-[2-(1H-indol-3-yl)-ethyl]-acetamide) to give the title compound as a yellow solid. MS: 445.1 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18](Cl)[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)[C:6]1=[O:17].C(O)C.COCCN(S(F)(F)[F:38])CCOC>ClCCl>[Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][C:13]([F:38])=[CH:12][CH2:11]2)[C:6]1=[O:17]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: COc1cc(Cl)c(CC2CCN(C3CCC(=O)CC3)C2=O)c(Cl)c1
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(CC2CCN(C3CC=C(F)CC3)C2=O)c(Cl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
Dissolve 3-(2,6-Dichloro-4-methoxybenzyl)-1-(4-oxocyclohexyl)-pyrrolidin-2-one (Preparation 17) (2.09 g, 5.4 mmol) in dichloromethane (50 mL) and ethanol (0.06 mL, 1.08 mmol) and cool to 0° C. Add deoxo-fluor (1.69 mL, 9.18 mmol) over several minutes. Stir overnight at room temperature. Add saturated sodium bicarbonate and extract aqueous layer with dichloromethane. Wash the organic layer with brine and dry with Na2SO4, filter and concentrate to dryness. Purify the crude mixture over silica gel (4/1 hexane in ethyl acetate) to give 650 mg (32%) of the title compound: mass spectrum (m/e): 374 (M+1).
Reaction SMILES: N1C=CC=C([C:7]([C@@:9]2([OH:34])[C@@H:13]([CH:14]([C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[OH:15])[O:12][C@@H:11]([N:22]3[CH:33]=[C:28]([C:29]([F:32])([F:31])[F:30])[C:26](=[O:27])[NH:25][C:23]3=[O:24])[CH2:10]2)=[O:8])C=1.C[I:36].[CH3:37][C:38]([CH3:40])=O>>[I-:36].[CH3:23][N:22]1[CH:11]=[CH:10][CH:40]=[CH2+:38][CH:37]1[C:7]([C@@:9]1([OH:34])[C@@H:13]([CH:14]([C:16](=[O:21])[C:17]([CH3:20])([CH3:18])[CH3:19])[OH:15])[O:12][C@@H:11]([N:22]2[CH:33]=[C:28]([C:29]([F:31])([F:32])[F:30])[C:26](=[O:27])[NH:25][C:23]2=[O:24])[CH2:10]1)=[O:8]
Reactant: CC(C)=O
Reactant: CI
Reactant: CC(C)(C)C(=O)C(O)[C@H]1O[C@@H](n2cc(C(F)(F)F)c(=O)[nH]c2=O)C[C@@]1(O)C(=O)c1cccnc1
Product: CN1C=CC=[CH2+]C1C(=O)[C@]1(O)C[C@H](n2cc(C(F)(F)F)c(=O)[nH]c2=O)O[C@@H]1C(O)C(=O)C(C)(C)C
Product: [I-]

Procedure:
To 440 mg of the product of Example 105 dissolved in 10 mL of acetone, 1.0 g of methyl iodide was added. The mixture was refluxed for 10 hours, then the precipitate which formed was collected by suction filtration to give 550 mg of the desired product as yellow leaves melting at 188°-190° C. with decomposition. NMR analysis confirmed that the product had the structural formula: ##STR135##
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([CH2:8][NH:9]CC2C=CC=CC=2)[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.[H][H]>CO.[Pd]>[NH2:9][CH2:8][C@@H:7]1[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:3][C@H:2]1[OH:1]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CNCc2ccccc2)[C@H](O)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](CN)[C@H](O)C1
Yield: 72.9 %

Procedure:
A mixture of intermediate (47) (0.028 mol) in methanol (100 ml) was hydrogenated with palladium-on-carbon (10%, 2 g) as a catalyst. After uptake of hydrogen (1 equivalent) the catalyst was filtered off and the filtrate was evaporated, yielding 4.7 g of 1,1-dimethylethyl (3S-trans)4-(aminomethyl)-3-hydroxy-1-piperidinecarboxylate (intermediate (48); [α]D20=+4.37° (c=24.03 mg/5 ml in CH3OH)).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])[C:5]=12.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][CH2:30]O)[CH:23]=1.N1CCCCC1>C(O)C>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][CH:30]=[C:18]2[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6]3[C:5]4[N:4]([CH:3]=[CH:2][N:1]=4)[CH:9]=[CH:8][CH:7]=3)[C:19]2=[O:20])[CH:23]=1
Reactant: O=C1CSC(=O)N1CCCCOc1cccn2ccnc12
Reactant: OCCCc1cccnc1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1SC(=CCCc2cccnc2)C(=O)N1CCCCOc1cccn2ccnc12

Procedure:
To a solution of 1.53 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-8-yloxy)butyl]thiazolidine-2,4-dione and 676 mg (5.0 mmol) of 3-(3-pyridyl)-1-propanol in 20 ml of ethanol, 43 mg (0.5 mmol) of piperidine was added, followed by refluxing for 3.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with purified water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform/methanol=50/1→25/1) to yield 0.49 g (23.0%, yellow oily substance) of the desired product.
Reaction SMILES: C(O[C:4](=O)[C:5]([C:10]1[CH:28]=[CH:27][C:13]2[N:14]=[C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[N:16]([CH3:17])[C:12]=2[C:11]=1[C:29]#[N:30])(C)[C:6](=O)[CH3:7])C.O.S(=O)(=O)(O)[OH:34].[OH-].[NH4+]>C(O)(=O)C>[F:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:15]2[N:16]([CH3:17])[C:12]3[C:11]4[C:29](=[O:34])[NH:30][C:6]([CH3:7])=[C:5]([CH3:4])[C:10]=4[CH:28]=[CH:27][C:13]=3[N:14]=2)=[C:20]([CH3:26])[CH:21]=1
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)C(C)(C(C)=O)c1ccc2nc(Nc3ccc(F)cc3C)n(C)c2c1C#N
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(F)ccc1Nc1nc2ccc3c(C)c(C)[nH]c(=O)c3c2n1C
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 70 %

Procedure:
To a glass scintillation vial equipped with a magnetic stir bar was added 2-[4-cyano-2-(4-fluoro-2-methyl-phenylamino)-3-methyl-3H-benzoimidazol-5-yl]-2-methyl-3-oxo-butyric acid ethyl ester (0.204 g, 0.483 mmol). A freshly prepared mixture of H2O (3.3 mL), glacial acetic acid (3.3 mL), and concentrated sulfuric acid (3.3 mL) at 60° C. was added to the vial. The vial was sealed with a screw cap and heated to 100° C. in a heating block. After 2.5 hours, the vial was allowed to cool to room temperature and stirred for an additional 12 h. The reaction mixture was then poured onto ice and neutralized by addition of concentrated ammonium hydroxide. The resulting precipitate was recovered by filtration and further purified by trituration with methanol to provide 2-(4-fluoro-2-methyl-phenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (0.1188 g, 70%) as a light gray solid. 1H NMR (400 MHz, DMSO-d6+TFA) δ 11.43 (br s, 1H), 10.49 (br s, 1H), 7.70-7.65 (m, 2H), 7.57 (dd, 1H, J1=5.5 Hz, J2=8.6 Hz), 7.37 (dd, 1H, J1=3.1 Hz, J2=9.8 Hz), 7.27 (td, 1H, J1=3.1 Hz, J2=11.7 Hz), 4.23 (s, 3H), 2.32 (app s, 6H), 2.23 (s, 3H); ESMS (m/z): found, 351.
Reaction SMILES: [CH3:1][NH:2][CH3:3].F[C:5]1[CH:19]=[CH:18][C:8]([C:9]([C:11]2[S:15][C:14](=[O:16])[NH:13][C:12]=2[CH3:17])=[O:10])=[CH:7][CH:6]=1>C(O)C>[CH3:1][N:2]([CH3:3])[C:5]1[CH:19]=[CH:18][C:8]([C:9]([C:11]2[S:15][C:14](=[O:16])[NH:13][C:12]=2[CH3:17])=[O:10])=[CH:7][CH:6]=1
Reactant: Cc1[nH]c(=O)sc1C(=O)c1ccc(F)cc1
Reactant: CNC
Solvent: CCO
Product: Cc1[nH]c(=O)sc1C(=O)c1ccc(N(C)C)cc1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
Dimethylamine (100 ml, 40% solution) was added to a solution of 5-(4-fluorobenzoyl)-4-methyl-2(3H)-thiazolone (4.7 g) in ethanol (200 ml). The mixture was stirred in a sealed stainless steel vessel at 120° C. for 16 hours. After cooling to ambient temperature the solvent and excess dimethylamino was evaporated. The residue was recrystallized twice from ethanol to give the title compound, mp. 224°-226° C.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[NH:11][C:12]([NH:14][C:15]2[C:19]([CH3:20])=[CH:18][S:17][CH:16]=2)=[NH:13])OCC1.[Cl:21]N1C(=O)CCC1=O>C(O)(=O)C>[ClH:21].[Cl:21][C:16]1[S:17][CH:18]=[C:19]([CH3:20])[C:15]=1[N:14]1[C:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:11]=[C:12]1[NH2:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cscc1NC(=N)NC1CCCCC12OCCO2
Solvent: CC(=O)O
Product: Cc1csc(Cl)c1-n1c(N)nc2c1CCCC2
Product: Cl
Yield: 103.8 %

Procedure:
N-(1,4-Dioxaspiro[4.5]dec-6-yl)-N′-(4-methylthiophen-3-yl)guanidine (49 mg) was dissolved in glacial acetic acid (3 ml), and a solution of N-chlorosuccinimide (20.3 mg) in glacial acetic acid (5 ml) was added slowly. The mixture was stirred for a number of hours and then allowed to stand at room temperature over the weekend, after which the glacial acetic acid was removed under reduced pressure, the residue was taken up in water and the mixture was adjusted to pH 10 using 2N sodium hydroxide solution. The basic phase was extracted three times with ethyl acetate and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative chromatography and the product-containing fractions were combined, freed from acetonitrile, made basic and extracted three times with ethyl acetate. The organic phases were combined, dried (MgSO4) and filtered. Removal of the solvent under reduced pressure gave 24 mg of the desired product which was used directly for the next step.
Reaction SMILES: [CH3:1][C:2]1([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7][CH2:6][C:5]2[C:8]([CH3:15])=[C:9]([OH:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:4]=2[O:3]1.O1CCCC1>[Pd].C(O)C>[CH3:1][C:2]1([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:7][CH2:6][C:5]2[C:8]([CH3:15])=[C:9]([OH:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:4]=2[O:3]1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccccc1)O2
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCc1ccccc1)O2
Yield: 69 %

Procedure:
A mixture of 1.3 g (4.2 mmol) of 3,4-dihydro-2,5,7,8-tetramethyl-2-(2-phenylethynyl)-2H-1-benzopyran-6-ol (Example 1), 0.3 g of 5 % palladium on carbon. 50 ml of tetrahydrofuran and 50 ml ethanol was hydrogenated at atmospheric pressure for 4 hours. The catalyst was filtered off and the filtrate was evaporated. Crystallization of the residue from hexane yielded 0.9 g (69 %) of colorless crystals with m.p. 96°-98°.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7]Br)=[CH:4][CH:3]=1.CN(C)[CH:14]=[O:15].N1(C2[CH2:27][CH2:26][S:25][CH2:24][CH:23]=2)CCCC1>O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7][CH:23]2[C:14](=[O:15])[CH2:27][CH2:26][S:25][CH2:24]2)=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: C1=C(N2CCCC2)CCSC1
Solvent: O
Product: O=C(CC1CSCCC1=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 41.7 g (0.15 moles) of p-bromophenacyl bromide and 50 ml. of dimethylformamide is added dropwise under nitrogen to a cold stirred solution of 25.4 g (0.15 mole) of 5,6-dihydro-4-(1-pyrrolidinyl)-2H-thiopyran [Example 1 (a)], and 150 ml. of anhydrous dimethylformamide. The reaction mixture is stirred at room temperature for 16 hours, diluted with water, and extracted with chloroform. The chloroform solution is dried over magnesium sulfate and concentrated. The residue is chromatographed on silica gel and eluted with a benzene and chloroform mixture. The solid product is recrystallized from ethanol to provide off-white crystals of 3-(4-bromophenacyl)-2,3,5,6-tetrahydrothiopyran-4-one, m.p. 87.5° to 89.5°C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21]C4C=CC(C(O)=O)=CC=4OC)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1N=CC2N(C)C(=O)C(F)(F)CN(C3CCCC3)C=2N=1.N[C:55]1[CH:65]=[CH:64][C:58]2[O:59][CH2:60][C:61](=[O:63])[NH:62][C:57]=2[CH:56]=1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:55]4[CH:65]=[CH:64][C:58]5[O:59][CH2:60][C:61](=[O:63])[NH:62][C:57]=5[CH:56]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc4c(c3)NC(=O)CO4)ncc21

Procedure:
The title compound was synthesized using an analogous procedure to that described in connection with 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid from 2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one and 6-amino-2H-benzo[b][1,4]oxazin-3(4H)-one. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48-1.80 (m, 6 H) 1.95 (br. s, 2 H) 3.40 (s, 3 H) 4.01 (t, J=14.15 Hz, 2 H) 4.52 (s, 2 H) 4.72 (t, J=8.08 Hz, 1 H) 6.77 (d, J=8.34 Hz, 1 H) 7.20 (dd, J=8.59, 2.02 Hz, 1 H) 7.46 (d, J=2.27 Hz, 1 H) 8.20 (s, 1 H) 9.35 (s, 1 H) 10.54 (br. s., 1 H) [M+H] calc'd for C21H22F2N6O3, 445; found 445.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH2:5][CH2:6][C:7](O)=[S:8].OS(O)(=O)=O.ClC(Cl)C.[NH2:23][OH:24].C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH2:5][CH2:6][C:7]([NH:23][OH:24])=[S:8]
Reactant: OC(=S)CCc1ccc(Cl)c(Cl)c1
Reactant: NO
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CO
Product: ONC(=S)CCc1ccc(Cl)c(Cl)c1
Yield: 75 %

Procedure:
20.2 g (0.08 mol) of 3,4-dichlorobenzylthioacetic acid are esterified with 10 ml of methanol, 0.6 ml of concentrated H2SO4 and 100 ml of dichloroethane. The mixture is heated under reflux for 4 hours, washed with water and with dilute bicarbonate solution, and dried. The mixture is evaporated in vacuo. The oily residue, in methanol, is treated with a solution of hydroxylamine (0.1 mol) in the presence of 0.18 mol of sodium methylate. After leaving the reactants in contact overnight, the mixture is evaporated to dryness in vacuo, the residue is taken up in water, the mixture is filtered over charcoal and the filtrate is precipitated with 3N HCl, the product is extracted with ether, the extract is dried and evaporated and the product is crystallised in diisopropyl ether. 15 g of the stated product are obtained (yield 71%). Melting point: 75°-76° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[CH2:25]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17][CH:8]([NH:7][C:6](=[O:18])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1Cc2ccccc2N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
A mixture of (1,2,3,4-tetrahydroquinolin-3-yl)-carbamic acid tert-butyl ester (507 mg, 2.04 mmol) and potassium carbonate (367 mg, 2.65 mmol) in ethanol (15 mL) was treated with benzyl bromide (367 mg, 2.14 mmol) and stirred overnight at ambient temperature. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The isolated organic phase was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated. The resulting oil was chromatographed on silica gel, eluting with 5-to-50% ethyl acetate in hexane to afford the title compound (529 mg, 77%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ: 1.38 (s, 9H), 2.65-2.75 (dd, 1H), 2.83-2.92 (dd, 1H), 3.11-3.22 (dd, 1H), 3.35-3.42 (dd, 1H), 3.77-3.90 (m, 1H), 4.39-4.51 (q, 2H), 6.45-6.52 (m, 2H), 6.82-6.94 (m, 3H), 7.20-7.34 (m, 5H). MS (ESI) m/z 222.2, 283.1, 339.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:9].[NH2:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1.C(N(C(C)C)CC)(C)C.O>CCCCO.CN(C1C=CN=CC=1)C>[C:20]([O:19][C:17]([N:13]1[CH2:14][CH2:15][CH2:16][C@@H:11]([NH:10][C:2]2[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N+:3]=2[O-:9])[CH2:12]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: Cc1ccc[n+]([O-])c1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCCCO
Product: Cc1ccc[n+]([O-])c1N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 100 °C
Yield: 25 %

Procedure:
To a solution of the compound from Step 1 2-chloro-3-methylpyridine 1-oxide (14.5 g, 101 mmol) and tert-butyl (3R)-3-aminopiperidine-1-carboxylate (24.27 g, 121.2 mmol) in n-BuOH (120 mL) were added diisopropylethyl amine (14.35 g, 111 mmol) and DMAP (1.22 g, 9.99 mmol) slowly at 0° C. The resulting mixture was heated at 100° C. for 36 h. The reaction was cooled, and water was added. The mixture was then extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude compound was purified by silica gel chromatography eluting with a gradient of petroleum ether:EtOAc (80:20 to 50:50) to afford the title compound (7.9 g, 25%) as a yellow oil.