Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].[CH3:31][N:32]1[C:36]([CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]2[OH:43])=[CH:35][N:34]=[CH:33]1.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:43][C@H:38]2[CH2:39][CH2:40][CH2:41][CH2:42][C@@H:37]2[C:36]2[N:32]([CH3:31])[CH:33]=[N:34][CH:35]=2)=[CH:12][C:11]=1[F:18])(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Reactant: Cn1cncc1C1CCCCC1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3cncn3C)cc2F)c(OC)c1
Yield: 28.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using the N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide (120 mg, 0.273 mmol) prepared in Example 14b, 2-(1-methyl-1H-imidazol-5-yl)cyclohexanol (50 mg, 0.277 mmol) prepared in Example 49b, sodium hydride (63%; 40 mg, 1.05 mmol) and DMF (2.0 mL), to yield the title compound (46 mg, 28%) as a colorless oil.
Reaction SMILES: [C:1]([CH2:3][C:4](O)=O)#[N:2].[C:7]([CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)([CH3:10])([CH3:9])[CH3:8].C=O.[C:19](=O)=O>CCOCC.O1CCOCC1>[C:7]([CH:11]1[CH2:16][CH2:15][N:14]([CH2:19][C:3](=[CH2:4])[C:1]#[N:2])[CH2:13][CH2:12]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)C1CCNCC1
Reactant: N#CCC(=O)O
Reactant: O=C=O
Agent: C=O
Solvent: C1COCCO1
Solvent: CCOCC
Product: C=C(C#N)CN1CCC(C(C)(C)C)CC1
Reaction time: 12 h

Procedure:
Cyanoacetic acid (1.75 g., 0.02 mole) was dissolved in 10 ml. of dioxane. In a five minute period 4-t-butylpiperidine (2.8 g., 0.02 mole) was added, the temperature rose to 25° C. from 15° C. obtained by prior cooling with an ice bath. The mixture which solidified became fluid upon the addition of 37% aqueous formaldehyde (3.6 g., 0.04 mole), the temperature rose to 30° C. and carbon dioxide evolution began. The mixture was stirred an additional 12 hours, was taken up in ether and the organic phase separated and washed with water. The dried ether solution was stripped of solvent to leave a solid residue product, 3.7 g. of practically analytical purity.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[C:11]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)([OH:13])=[O:12].C(=O)([O-])[O-].[K+].[K+]>O.O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:9]([CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:17]1[CH:18]=[CH:19][C:14]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=1)#[N:10]
Reactant: N#CCc1ccccc1Br
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: N#CCc1ccccc1-c1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
A stirred mixture containing 5.88 g (0.03 mol) of (2-bromo-phenyl)-acetonitrile, 4.978 g. (0.03 mol) of 4-carboxyphenylboronic acid, 8.29 g (0.06 mol) of potassium carbonate and 0.52 g of dichlorobis(triphenylphosphine)palladium(II) in 46 mL of water and 25 mL of 1,4-dioxane was heated under reflux for two hours in an atmosphere of nitrogen. The reaction mixture was allowed to cool to room temperature and filtered. The dioxane was removed in vacuo and the residue diluted with 100 mL of water and then acidified with 20% hydrochloric acid. The crude product (1.2g) was recrystallized from ethanol to give a solid, m.p. 218-220° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:21]1[N:26]=[C:25]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][C:37]3[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=3)[CH2:32][CH2:31]2)=[O:28])[CH:24]=[CH:23][CH:22]=1.C(Cl)Cl>CN(C=O)C.C(OCC)C>[N:40]1[CH:39]=[CH:38][C:37]([CH2:36][N:33]2[CH2:34][CH2:35][CH:30]([NH:29][C:27](=[O:28])[C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([O:15][CH:12]4[CH2:13][CH2:14][N:9]([C:6]5[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][CH:7]=5)[CH2:10][CH2:11]4)[N:26]=3)[CH2:31][CH2:32]2)=[CH:42][CH:41]=1
Reactant: OC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: O=C(NC1CCN(Cc2ccncc2)CC1)c1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(NC1CCN(Cc2ccncc2)CC1)c1cccc(OC2CCN(c3ccc(C(F)(F)F)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25 %

Procedure:
To a solution of 1-(4-(trifluoromethyl)phenyl)-piperidin-4-ol (0.1 g, 0.4 mmol) in anhydrous DMF, NaH (60% in mineral oil, 18 mg, 0.45 mmol) was added. The mixture was allowed to stir at room temperature under N2 atmosphere for 10 min, followed by the addition of 6-chloro-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)picolinamide (0.15 g, 0.4 mmol). The resulting reaction mixture was then stirred with heating at 105° C. overnight. A significant amount of starting material was still present and hence, an additional amount of NaH was added (82 mg, 2.1 mmol). The reaction mixture was allowed to stir at 105° C. for an additional 8 h, and quenched with saturated sodium bicarbonate solution (20 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL), and the combined organic layer was washed with water (2×20 mL) and brine (1×20 mL), dried (MgSO4), filtered and concentrated to give a yellow residue. Column chromatography (100% CH2Cl2 3% MeOH/CH2Cl2) provided a yellow solid, which upon trituration with ethyl ether, yielded N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)picolinamide as a tan solid (54 mg, 25%). 1H NMR (CD3OD) δ 8.53 (d, J=4.1 Hz, 2H), 8.28 (d, J=7.4 Hz, 1H), 7.80 (t, J=7.7 Hz, 1H), 7.65 (d, J=7.2 Hz, 1H), 7.51 (d, J=4.1 Hz, 2H), 7.46 (d, J=8.5 Hz, 2H), 7.05 (d, J=8.3 Hz, 2H), 6.96 (d, J=8.3 Hz, 1H), 5.43 (br s, 1H), 4.10-3.95 (m, 1H), 3.90 (s, 2H), 3.77-3.56 (m, 2H), 3.23-2.98 (m, 3H), 2.71-2.57 (m, 2H), 2.23-1.81 (m, 9H). MS (m/z): 540 (M+H)+.
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:6][C@H:7]([NH:27][C:28](=[O:30])[CH3:29])[C@H:8]([OH:26])[CH2:9][NH:10][C:11]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:18]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.Br[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>>[ClH:1].[CH2:36]([O:2][C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:6][C@H:7]([NH:27][C:28](=[O:30])[CH3:29])[C@H:8]([OH:26])[CH2:9][NH:10][C:11]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:18]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCBr
Reactant: CC(=O)N[C@@H](Cc1cc(O)cc(F)c1)[C@H](O)CNC1(c2cccc(C(C)C)c2)CCCCC1
Agent: Cl
Product: CCCCCCCOc1cc(F)cc(C[C@H](NC(C)=O)[C@H](O)CNC2(c3cccc(C(C)C)c3)CCCCC2)c1
Yield: 34 %

Procedure:
Using methods analogus to those previously described, hydrochloride 11 (0.4 mmol) is reacted with 1-bromoheptane to afford the title compound 59 (0.14 mmol, 34%) as a glass, which can be pulverized to an off-white solid: 1H NMR (CDCl3+CD3OD drop) δ 7.49 (s, 1H), 7.37 (m, 2H), 7.27 (m, 1H), 6.51 (s, 1H), 6.45 (s, 1H), 6.43 (s, 1H), 4.05 (m, 1H), 3.98 (m, 1H), 3.88 (t, J=6.5 Hz, 2H), 2.96 (hept, J=7 Hz, 1H), 2.84 (m, 1H), 2.6 (3H obscured by solvent), 2.36 (m, 1H), 2.16 (m, 2H), 2.01 (s, 3H), 1.85-1.75 (m, 4H), 1.58 (m, 1H), 1.5-1.26 (m, 18H), 0.89 (t, J=6.6 Hz, 3H); MS (CI) m/z 555.5 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15](=[N:17][NH2:18])[CH3:16])[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:19]([C:22]1[CH:31]=[CH:30][C:25]2[O:26][CH2:27][CH2:28][O:29][C:24]=2[CH:23]=1)=[C:20]=[S:21].CO.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15](=[N:17][NH:18][C:20](=[S:21])[NH:19][C:22]3[CH:31]=[CH:30][C:25]4[O:26][CH2:27][CH2:28][O:29][C:24]=4[CH:23]=3)[CH3:16])[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=NN)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: S=C=Nc1ccc2c(c1)OCCO2
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CC(=NNC(=S)Nc1ccc2c(c1)OCCO2)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reaction time: 4 h
Yield: 65 %

Procedure:
2-(3,4-Dichlorophenyl)-4-(1-hydrazonoethyl)-thiophen-3-ol (25 mg, 0.08 mmol) prepared in Reference Synthetic Example 13 in dimethylformamide (0.25 mL) was stirred with 6-isothiocyanato-2,3-dihydrobenzo[1,4]dioxine (24 mg, 0.13 mmol, at 30° C. for 4 hours. Methanol and water were added to the reaction solution, and the resulting crystals were collected by filtration, washed and dried to give 28 mg of the desired product (yield 65%).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH3:4][C:5]1([CH2:10]Br)[O:9][CH2:8][CH2:7][O:6]1.[OH-].[Na+]>CCOCC>[CH2:1]([NH:3][CH2:4][C:5]1([CH3:10])[O:9][CH2:8][CH2:7][O:6]1)[CH3:2]
Reactant: CCN
Reactant: CC1(CBr)OCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCNCC1(C)OCCO1
Temperature: 120 °C
Reaction time: 5 h
Yield: 40.1 %

Procedure:
Ethylamine (115 grams; 1.77 mole) and 2-methyl-2-bromomethyl-1,3-dioxolane (32 grams; 0.177 mole) were placed in a stainless steel bomb and placed on a steam bath for 5 hours. The temperature of the mixture was raised to 120° C. for 15 hours. The mixture was cooled and ether (200 ml) added to it. Sodium hydroxide (25 grams) was added and the ether layer separated and dried over magnesium sulfate. The ether was evaporated leaving the desired product (10.3 grams) as identified by nuclear magnetic resonance.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][NH2:11])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(N(CC)CC)C.C[O:20][C:21](=O)[N:22]=[C:23](SC)[C:24]([C:38]1[CH:48]=[C:47]([O:49][CH3:50])[C:41]2[O:42][CH2:43][CH2:44][CH2:45][O:46][C:40]=2[CH:39]=1)=[N:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([CH3:37])[O:34][N:33]=2)=[CH:28][CH:27]=1>CN(C=O)C>[CH3:50][O:49][C:47]1[C:41]2[O:42][CH2:43][CH2:44][CH2:45][O:46][C:40]=2[CH:39]=[C:38]([CH:24]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[N:36]=[C:35]([CH3:37])[O:34][N:33]=3)=[CH:28][CH:27]=2)[C:23]2[NH:22][C:21](=[O:20])[N:10]([C:5]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=3)[N:11]=2)[CH:48]=1
Reactant: NNc1ncccc1[N+](=O)[O-]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1)OCCCO2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccc3[N+](=O)[O-])c(=O)[nH]2)cc2c1OCCCO2
Temperature: 85 °C
Reaction time: 24 h
Yield: 46.9 %

Procedure:
After adding 37.3 mg of (3-nitropyridin-2-yl)hydrazine and 37 μl of triethylamine to a solution of 109 mg of [2-(9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example (30c)) in 5 ml of DMF under a nitrogen atmosphere, the mixture was heated at 85° C. for 20 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in 20 ml of a methanol:THF=1:1 mixed solvent, 83 mg of sodium cyanotrihydroborate and 32 μl of acetic acid were added and the mixture was stirred at room temperature for 24 hours. After adding 100 ml of ethyl acetate and 50 ml of water, filtration was performed with celite. The aqueous layer was extracted with 50 ml of ethyl acetate, and then the organic layers were combined and dried over anhydrous magnesium sulfate, the desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate (1:40)) to give the title compound (59 mg) as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH3:11][NH:12][CH3:13]>C(O)C.O1CCCC1>[CH3:11][N:12]([CH3:13])[C:2]1[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C)c1ccc([N+](=O)[O-])nc1
Temperature: 140 °C

Procedure:
To a solution of 1 g of 5-bromo-2-nitropyridine in 5 mL of ethanol are added 6 mL of a 2 M solution of dimethylamine in tetrahydrofuran. The reaction mixture is heated for 2 hours at 140° C. in a microwave machine. After cooling, the solid formed is separated off and washed with ethyl ether to give 850 mg of N,N-dimethyl-6-nitropyridine-3-amine in the form of a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C@H:17]1([NH:27][C:28]([C@@H:30]2[CH2:39][C:38]3[C:33](=[CH:34][C:35]([C:40]([O:42][CH3:43])=[O:41])=[CH:36][CH:37]=3)[CH2:32][NH:31]2)=[O:29])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([N:31]1[C@H:30]([C:28](=[O:29])[NH:27][C@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)[CH2:39][C:38]2[C:33](=[CH:34][C:35]([C:40]([O:42][CH3:43])=[O:41])=[CH:36][CH:37]=2)[CH2:32]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc2c(c1)CN[C@H](C(=O)N[C@@H]1CCCc3ccccc31)C2
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: COC(=O)c1ccc2c(c1)CN(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)[C@H](C(=O)N[C@@H]1CCCc3ccccc31)C2
Temperature: 25 °C
Yield: 100.2 %

Procedure:
To a 0° C. solution of (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (473 mg, 2.04 mmol) and (S)-methyl 3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (745 mg, 2.04 mmol) in CH2Cl2 (12.4 mL) was added EDC (471 mg, 2.45 mmol), HOAt (334 mg, 2.45 mmol) and NMM (675 μL, 6.14 mmol). The resulting reaction mixture was allowed to warm to room temperature overnight and then quenched with EtOAc and sat. NaHCO3. The aqueous layer was extracted with EtOAc (3×). The combined organic extracts were washed with 1N HCl (2×), sat. aq. NaCl solution (1×), dried over MgSO4, filtered and concentrated in vacuo to give the title compound (1.18 g, 2.045 mmol, 100%) as a light yellow foam, which was used without further purification. MS (ESI+) m/z 578.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]([CH2:22][CH2:23][OH:24])[C:6]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]=[C:8](OC3C=CC=CC=3)[C:7]=2[N:21]=1.[CH2:25](Br)[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C[N:36](C)C=O>C(Br)C=CC1C=CC=CC=1>[CH3:3][C:4]1[N:5]([CH2:22][CH2:23][O:24][CH2:25]/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:6]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]=[C:8]([NH2:36])[C:7]=2[N:21]=1
Reactant: CN(C)C=O
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCO)c2c1C
Reactant: BrCC=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: Cc1nc(N)c2nc(C)n(CCOC/C=C/c3ccccc3)c2c1C
Reaction time: 0.08 h

Procedure:
Sodium hydride (0.41 g, 10.24 mmol, 60% in mineral oil) and anhydrous N,N-dimethylformamide (10 mL) were combined and stirred for 5 minutes under nitrogen. A solution of 1-[2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]ethan-2-ol (2.9 g, 9.752 mmol) from Part G of Example 7 in N,N-dimethylformamide (15 mL) was then added to the sodium hydride over 5 minutes. After stirring the resulting reaction solution for 10 minutes at room temperature, a solution of cinnamyl bromide (2.11 g, 10.73 mmol) in N,N-dimethylformamide (15 mL) was added to the reaction solution, and the resulting reaction mixture was stirred for 4 hours and 10 minutes. Sodium hydride (0.10 g, 60% in mineral oil) and then cinnamyl bromide (0.1 g) were added to the reaction mixture, and after stirring for 30 minutes, HPLC monitoring of the reaction mixture indicated about 9% starting material remaining. The reaction mixture was concentrated under reduced pressure, and the resulting oil was dissolved in dichloromethane. The dichloromethane solution was washed with saturated ammonium chloride (3×), water (3×), and brine (3×), dried with magnesium sulfate, filtered, and concentrated under reduced pressure to a white solid, which contained about 6% starting material by HPLC analysis. The white solid was passed through a column of silica (120 g, 40×200 mm) using 95/5 ethyl acetate/dichloromethane. The isolated product was triturated with diethyl ether, filtered off, and dried to provide 2.9 g of product with no starting material. This was carried on to the next step.
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:10])=[C:5]([C:8]#[N:9])[S:6][CH:7]=1)=[CH2:2].C1C(=O)N(Br)C(=[O:14])C1.[OH-].[Na+]>C(O)(C)(C)C.O>[CH3:10][C:4]1[C:3]([CH:1]2[CH2:2][O:14]2)=[CH:7][S:6][C:5]=1[C:8]#[N:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=Cc1csc(C#N)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1c(C2CO2)csc1C#N
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A suspension of 4-ethenyl-3-methylthiophene-2-carbonitrile (1.70 g, 11.4 mmol) in 30 mL of t-Bu-OH and 60 mL of water was added NBS (2.40 g, 13.7 mmol) portionwise. The mixture was stirred at 90° C. for 1 hour then cooled down to 10° C. Then a solution of NaOH (0.7 g in 10 mL of water, 17.5 mmol) was added dropwise and stirred for 15 minutes. The reaction mixture was extracted with EtOAc twice and concentrated. The residue was purified by silica column chromatography (petrol ether: EtOAc=20:1) to afford 3-methyl-4-(oxiran-2-yl)thiophene-2-carbonitrile.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1([NH:13][C:14]([C:16]2[O:17][C:18]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)=[CH:19][CH:20]=2)=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7]>O.O1CCCC1.CO>[C:26]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:25]=[CH:24][C:23]([O:22][CH2:21][C:18]2[O:17][C:16]([C:14]([NH:13][C:8]3([C:6]([OH:7])=[O:5])[CH2:9][CH2:10][CH2:11][CH2:12]3)=[O:15])=[CH:20][CH:19]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)C1(NC(=O)c2ccc(COc3ccc(-c4ccccc4)cc3)o2)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC1(C(=O)O)CCCC1)c1ccc(COc2ccc(-c3ccccc3)cc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
A solution of lithium hydroxide monohydrate (0.085 g, 2.0 mmol) in water (1 mL) was added to a solution of 1-{[5-(biphenyl-4-yloxymethyl)-furan-2-carbonyl]-amino}-cyclopentanecarboxylic acid methyl ester (0.092 g, 0.22 mmol) in tetrahydrofuran (3 mL) and methanol (1 mL). The mixture was stirred overnight at room temperature and then the solvents were evaporated under reduced pressure. 0.5 M NaOH was added and the solution was extracted with ether. The aqueous layer was acidified with 1 M HCl and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried (sodium sulfate), filtered, and evaporated to give 1-{[5-(biphenyl-4-yloxymethyl)-furan-2-carbonyl]-amino}-cyclopentanecarboxylic acid (61 mg, 69%) as a white solid.
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][N:16]1[C:24]2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=[C:20]([NH2:27])[C:19]=2[N:18]=[C:17]1[CH3:28]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[NH2:27][C:20]1[C:19]2[N:18]=[C:17]([CH3:28])[N:16]([CH2:15][CH2:14][O:13][CH2:12][CH2:11][NH:10][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[C:24]=2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=1
Reactant: Cc1nc(N)c2nc(C)n(CCOCCN)c2c1C
Reactant: O=C(Cl)N1CCOCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc(N)c2nc(C)n(CCOCCNC(=O)N3CCOCC3)c2c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, 4-morpholinecarbonyl chloride (370 μL) was added to a solution of 1-[2-(2-aminoethoxy)ethyl]-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine (0.757 g) in chloroform (11 mL) and triethylamine (520 μL). The reaction mixture was stirred at ambient temperature for about 3 hours; then it was diluted with chloroform (20 mL) and washed with saturated sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was recrystallized from acetonitrile and dried in a vacuum oven at 60° C. for 24 hours to provide 0.7014 g of N-{2-[2-(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)ethoxy]ethyl}morpholine-4-carboxamide as a white powder, m.p. 205-207° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([OH:33])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[C:21]([F:32])[CH:20]=3)=[C:14]([O:16][CH2:17][CH3:18])[CH:15]=2)=[CH:4][N:3]=1.CC([O-])(C)C.[K+].[CH3:40][N:41]([CH3:46])[S:42](Cl)(=[O:44])=[O:43]>O1CCCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[C:21]([F:32])[CH:20]=3)=[C:12]([O:33][S:42](=[O:44])(=[O:43])[N:41]([CH3:46])[CH3:40])[CH:11]=2)=[CH:4][N:3]=1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(O)c1-c1ccc(CN2CCOCC2)c(F)c1
Reactant: CN(C)S(=O)(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)N(C)C)c1-c1ccc(CN2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49 %

Procedure:
4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6-ethoxy-3′-fluoro-4′-morpholin-4-ylmethyl-biphenyl-2-ol (250 mg, 0.55 mmol) are [sic] suspended in 11 ml tetrahydrofuran, 0.5 g powdered molecular sieve are added and the mixture is stirred for 15 minutes at room temperature. Potassium tert-butylate (93 mg; 0.83 mmol) is added and the suspension is stirred again for 1 hour at room temperature. The beige suspension is then cooled to −20° C., and N,N-dimethylsulphamoyl chloride (158 mg; 1.1 mmol) is added. The reaction mixture is stirred for 4 hours at 0° C. and 2 hours at 10° C and then concentrated. The residue is chromatographed over silica gel with methylene chloride/MeOH (99:1). 151 mg (49%) dimethylsulphamic acid 4-(2,4-diamino-pyrimidin-5-ylmethyl)-6-ethoxy-3′-fluoro-4′-morpholin-4-ylmethyl-biphenyl-2-yl ester are obtained as a light-yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16]([CH2:18][C:19]([OH:21])=[O:20])=[O:17])[CH3:15])=[CH:10][CH:9]=1.[C:22]1(C)C=CC(S(O)(=O)=O)=CC=1.O>CO.COC(OC)(C)C>[CH3:22][O:20][C:19](=[O:21])[CH2:18][S:16]([CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:9][CH:10]=1)[CH3:15])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(c1ccc(-c2ccccc2F)cc1)S(=O)CC(=O)O
Solvent: O
Solvent: CO
Solvent: COC(C)(C)OC
Product: COC(=O)CS(=O)C(C)c1ccc(-c2ccccc2F)cc1
Reaction time: 288 h

Procedure:
1.5 gm (50 millimols) of [1-(2'-fluoro-4-biphenylyl)-ethylsulfinyl]-acetic acid, m.p. 164°-165° C., were dissovled in 3 ml of methanol and 1.2 ml of 2,2-dimethoxypropane, 100 mgm of p-toluenesulfonic acid were added to the solution, and the mixture was allowed to stand for 12 days at room temperature. Then, water was added and the ester was extracted with toluene. The organic extract was washed with water, dried and evaporated, and the residue was purified by chromatography on 75 gm of silicagel (grain size 0.05-0.2 mm) with cyclohexane/ethyl acetate--1/4. The combined ester--containing fractions were evaporated, and the residue was recrystallized from 3 ml of isopropanol. Yield: 800 mgm (50% of theory); m.p. 77°-79° C.