Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH2:8]Cl)[N:4]1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>COCCOCCOC.C(OCC)C>[CH2:23]([N:30]1[CH2:8][CH:5]2[N:4]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[CH:3]([CH2:7][CH2:6]2)[CH2:2]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ClCC1CCC(CCl)N1c1ccc(Cl)cc1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: COCCOCCOC
Product: Clc1ccc(N2C3CCC2CN(Cc2ccccc2)C3)cc1
Temperature: 25 °C
Yield: 23.6 %

Procedure:
2,5-Bis-chloromethyl-1-(4-chlorophenyl)-pyrrolidine (3.73 g, 13.57 mmol), potassium carbonate (3.75 g, 27.14 mmol), and benzyl amine (4.45 mL, 40.71 mmol) in diglyme (25 mL) was heated at reflux for 15 h. The reaction mixture was cooled to room temperature, diluted with diethyl ether (600 mL) and washed with water (6×300 mL). The combined organic layers were dried with magnesium sulfate and concentrated to a brown oil. Silica gel flash chromatography using 50% chloroform/hexanes as eluent yielded 3-Benzyl-8-(4-chloro-phenyl)-3,8-diaza-bicyclo[3.2.1]octane (1.0 g, 23.5%) as a golden solid which had the following properties: Mp. 115-117° C.; 1H NMR CDCl3 δ: 7.29 (s, 5H), 7.14 (d, J=8.1 Hz, 2H), 6.67 (d, J=8.3 Hz, 2H), 4.08 (brd s, 2H), 3.38 (s, 2H), 2.54-2.42 (m, 4H), 2.08-2.00 (m, 2H), 1.95-1.86 (m,2H).
Reaction SMILES: S(Br)([Br:3])=O.[Br:5][C:6]1[N:11]=[C:10]([CH2:12]O)[C:9]([F:14])=[CH:8][CH:7]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:5][C:6]1[N:11]=[C:10]([CH2:12][Br:3])[C:9]([F:14])=[CH:8][CH:7]=1
Reactant: O=S(Br)Br
Reactant: OCc1nc(Br)ccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: Fc1ccc(Br)nc1CBr
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
To a stirred solution thionyl bromide (2.44 g, 11.78 mmol, 1.05 eq.) in 50 ml dry DCM, cooled to 5° C., was added dropwise a solution of (6-bromo-3-fluoropyridin-2-yl)methanol (2.54 g, 11.22 mmol, 1 eq.) and pyridine (0.931 g, 11.78 mmol, 1.05 eq.) in 15 ml dry DCM. On complete addition, the cooling bath was removed, the reaction warmed to room temperature and stirred 1.5 hr. 150 ml of water and 150 ml of DCM were added and stirring allowed for 2 mins. The organic layer was separated, dried of MgSO4 and concentrated. The residue was purified by chromatography on silica gel to give 6-bromo-2-(bromomethyl)-3-fluoropyridine (2.89 g, 87% yield) as a white solid.
Reaction SMILES: S([O-])(=O)(=O)[CH3:2].[C:6](O[K])(C)([CH3:8])[CH3:7].[CH2:12]1[CH2:16][O:15][CH2:14][CH2:13]1>O>[CH2:8]([CH:14]1[CH:13]=[CH:2][CH:12]=[CH:16][O:15]1)[CH:6]=[CH2:7]
Reactant: C1CCOC1
Reactant: CC(C)(C)O[K]
Reactant: CS(=O)(=O)[O-]
Solvent: O
Product: C=CCC1C=CC=CO1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 88 %

Procedure:
To a solution of allylsulfone from Step 3 (1.78 g, 3.87 mmol) in DCM (40 mL) was added methanesulfonyl chloride (480 uL, 6.20 mmol) followed by triethylamine (730 uL, 5.2 mmol) and the reaction was stirred overnight at RT. Workup with diluted HCl and DCM afforded 2.46 g of mesylate intermediate. This mesylate intermediate (2.46 g) in THF (40 mL) was treated slowly with tBuOK 1N in THF (10 mL, 10 mmol) and the reaction was stirred 35 min at RT then diluted with water, extracted with AcOEt and DCM, dried and concentrated. The residue was purified by flash-chromatography over silica gel (eluted with Hexanes/AcOEt 95:5 to 60:40) to give 1.50 g (88%) of allyl pyrane.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:32])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][C:5]2=O.Cl.[CH2:34]([O:41][NH2:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CO.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH2:34]([O:41]/[N:42]=[C:5]1\[CH2:6][C:7]([CH2:15][O:16][C:17]2[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=2)([CH3:14])[O:8][C:9]2[C:4]\1=[C:3]([CH3:32])[C:2]([OH:1])=[C:11]([CH3:12])[C:10]=2[CH3:13])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NOCc1ccccc1
Reactant: Cc1c(C)c2c(c(C)c1O)C(=O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1O)/C(=N/OCc1ccccc1)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Reaction time: 168 h

Procedure:
A mixture of 1 g of 5-[4-(6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione (prepared as described in Example 22 of copending U.S. Ser. No. 644,996), 1.2 g of benzyloxylamine hydrochloride and 10 g of methanol was allowed to stand for 7 days at room temperature. At the end of this time, ethyl acetate and an aqueous solution of potassium carbonate were added. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography eluted with a 3:1 by volume mixture of hexane and ethyl acetate, to give the title compound, softening at 64°-69° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:12][C:11]([CH2:13][CH2:14][CH2:15][CH3:16])=[N:10][C:5]2=[N+:6]([O-])[C:7]=1[CH3:8].C(O)(=[O:19])C>>[Br:1][C:2]1[CH:3]=[C:4]2[NH:12][C:11]([CH2:13][CH2:14][CH2:15][CH3:16])=[N:10][C:5]2=[N:6][C:7]=1[CH2:8][OH:19]
Reactant: CCCCc1nc2c(cc(Br)c(C)[n+]2[O-])[nH]1
Reactant: CC(=O)O
Product: CCCCc1nc2nc(CO)c(Br)cc2[nH]1
Temperature: 120 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
8.0 g (0.02817 mole) of the compound obtained in step 5 was dissolved in 20 ml of anhydrous acetic acid. The resulting solution was stirred for 1 hour at 120° C., and evaporated under reduced pressure to remove anhydrous acetic acid. Thereafter, the residue was dissolved in a mixture of 30 ml of methanol and 40 ml of 3N LiOH. The resulting solution was refluxed for 1 hour, evaporated under reduced pressure to remove methanol, neutralized with 1N HCl and extracted with ethyl acetate(50 ml×3). The organic layer was dried over Na2SO4. The residue was concentrated under reduced pressure and purified with column chromatography(hexane:ethyl acetate =1:2) to obtain 5.3 g of the title compound(yield 66%).
Reaction SMILES: [O:1]=[C:2]([CH3:17])[CH2:3][N:4]([S:13]([CH3:16])(=[O:15])=[O:14])[C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:29](OC)(OC)[O:30]C.[C:36](=O)(O)[O-].[Na+]>CO>[CH3:36][O:1][C:2]([O:30][CH3:29])([CH3:17])[CH2:3][N:4]([S:13]([CH3:16])(=[O:15])=[O:14])[C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12]
Reactant: COC(OC)OC
Reactant: CC(=O)CN(c1c(C)cccc1Cl)S(C)(=O)=O
Reactant: O=C([O-])O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CO
Product: COC(C)(CN(c1c(C)cccc1Cl)S(C)(=O)=O)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-(2-oxopropyl)-2'-chloro-6'-methyl-methanesulphonanilide (5.7 g) in methanol (80 ml) was added 4-toluenesulphonic acid (0.2 g), followed by trimethyl orthoformate (6.65 ml). The mixture was stirred at room temperature for 24 hours, then allowed to stand for 6 days. The solution was poured into dilute sodium bicarbonate solution, and the precipitated solid was collected by filtration, washed with water, and dried to give an off-white coloured solid of melting point 84°. Yield 6.0 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][NH:16][CH2:15]2)[C:10](F)([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.C([O-])([O-])=[O:19].[Cs+].[Cs+].Br[CH:25]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30]>C(#N)C>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([C@H:25]([N:16]2[CH2:17][CH:14]([C@@H:9]([C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=3)[C:10]([OH:19])([CH3:12])[CH3:11])[CH2:15]2)[C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[C:29]#[N:30])=[CH:35][CH:36]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cccc(C(Br)c2ccc(Cl)cc2)c1
Reactant: CC(C)(F)[C@H](c1cc(F)cc(F)c1)C1CNC1
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(O)[C@H](c1cc(F)cc(F)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A solution of the crude amine from Step 3 and 6.51 g (20 mmole) of Cs2CO3 in 30 mL dry acetonitrile was stirred at rt in a flask fitted with a small Dean-Stark trap. After 15 minutes, 4.6 g (15 mmole) of 3-[bromo(4-chlorophenyl)methyl]benzonitrile was added and the mixture was heated at 60° C. After 18 h, the solution was filtered through CELITE and the residue was washed with acetonitrile. The combined filtrates were concentrated and the residue was purified by flash chromatography using a step gradient of 5 to 20% ethyl acetate-hexane. Fractions containing the faster product diastereomer were pooled and concentrated to afford the title compound; 1NMR (CDCl3) δ 1.25 (t, J=22 Hz, 611), 2.33 (t, J=6.5 Hz, 1H), 2.83-2.89 (m, 2H), 3.09-3.11 (m, 2), 3.60 (m, 1), 4.24 (s, 1H), 6.68-6.71 (m, 3H), 7.21-7.8 (m, 8H); Mass Spectrum: m/e=469 (M+1, 35Cl) and 471 (M+1, 37Cl).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17](Br)[CH:16]=[CH:15]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:23]([O:28][CH:29]([C:31]#[CH:32])[CH3:30])#[C:24][CH2:25][CH2:26][CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cu](I)I.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(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([C:32]#[C:31][CH:29]([O:28][C:23]#[C:24][CH2:25][CH2:26][CH3:27])[CH3:30])[CH:16]=[CH:15]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C#CC(C)OC#CCCC
Reactant: CCCCCCCCCCOc1ccc2cc(Br)ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCC#COC(C)C#Cc1ccc2cc(OCCCCCCCCCC)ccc2c1
Yield: 82 %

Procedure:
18.2 g (0.05 mol ) of 6-decyloxy-2-bromonaphthalene (VI-60), 15.4 g (0.1 mol ) of (+)-2-pentynyloxy-3-butyne (VII*-60), 0.5 g of copper iodide, 0.8 g of triphenylphosphine, 0.4 g of bis(triphenylphosphine)-palladium chloride and 100 ml of triethylamine were stirred under reflux for 7 hours in an atmosphere of nitrogen gas. After completion of the reaction, the reaction mixture was poured into ice-aqueous hydrochloric acid and extracted with 200 ml of ethyl acetate. The organic layer was further washed with water and concentrated under reduced pressure. The residue was purified by silica gel chromatography using toluene-ethyl acetate as eluent to obtain 17.9 g (yield 82%) of optically active (+)-6-decyloxy-2-(3-pentynyloxy-1-butynyl)naphthalene (I'-60), [α]D20 =+93 (c=1, chloroform).
Reaction SMILES: [CH3:1][N:2]([CH:4]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]=O)[CH2:7][CH2:6]1)[CH3:3].Cl.[NH2:21][OH:22]>C(O)C>[CH3:1][N:2]([CH:4]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]=[N:21][OH:22])[CH2:7][CH2:6]1)[CH3:3]
Reactant: CN(C)C(c1cccc(F)c1)C1CCC(C=O)CC1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CN(C)C(c1cccc(F)c1)C1CCC(C=NO)CC1
Reaction time: 3.5 h

Procedure:
The carbaldehyde 34 (6.32 g, 24 mmol) and hydroxylamine hydrochloride (2.5 g, 36 mmol) were dissolved in abs. ethanol (90 ml); basic ion exchanger Amberlyst A21 (17 g) was added and stirring was carried out for 3.5 h at RT. The ion exchanger was filtered off and washed with ethanol (2×50 ml). The solution was concentrated and the residue was adjusted to pH 11 with 5N NaOH. The aqueous phase was extracted with ethyl acetate (3×50 ml) and the organic phase was dried over sodium sulfate and concentrated in vacuo.
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=1[Cl:33]>CN(C=O)C>[Br:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][CH:9]2[CH2:10][CH2:11][CH2:12][N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:8]2=[O:13])=[C:27]([Cl:33])[CH:28]=1
Reactant: Clc1cc(Br)ccc1CBr
Reactant: O=C1CCCCN1C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C1C(Cc2ccc(Br)cc2Cl)CCCN1C1CCCCC1
Temperature: -78 °C
Yield: 37.8 %

Procedure:
Dissolve 1-cyclohexyl-piperidin-2-one (0.2 g, 1.10 mmol) in dry DMF (11 mL) cool to −78° C. and add lithium bis(trimethylsilyl)amide (1.66 mL of 1.0 M solution in THF, 1.66 mmol). After 15 min add 1-bromomethyl-2-chloro-4-bromobenzene (0.63 g, 2.21 mmol), and allow the mixture to warm to room temperature over 15 h. Partition the mixture between ether and brine, dry the organic layer over sodium sulfate and evaporate. Purify the residue by chromatography on silica gel (eluting 0% to 100% ethyl acetate in hexane) to give the desired product (0.16 g, 38%). MS (ES+) m/z=384, 386 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[S:26]([NH2:29])(=[O:28])=[O:27])=[CH:16][CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:30])[CH:3]=1.CC1(C)[SiH2][SiH]=[N:35][C:34](C)(C)C1(C)C.[Na].BrC#N.CC(O)=O>C1COCC1>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[S:26]([NH:29][C:34]#[N:35])(=[O:27])=[O:28])=[CH:18][CH:19]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:30])[CH:3]=1
Reactant: CC1(C)N=[SiH][SiH2]C(C)(C)C1(C)C
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Agent: N#CBr
Agent: [Na]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2S(=O)(=O)NC#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5,7-dimethyl-2-ethyl-3-[2'-(aminosulfonyl)[1,1']-biphenyl-4-yl]methyl-3H-imidazo[4,5-b]pyridine (122 mg, 0.29 mmol) in THF (1.5 mL) at 0° C. was added sodium hexamethyldisilazine (0.35 mL of a 1M solution in THF). After 10 min, a solution of BrCN (37 mg, 0.35 mmol) in THF (1 ml) was added dropwise via a double tipped needle. The reaction was warmed to r.t. and stirred for 3 h at which time 0.3 mL of HOAc was added. Extraction with CH2Cl2 (5×30 mL) from H2O (30 mL), evaporation of the organic extracts and purification (SiO2, 80:19:1 CH2Cl2 /CH3OH/NH4OH) gave 5,7-dimethyl-2-ethyl-3-[2'-(N-cyanoaminosulfonyl)[1,1']-biphenyl-4-yl]methyl-3H-imidazo[4,5-b]pyridine as a glass.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C@@H:19]1[CH2:23][C@@H:22]([N:24]([CH3:26])[CH3:25])[CH2:21][C@H:20]1[C:27]([OH:29])=O.Cl.[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)=[C:36]([C@@H:38]([NH:40][C:41](=[O:43])[CH3:42])[CH3:39])[CH:37]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([CH:44]2[CH2:45][CH2:46][N:47]([C:27]([C@@H:20]3[CH2:21][C@H:22]([N:24]([CH3:25])[CH3:26])[CH2:23][C@H:19]3[C:13]3[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=3[F:11])=[O:29])[CH2:48][CH2:49]2)=[C:36]([C@@H:38]([NH:40][C:41](=[O:43])[CH3:42])[CH3:39])[CH:37]=1
Reactant: CN(C)[C@H]1C[C@@H](C(=O)O)[C@H](c2ccc(F)cc2F)C1
Reactant: CC(=O)N[C@@H](C)c1cc(Cl)ccc1C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H](C)c1cc(Cl)ccc1C1CCN(C(=O)[C@@H]2C[C@H](N(C)C)C[C@H]2c2ccc(F)cc2F)CC1
Reaction time: 18 h

Procedure:
N,N-diisopropylethylamine (82.4 μL, 0.473 mmol) was added to a stirred suspension of (1R,2R,4R)-2-(2,4-difluorophenyl)-4-(dimethylamino)cyclopentanecarboxylic acid hydrochloride (48.2 mg, 0.158 mmol, prepared essentially as described in EXAMPLE 44), N-[(1S)-1-(5-chloro -2-piperidin-4-ylphenyl)ethyl]acetamide hydrochloride (50 mg, 0.158 mmol), and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (72.0 mg, 0.189 mmol) in N,N-dimethylformamide (1.5 mL) at ambient temperature. After approximately 18 h, the reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification of the crude residue by preparative reversed phase high pressure liquid chromatography on YMC Pack Pro C18 phase (gradient elution; 0-100% acetonitrile/water as eluent, 0.1% TPA modifier) afforded the title compound as a buff white solid (m/z (ES) 532 (MH+).
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[N+:8]([C:11]1[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9].C(N(CC)CC)C.O>O1CCOCC1>[OH:4][CH2:3][C:2]([NH:1][S:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=1)(=[O:18])=[O:19])([CH2:5][OH:6])[CH3:7]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CC(N)(CO)CO
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: CC(CO)(CO)NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 24.8 %

Procedure:
To a stirred solution of 2-amino-2-methyl-1,3-propanediol (1.04 ml, 9.93 mmol) in dioxane (25 ml) was added at room temperature 3-nitrobenzenesulfonyl chloride (2.0 g, 9.02 mmol) and triethylamine (1.38 ml, 9.93 mmol). The light yellow suspension was stirred at room temperature for 6 h, poured into water (100 ml) and extracted with dichloromethane (3×75 ml). The combined organic layers were washed with water (100 ml) and brine (70 ml), dried (MgSO4) and evaporated. The crude product was further purified by column chromatography on silica gel (heptane/ethyl acetate 1:1) to yield N-(2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-3-nitro-benzenesulfonamide (0.65 g, 25%) as a white solid. MS (ISP) 289.1 [(M−H)−]; mp 116° C.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)cc1F
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f44) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[N:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1.[F:23][C:24]1[C:29]2[O:30][CH2:31][CH2:32][O:33][C:28]=2[CH:27]=[C:26]([CH:34]=O)[CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].C(Cl)(Cl)[Cl:56]>CO>[ClH:56].[F:23][C:24]1[C:29]2[O:30][CH2:31][CH2:32][O:33][C:28]=2[CH:27]=[C:26]([CH2:34][NH:1][CH:2]2[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]3[N:19]4[C:20]5[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=5[N:16]=[CH:17][C:18]4=[O:21])[CH2:10]3)[CH2:4][CH2:3]2)[CH:25]=1
Reactant: ClC(Cl)Cl
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ncc(=O)n2c43)CC1
Reactant: O=Cc1cc(F)c2c(c1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cl
Product: O=c1ccc2ncc(=O)n3c2n1C[C@H]3CN1CCC(NCc2cc(F)c3c(c2)OCCO3)CC1
Reaction time: 1.5 h
Yield: 49.5 %

Procedure:
A suspension of (2R)-2-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (for a preparation see Example 16A(j)) (58.5 mg, 0.194 mmol) and 8-fluoro-2,3-dihydro-1,4-benzodioxin-6-carbaldehyde (for a synthesis see WO2007122258, Example 8(b)) (31.8 mg, 0.175 mmol) in chloroform (2 ml) and methanol (0.100 ml) at room temperature under nitrogen was stirred for 0.5 h. This was then treated with sodium triacetoxyborohydride (123 mg, 0.582 mmol) and stirred for 90 min. This was then treated with saturated aqueous NaHCO3 (10 ml) and extracted with 20% methanol/DCM (3×25 ml). The combined organic extracts were dried (NaSO4), filtered, evaporated and purified using silica chromatography (0-20% methanol/DCM) to give the free base of the title compound as a yellow gum (44.9 mg, 49.5%).
Reaction SMILES: O.[OH-].[Li+].[NH:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:5][C:6]([N:8]([CH2:10][C:11]([O:13]C)=[O:12])[CH3:9])=[O:7].Cl>C1COCC1.CO.O>[NH:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:5][C:6]([N:8]([CH2:10][C:11]([OH:13])=[O:12])[CH3:9])=[O:7]
Reactant: COC(=O)CN(C)C(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN(CC(=O)O)C(=O)CNC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
Lithium hydroxide monohydrate (598 mg, 14.3 mmol) was added to a solution of 200 (1.22 g, 4.7 mmol) in 20 mL of THF—CH3OH—H2O (3:1:1) at 25° C. and the resulting reaction mixture was stirred for 3 h. The reaction mixture was poured onto 3M aqueous HCl (10 mL) and extracted with EtOAc (3×20 mL). The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo to give 300 (1.16 g, 1.16 g theoretical, 100%) as a colorless oil. This acid was identical to authentic material14 and was used directly in the next step without further purification: 1H NMR (CDCl3, 400 MHz)14 5.76 and 5.66 (two br s, 1H), 4.11, 4.00, and 3.91 (three s, 4H), 2.99 and 2.95 (two s, 3H), 1.38 (s, 9H); IR (neat)max 3348, 2979, 2937, 1717, 1654, 1691, 1409, 1368, 1287, 1252, 1167, 1053, 1030, 954, 866, 782, 736 cm−1.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[N:16]#[C:17]Br.C(N(CC)CC)C>C1COCC1>[Br:1][C:2]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][N:8]([C:17]#[N:16])[CH2:9][CH2:10]1
Reactant: N#CBr
Reactant: Fc1ccc(Br)c(OC2CCNCC2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CN1CCC(Oc2cc(F)ccc2Br)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2-bromo-5-fluorophenoxy)piperidine (2.0 g, 7.30 mmol) in THF (24.3 ml) was added cyanogen bromide (0.77 g, 7.30 mmol) followed by triethylamine (1.01 ml, 7.3 mmol) at 0° C. The mixture was warmed to rt and further stirred for 1 h. Solvent was evaporated and the residue was diluted with 1N HCl (20 mL). The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic fractions were washed with water (20 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure to afford the title compound as a solid which was used in the next step without further purification.