Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:16]=3[C:26]([F:29])([F:28])[F:27])[O:12][N:11]=2)=[CH:6][CH:5]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([CH2:36][OH:37])[CH2:31]1.CS(C)=O>CC(O)C>[OH:37][CH2:36][CH:32]1[CH2:33][CH2:34][CH2:35][N:30]([CH2:3][CH:2]([C:4]2[CH:9]=[CH:8][C:7]([C:10]3[N:14]=[C:13]([C:15]4[O:19][N:18]=[C:17]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:16]=4[C:26]([F:28])([F:27])[F:29])[O:12][N:11]=3)=[CH:6][CH:5]=2)[OH:1])[CH2:31]1
Reactant: FC(F)(F)c1c(-c2ccccc2)noc1-c1nc(-c2ccc(C3CO3)cc2)no1
Reactant: OCC1CCCNC1
Solvent: CC(C)O
Solvent: CS(C)=O
Product: OCC1CCCN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(4-(oxiran-2-yl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole, Preparation 28C (30 mg, 0.075 mmol) in 2-propanol (2 mL) was added piperidin-3-yl-methanol (17.31 mg, 0.150 mmol). The reaction mixture was heated to 80° C. DMSO (1 mL) was added to help solubilize. The reaction mixture was stirred overnight. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 MeOH:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 MeOH:water with 10-mM ammonium acetate; Gradient: 45-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the Example 30 was 16.0 mg, and its purity was 100%. 1H NMR (400 MHz, MeOD) δ ppm 8.18 (2H, d, J=8.28 Hz), 7.49-7.75 (7H, m), 5.05 (1H, d, J=9.03 Hz), 3.36-3.56 (4H, m), 2.83 (2H, br. s.), 2.11-2.53 (2H, m), 1.62-2.02 (4H, m), 1.03-1.20 (1H, m). MS (m+1)=515.
Reaction SMILES: [C:1](Cl)(=[O:3])C.[OH:5][C:6]1([C:14]#N)[CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]1.C[OH:17]>>[CH3:1][O:3][C:14]([C:6]1([OH:5])[CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]1)=[O:17]
Reactant: CON1CCC(O)(C#N)CC1
Reactant: CC(=O)Cl
Reactant: CO
Product: COC(=O)C1(O)CCN(OC)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Acetyl chloride (40.7 g, 0.52 mol) was added slowly to dry methanol (115 ml) cooled to 0° C. under argon. After the addition, the solution was stirred for an additional ½ hour at 0° C. This solution was then added dropwise into a cold (0° C.) solution of 4-hydroxy-1-methoxypiperidine-4-carbonitrile (5.40 g, 34.6 mmol) in methanol (45 ml). The cooling was removed and the suspension formed was left stirring at room temperature overnight. The solvent was evaporated under vacuum and the residue was dissolved in cold (0° C.) water. NaHCO3 (saturated aqueous solution) was added carefully to adjust the pH to 7. The aqueous phase was thoroughly extracted three times with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The crude product was used without further purification. Yield: 4.9 g of 4-hydroxy-1-methoxy-piperidine-4-carboxylic acid methyl ester (title compound P4.4) as light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[C:12](=[O:36])[N:13](CC4C=CC(OC)=CC=4)[C:14](=[O:26])[N:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=4)[C:5]=3[C:4]=2[N:3]=1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[Ce]>C(#N)C.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[C:12](=[O:36])[NH:13][C:14](=[O:26])[N:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=4)[C:5]=3[C:4]=2[N:3]=1
Reactant: COc1ccc(Cn2c(=O)c3cnc4ccc(Cl)nc4c3n(-c3cccc(C(F)(F)F)c3)c2=O)cc1
Agent: [Ce]
Solvent: O=[N+]([O-])O
Solvent: CC#N
Solvent: O
Product: O=c1[nH]c(=O)n(-c2cccc(C(F)(F)F)c2)c2c1cnc1ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.9 %

Procedure:
9-chloro-3-(4-methoxybenzyl)-1-(3-(trifluoromethyl)phenyl)pyrimidino[5,4-c][1,5]naphthyridine-2,4(1H,3H)-dione (700 mg, 1.36 mmol) was dissolved in acetonitrile (40 mL) and water (10 mL). Ammonium ceric nitrate (2.9 g, 5.65 mmol) was added in batch at room temperature. The reaction mixture was stirred at room temperature for 18 hrs, and then rotary-evaporated to remove the solvent. The resulting crude product was separated by silicagel column chromatography (EtOAc/PE=0-1/4) to obtain a yellow solid (400 mg).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([CH2:7][N:8]([C:26](=[O:35])/[CH:27]=[CH:28]/[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:9]1[CH:14]=[CH:13][C:12]([O:15]C(=O)/C=C/C2C=CC=CC=2)=[CH:11][CH:10]=1)=[O:6].Cl>O.C1COCC1.CO>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([N:8]([CH2:7][C:5]([OH:6])=[O:4])[C:26](=[O:35])/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)CN(C(=O)/C=C/c1ccccc1)c1ccc(OC(=O)/C=C/c2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CN(C(=O)/C=C/c1ccccc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
Lithium hydroxide (119 mg, 4.96 mmol) in water (10 mL) was added to a solution of (E)-3-phenylacrylic acid 4-{methoxycarbonylmethyl-[(E)-(3-phenylacryloyl)]-amino}phenyl ester 12 (734 mg, 1.66 mmol) in THF (30 mL) and methanol (10 mL). The reaction mixture was stirred at room temperature for 2 h. A further quantity of lithium hydroxide (119 mg, 4.96 mmol) in water (5 mL) was added and the reaction mixture stirred for a further 1 h. It was then acidified to pH1 with conc. hydrochloric acid and concentrated in vacuo. The aqueous mixture was extracted with ethyl acetate (×2) and the organic layers combined, washed with brine, dried (Na2SO4) and evaporated. The resultant residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate, to afford the title compound (0.37 g, 75%). 1HNMR (300 MHz) (d6-DMSO) δ 4.07 (2H, br s), 6.37 (1H, d, J=15 Hz), 6.78 (2H, d), 7.22 (2H, d), 7.34 (5H, m) and 7.44 (1H, d, J=15 Hz).
Reaction SMILES: [CH3:1][NH2:2].Cl.C[Al](C)C.CO[C:10](=[O:30])[CH2:11][CH:12]([C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[CH:26][NH:27]2)=[CH:23][CH:22]=1)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>C1C=CC=CC=1>[NH:27]1[C:28]2[C:24](=[CH:23][CH:22]=[C:21]([CH:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[CH2:11][C:10]([NH:2][CH3:1])=[O:30])[CH:29]=2)[CH:25]=[CH:26]1
Reactant: COC(=O)CC(c1ccc(OC)cc1)c1ccc2cc[nH]c2c1
Reactant: CN
Agent: C[Al](C)C
Agent: Cl
Solvent: c1ccccc1
Product: CNC(=O)CC(c1ccc(OC)cc1)c1ccc2cc[nH]c2c1
Temperature: 5 °C
Yield: 79 %

Procedure:
To a 5° C. stirring suspension of MeNH2.HCl (220 mg, 3.2 mmol) in benzene (3 ml) was added dropwise Me3Al (2 M in toluene, 1.6 ml, 3.2 mmol). The mixture was stirred at room temperature for 45 minutes. A solution of 3-(1H-indol-6-yl)-3-(4-methoxy-phenyl)-propionic acid methyl ester XXXIV (480 mg, 1.6 mmol) in benzene (15 ml) was added and the resulting mixture was stirred at reflux for 3 hours. The reaction mixture was cooled to room temperature and additional mixture of MeNH2.HCl (110 mg, 1.6 mmol) in benzene (1.5 ml) and Me3Al (2M in toluene, 0.8 ml, 1.6 mmol) was added. The resulting mixture was stirred at reflux for 1.5 hours, cooled to room temperature, and the reaction was quenched by slow addition of HCl (1M, 35 ml). The mixture was stirred vigorously for 5 minutes and extracted with EtOAc (50 ml). The combined organic layers were washed with water and brine, dried over MgSO4, filtered, concentrated and purified via flash chromatography (hexane/EtOAc) to provide 3-(1H-indol-6-yl)-3-(4-methoxy-phenyl)-N-methyl-propionamide XXXV (390 mg, 81% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4](Cl)[C:3]=1[Cl:11].ClC1C=CC=CN=1>[Zn]>[Cl:8][C:6]1[C:5]([Cl:9])=[CH:4][C:3]([Cl:11])=[C:2]([Cl:1])[N:7]=1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: Clc1ccccn1
Agent: [Zn]
Product: Clc1cc(Cl)c(Cl)nc1Cl

Procedure:
at 96.75 percent pentachloropyridine conversion. Of the metallic zinc used in the reaction. 95.61 percent reacts with chloropyridine with 91.71 percent resulting in the formation of 2,3,5,6-tetrachloropyridine. Of the metallic zinc added, 100 percent oxidizes during the reaction with 99.16 percent of it accounted for in the final products.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH2:10]C=O)=N.[NH2:13][C:14]([NH2:16])=[O:15].[CH2:17](O)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:10]=[N:13][C:14]([OH:15])=[N:16][CH:17]=1
Reactant: CCO
Reactant: N=C(CC=O)c1ccccc1Cl
Reactant: NC(N)=O
Product: Oc1ncc(-c2ccccc2Cl)cn1

Procedure:
By the procedure described in Example 4 (o-chlorophenyl)formimidoylacetaldehyde is reacted with urea to give the product of the Example (recrystallized from ethanol), m.p. 232°-233° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].Br[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:59][CH:58]4[CH:54]([CH2:55][N:56]([CH3:60])[CH2:57]4)[CH2:53]3)=[CH:48][N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1>>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:59][CH:58]4[CH:54]([CH2:55][N:56]([CH3:60])[CH2:57]4)[CH2:53]3)=[CH:48][N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CN1CC2CN(c3ccc(Nc4cc(Br)cn(C)c4=O)nc3)CC2C1
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CC5CN(C)CC5C4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 50.7 %

Procedure:
Following Examples 148h, 142 mg of 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d (0.29 mmol) and 119 mg of 335e (0.29 mmol) were reacted to give 335f as a yellow solid (100 mg, 51%). LCMS: [M+H]+ 680
Reaction SMILES: [CH:1]12[C:10](=[O:11])[O:9][C:7](=[O:8])[CH:3]([CH2:4][CH2:5][CH2:6]1)[CH2:2]2.[Br-].CCO[CH2:16][CH3:17]>C1COCC1.[Cu]I>[C:7]([C@@H:3]1[CH2:4][CH2:5][CH2:6][C@H:1]([C:10]([OH:9])=[O:11])[CH2:2]1)(=[O:8])[C:17]1[CH:16]=[CH:3][CH:2]=[CH:1][CH:6]=1
Reactant: CCOCC
Reactant: O=C1OC(=O)C2CCCC1C2
Agent: [Cu]I
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)[C@H]1CCC[C@@H](C(=O)c2ccccc2)C1
Temperature: -70 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
A stirred solution of 1,3-cyclohexanedicarboxylic anhydride (67 mg, 0.43 mmol) (prepared from 1,3-cyclohexanedicarboxylic acid as described in patent application US 2004010005) and copper(I) iodide (8 mg, 0.04 mmol) in dry THF (3 mL) was cooled to −70° C. and phenmagnesium bromide in THF (0.4 mL of 1 M, 0.40 mmol) was added dropwise over 2 min. The mixture was stirred at −70° C. for 1 h and allowed to warm slowly to rt. After 2 h the mixture was poured into ether (75 mL) and extracted with satd aqueous NaHCO3 (2×30 mL). The combined aqueous extracts were acidified to pH 1 by cautious addition of concentrated HCl and back extracted with ether (2×50 mL). These ether extracts were combined, dried over Na2SO4 and evaporated under reduced pressure to afford cis-3-benzoylcyclohexane-1-carboxylic acid (78 mg, 77%) as an oil which solidified on standing. 1H NMR (CDCl3) δ 1.3-2.8 (9H), 3.32 (m, 1H), 7.45 (m, 2H), 7.55 (1=m, 1H), 7.92 (m, 2H). MS ESI +ve m/z 233 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]([C:16]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:17])=[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)=[O:4].O1CCCCC1[O:30][C@@H:31]1[CH2:39][N:34]2[CH2:35][CH2:36][NH:37][CH2:38][C@@H:33]2[CH2:32]1>C1COCC1>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]1[N:10]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:37]2[CH2:36][CH2:35][N:34]3[CH2:39][C@@H:31]([OH:30])[CH2:32][C@H:33]3[CH2:38]2)[S:7][C:8]=1[C:16]([CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17]
Reactant: C1CCC(O[C@H]2C[C@H]3CNCCN3C2)OC1
Reactant: O=C(CBr)Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Solvent: C1CCOC1
Product: O=C(CN1CCN2C[C@@H](O)C[C@H]2C1)Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 33.7 %

Procedure:
Compound 531 (120 mg, 0.300 mmol) was dissolved in THF (2 mL), and (7S,8aS)-7-(tetrahydropyran-2-yl)oxyoctahydropyrrolo[1,2-a]pyrazine (204 mg, 0.900 mmol) was added thereto, followed by stirring at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in ethanol (3 mL), and 2 mol/L hydrochloric acid (3 mL) was added thereto, followed by stirring overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was poured into water. A 2 mol/L sodium hydroxide solution added thereto to adjust the pH to 8, followed by extraction with chloroform. The organic layer was washed with a solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=23:2), followed by recrystallizing from a mixed solvent of ethanol and diethyl ether to afford the entitled Compound 569 (46.5 mg, 34%).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[H][H].[CH3:18][O:19][C:20](=[O:30])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28]Br)=[CH:23][CH:22]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:18][O:19][C:20](=[O:30])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[CH:23][CH:22]=1
Reactant: [H][H]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: COC(=O)c1ccc(CCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CCn2c3ccccc3c3ccccc32)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 29.5 %

Procedure:
Carbazole (0.50 g, 2.99 mmol) and sodium hydride (60 wt. % in mineral oil, 0.14 g, 3.59 mmol) were placed under argon and dissolved in 6 mL of anhydrous DMF at room temperature, giving a dark brown solution. Following the evolution of hydrogen gas, 4-(2-bromo-ethyl)benzoic acid methyl ester (26) (0.73 g, 2.99 mmol) in DMF (2 mL) was added and the reaction was stirred at 70° C. for 2 h. The mixture was taken up in ethyl acetate (30 mL) and water (30 mL), the organic layer was separated and the aqueous layer extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (2×25 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by MPCC(C18, 10-100% gradient of MeOH in H2O). The product co-eluted with unreacted carbazole. Cold MeOH (8 mL) was added to the product mixture and the suspension was filtered to remove the solid carbazole. The filtrate was concentrated to give the title compound (291 mg, 43%) as a red solid. 1H NMR (400 MHz, CDCl3): δ 8.11 (m, 2H), 7.92 (d, 2H, J=8.0 Hz), 7.43 (m, 2H), 7.30 (m, 2H), 7.25 (m, 4H), 4.55 (t, 2H, J=7.3 Hz), 3.91 (s, 3H), 3.20 (t, 2H, J=7.4 Hz). 13C NMR (100 MHz, CDCl3): δ 167.0, 144.1, 140.1, 123.0, 128.9, 125.8, 122.9, 120.4, 119.4, 110.6, 108.4, 52.1, 44.4, 35.2. ESI-HRMS (m/z): [M+H]+ calcd. for C22H19NO2, 330.1489. found, 330.1460.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][CH2:12][CH2:13][C@H:14]([NH2:18])[C:15](=O)[NH2:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B>C1COCC1>[CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][CH2:12][CH2:13][C@H:14]([NH2:18])[CH2:15][NH2:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)[C@@H](N)CCCNC(=O)OCc1ccccc1
Agent: B
Solvent: C1CCOC1
Product: NC[C@@H](N)CCCNC(=O)OCc1ccccc1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
((S)-4-Amino-4-carbamoyl-butyl)-carbamic acid benzyl ester (1.87 g, 7.071 mmol) is suspended in dry THF (40 ml) and cooled to 10° C. in an ice bath under nitrogen. Borane (28.3 ml of a 1 M solution in THF, 28.3 mmol) is added. The ice bath is removed and the suspension heated to 70° C. and then left to stir at this temperature for 3 hours. Further borane (28.3 ml of a 1 M solution in THF, 28.3 mmol) is added and then after an hour the same amount of 1M borane in THF is added again. After a final hour at 70° C. the reaction mixture is quenched with MeOH (40 ml). The solvent is reduced in vacuo to approximately 50 ml. This is diluted with 5 M HCl (100 ml) and washed with diethyl ether (3×100 ml). The aqueous phase is basified to pH12 with 2N NaOH and product extracted into EtOAc (3×100 ml). The organic phases are combined, dried over MgSO4 and the solvent evaporated in vacuo to yield the title compound as a colourless oil.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH:24]4[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]4)[CH2:20]3)=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH3:27][O:28][CH2:29][C:30]([Cl:32])=[O:31].CS(C)=O>N1C=CC=CC=1>[ClH:32].[CH3:27][O:28][CH2:29][C:30]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([C@@H:19]3[CH:24]4[CH2:23][CH2:22][N:21]([CH2:26][CH2:25]4)[CH2:20]3)=[O:18])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)=[O:31]
Reactant: Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: COCC(=O)Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1

Procedure:
A solution of 50 mg (0.13 mmol) of ((3R)-N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) and 27.5 mg (0.25 mmol) of methoxyacetyl chloride in 1.0 ml of pyridine is stirred at room temperature for 18 h. The reaction mixture is mixed with 3 ml of DMSO and purified by preparative HPLC. The product fractions are concentrated, mixed with 5 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum. 16 mg (29.4% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])=[N:4][C:5]([NH:8][C:9]2[CH:21]=[CH:20][C:12]3[N:13]([CH3:19])[CH2:14][CH2:15][NH:16][C:17](=[O:18])[C:11]=3[CH:10]=2)=[N:6][CH:7]=1.CO.C(Cl)[Cl:36]>>[NH2:8][C:9]1[CH:21]=[CH:20][C:12]2[N:13]([CH3:19])[CH2:14][CH2:15][NH:16][C:17](=[O:18])[C:11]=2[CH:10]=1.[Cl:36][C:5]1[N:4]=[C:3]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])[C:2]([Cl:1])=[CH:7][N:6]=1.[Cl:1][C:2]1[C:3]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])=[N:4][C:5]([NH:8][C:9]2[CH:21]=[CH:20][C:12]3[N:13]([CH3:19])[CH2:14][CH2:15][NH:16][C:17](=[O:18])[C:11]=3[CH:10]=2)=[N:6][CH:7]=1
Reactant: ClCCl
Agent: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C(=O)NCCN3C)ncc1Cl
Solvent: CO
Product: CN1CCNC(=O)c2cc(N)ccc21
Product: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl

Procedure:
2-[5-Chloro-2-(1-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-7-ylamino)-pyrimidin-4-ylamino]-N-methylbenzamide. This compound was prepared according to the procedure for Example 417b. From 7-amino-1-methyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (75 mg, 0.39 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methylbenzamide (111 mg, 0.37 mmol) was obtained 48 mg (30%) of the title compound following preparative tlc (20% MeOH/DCM); m.p. 235-245° C. (dec.); MS: m/z/=452/454 (M+H)+, Cl-isotope pattern; 1H-NMR (DMSO-d6, δ): 11.64 (s, 1H), 9.36 (s, 1H), 8.75 (m, 2H), 8.19 (s, 2H), 7.76 (d, 7 Hz, 1H), 7.70 (m, 2H), 7.47 (t, 7 Hz, 1H), 7.11 (t, 7 Hz, 1H), 6.88 (d, 8 Hz, 1H), 3.13 (m, 4H), 2.79 (s, 3H), 2.75 (s, 3H).
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.[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH2:33][CH2:34][NH:35][C:36](=[O:38])[CH3:37])=[CH:25]1>>[CH2:1]([CH:8]1[O:12][C:11](=[O:13])[C:10]([CH:18]([C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[F:15])[C:25]2[NH:24][C:32]3[C:27]([C:26]=2[CH2:33][CH2:34][NH:35][C:36](=[O:38])[CH3:37])=[CH:28][CH:29]=[CH:30][CH:31]=3)=[C:9]1[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)NCCc1c[nH]c2ccccc12
Reactant: O=C1C=C(O)C(Cc2ccccc2)O1
Reactant: O=Cc1ccccc1F
Product: CC(=O)NCCc1c(C(C2=C(O)C(Cc3ccccc3)OC2=O)c2ccccc2F)[nH]c2ccccc12

Procedure:
Using general procedure C, 5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) was reacted with 2-fluoro-benzaldehyde and N-[2-(1H-indol-3-yl)-ethyl]-acetamide) to give the title compound as a white solid. MS: 497.3 ([M−H]−).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[NH:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1.Br[CH2:18][C:19]([C:21]1[C:22]([CH3:31])=[C:23]2[C:27](=[CH:28][CH:29]=1)[C:26](=[O:30])[O:25][CH2:24]2)=[O:20].CCN(C(C)C)C(C)C>O1CCCC1.[Cl-].[Na+].O>[OH:1][CH2:2][CH2:3][CH:4]1[N:9]([CH2:18][C:19]([C:21]2[C:22]([CH3:31])=[C:23]3[C:27](=[CH:28][CH:29]=2)[C:26](=[O:30])[O:25][CH2:24]3)=[O:20])[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCNC(CCO)C1
Reactant: Cc1c(C(=O)CBr)ccc2c1COC2=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)CN2CCN(C(=O)OC(C)(C)C)CC2CCO)ccc2c1COC2=O

Procedure:
tert-Butyl 3-(2-hydroxyethyl)piperazine-1-carboxylate (6.91 g, 30.0 mmol) and 5-(2-bromoacetyl)-4-methylisobenzofuran-1(3H)-one (6.73 g, 25 mmol) were dissolved in tetrahydrofuran (100 mL) then added Hunig's base (8.73 mL, 50.0 mmol) and stirred at RT overnight. The reaction was poured into brine and extracted with EtOAc (2×). The combined organic layer was dried over Na2SO4, filtered and evaporated to dryness. The crude product was chromatographed through an ISCO Redi-Sep 330 g column and eluted with 5% MeOH/DCM solvent system to the title compound. LC-MS (IE, m/z): 419 [M+1]+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][C:16]([Br:21])=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[NH:10][C:9]1=[S:22])(=[O:3])[CH3:2].O.[OH-].[NH4+].I[CH3:27]>C(O)C>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][C:16]([Br:21])=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[S:22][CH3:27])(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)OCCCn1c(=S)[nH]c2cnc3cc(Br)ccc3c21
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1nc2cnc3cc(Br)ccc3c2n1CCCOC(C)=O
Temperature: 25 °C
Yield: 74.1 %

Procedure:
To a round-bottomed flask containing 3-(7-bromo-2-thioxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)propyl acetate (28.9 g, 76.0 mmol) was added water (180 mL), ethanol (180 mL), and ammonium hydroxide (38 mL). The resulting suspension was stirred at ambient temperature. To this suspension was added iodomethane (9.5 mL, 152 mmol), and the reaction was stirred for 2 h. The suspension was filtered through a sintered glass funnel and the residue was washed with diethyl ether and dried under reduced pressure to afford 3-[7-bromo-2-(methylthio)-1H-imidazo[4,5-c]quinolin-1-yl]propyl acetate (22.2 g) as tan solid.