Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2](C)CCCN=C=NCC.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)=[CH:15][CH:14]=1.ON1C2C=CC=CC=2N=N1.CN.CO>CN(C)C=O.C(Cl)Cl.C(OCC)(=O)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C:22]([NH:2][CH3:1])=[O:24])=[CH:15][CH:14]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)CCCc1ccc(F)cc1
Agent: CN
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: CNC(=O)CCCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 18.4 %

Procedure:
At 0° C., 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (6.99 g, 36.5 mmol) was added to a solution of crude 4-(4-fluorophenyl)butyric acid (6.64 g, 36.5 mmol) and 1-hydroxybenzotriazole (4.92 g, 36.5 mmol) in N,N-dimethylformamide (50 ml) and DCM (50 ml). The reaction mixture was stirred for 20 min at 0° C. An 8.0 M solution of methylamine in methanol (91 ml. 729 mmol) was added. The reaction mixture was stirred for 16 hours, while it was warming up to room temperature. It was diluted with ethyl acetate (200 ml) and washed with a 10% aqueous solution of sodium hydrogen sulphate (100 ml). The aqueous phase was extracted with ethyl acetate (100 ml). The combined organic layers were washed with a saturated solution of sodium hydrogen carbonate (200 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (100 g), using ethyl acetate/heptane 3:1 as eluent. The product was dissolved in ethyl acetate (200 ml) and washed with water (200 ml). The organic layer was dried over magnesium sulphate. The solvent was removed in vacuo to give 1.31 g of 4-(4-fluorophenyl)-N-methylbutyramide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:11]/[C:12]2[NH:13][CH:14]=[CH:15][CH:16]=2)/[C:9]#[N:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:23][C:24]([CH3:28])=[CH:25][CH2:26]Br>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:11]/[C:12]2[N:13]([CH2:26][CH:25]=[C:24]([CH3:28])[CH3:23])[CH:14]=[CH:15][CH:16]=2)/[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: N#C/C(=C\c1ccc[nH]1)c1ccc(Cl)cc1
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)=CCn1cccc1/C=C(\C#N)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A solution of (Z)-2-(4-Chloro-phenyl)-3-(1H-pyrrol-2-yl)acrylonitrile being Compound 2 in Table 8 (200 mg, 0.875 mmol) in dry acetone (35 ml) was treated with K2CO3 (121 mg) followed by dimethylallyl bromide (111 μl, 0.962 mmol, 1.1 equivalents). The mixture was heated to a gentle reflux for 20 h. The reaction was cooled to room temperature and filtered. The filtrate was chromatographed on silica gel using ethylacetate/petroleum spirits (1:1) as eluant to afford the title compound as a yellow oil (85 mg). This is Compound 80 in Table 8.
Reaction SMILES: C(O[C:6](=[O:30])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH:14]2[CH2:27][C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH3:29])[N:24]=4)[N:19]=[CH:18][C:17]=3[NH:16][CH2:15]2)[CH2:10][CH2:9]1)(C)(C)C.[O:31]=[C:32]1[NH:37][C:36]2[CH:38]=[C:39](C(O)=O)[CH:40]=[CH:41][C:35]=2[S:34][CH2:33]1>>[CH3:29][O:28][C:23]1[N:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]1[NH:16][CH2:15][CH:14]([C@H:11]3[CH2:12][CH2:13][C@H:8]([NH:7][C:6]([C:39]4[CH:40]=[CH:41][C:35]5[S:34][CH2:33][C:32](=[O:31])[NH:37][C:36]=5[CH:38]=4)=[O:30])[CH2:9][CH2:10]3)[CH2:27][C:26]2=1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: COc1ccc2ncc3c(c2n1)CC([C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)CN3
Product: COc1ccc2ncc3c(c2n1)CC([C@H]1CC[C@H](NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1)CN3

Procedure:
The titled compound is prepared as an off-white lyophilizated powder following Scheme 8 and in analogy to Example 1 using [trans-4-(6-methoxy-1,2,3,4-tetrahydro-1,5,9-triaza-phenanthren-3-yl)-cyclohexyl]-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6](C(OC(C)(C)C)=O)[C:7]([CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([O:17][CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13][CH2:12]2)=[CH:8][CH:9]=1)=[O:4].[OH-].[Na+]>CO>[CH:18]([O:17][CH:14]1[CH2:13][CH2:12][N:11]([CH2:10][C:7]2[NH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=2)[CH2:16][CH2:15]1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)n1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)[nH]1
Temperature: 25 °C

Procedure:
Into a 50-mL recovery flask (eggplant flask), 790 mg (1.5 mmol) of 5-(4-benzhydryloxypiperidin-1-ylmethyl)pyrrole-1,2-dicarboxylic acid1-tert-butyl ester 2-methyl ester synthesized in Production Example 49 and 20 mL of methanol were fed, and the mixture was stirred under a room temperature. Then, 6.0 mL (6.0 mmol, 4.0 eq.) of a 1-N sodium hydroxide aqueous solution was dropped thereinto, and the mixture was stirred all night at an internal temperature of 60° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:13]=1[CH3:19]>O1CCOCC1>[CH3:19][C:13]1[CH:14]=[CH:15][C:16]([NH:18][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[S:10])=[CH:17][C:12]=1[NH:11][C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[S:10]
Reactant: Cc1ccc(N)cc1N
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: C1COCCO1
Product: Cc1ccc(NC(=S)Nc2ccc(Cl)cc2)cc1NC(=S)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4-chlorophenylisothiocyanate (1.39 g, 8.20 mmol) in dry dioxane (20 mL) is added dropwise, under nitrogen atmosphere, to a solution of 2,4-diaminotoluene (0.5 g, 4.10 mmol) in dry dioxane (20 mL). After 72 hours of stirring at room temperature the mixture is heated to 80° C. for 6 hours, and the solvent is eliminated under reduced pressure. The oily residue obtained is stirred with IsprOH (25 mL) for 4 hours. The white solid that precipitates is filtered and washed with n-hexane (3×25 mL) and ethyl ether (3×25 mL). The title compound is obtained as white powder. mp: 93-95° C.
Reaction SMILES: [Cl:1][C:2]1([Cl:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[BH4-].[Na+]>CO>[Cl:1][C:2]1([Cl:9])[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1
Reactant: O=C1CCC(Cl)(Cl)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCC(Cl)(Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.1 %

Procedure:
To a mixture of 4,4-dichlorocyclohexanone (WO2011/006794A 1) (5.20 g, 31.10 mmol) in anhydrous methanol (100 mL) was added sodium borohydride (2.35 g, 62.20 mmol) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 hour. Concentration in vacuo yielded a residue which was re-dissolved in methanol (50 mL) and concentrated again in vacuo. The residue was then purified by silica gel column chromatography using 10-100% ethyl acetate in hexanes as eluent to afford 4,4-dichlorocyclohexanol as an orange solid (1.90 g, 36%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[N:16]=[N:15][C:14]([NH2:17])=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:18]=1.C(Cl)Cl.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>O>[NH2:17][C:14]1[N:15]=[N:16][C:11]([C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:18][C:7]=3[CH:8]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc2oc(-c3ccc(N)nn3)cc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Nc1ccc(-c2cc3cc(O)ccc3o2)nn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
6-(5-Methoxy-benzofuran-2-yl)-pyridazin-3-ylamine (0.14 mmol) was mixed with CH2Cl2 (3 mL) at 0° C. under argon atmosphere. BBr3 (1M in CH2Cl2, 1.0 mL) was added dropwise and the mixture was stirred for 2 h at rt. The mixture was hydrolysed with H2O followed by NaHCO3 (sat. aq.). The resulting mixture was extracted with EtOAc and the organic extracts were dried over Na2SO4. After filtration and evaporation of the solvent, the crude material was purified by preparative HPLC to afford the title compound as a yellow solid (8 mg). 1H NMR δ ppm 9.21 (s, 1 H) 7.74 (d, 1 H) 7.40 (d, 1 H) 7.27 (s, 1 H) 6.96 (d, 1 H) 6.86 (d, 1 H) 6.76 (dd, 1 H) 6.69 (s, 2 H); MS m/z 228 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[O:18]1[CH2:22][CH2:21][C@@H:20]([OH:23])[CH2:19]1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:3]2[C:2]([O:23][C@@H:20]3[CH2:21][CH2:22][O:18][CH2:19]3)=[N:7][CH:6]=[C:5]([CH:4]=2)[C:8]([OH:10])=[O:9])=[CH:12][CH:13]=1
Reactant: O=C(O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Reactant: O[C@@H]1CCOC1
Product: O=C(O)c1cnc(O[C@@H]2CCOC2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example CI using 6-chloro-5-(4-chlorophenyl)-3-pyridinecarboxylic acid (CAN 1012792-56-1) and (3R)-tetrahydro-3-furanol (CAN 86087-24-3) as starting materials; LC-MS (UV peak area/ESI) 88.1%, 318.1 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[C:4]([CH3:17])[N:3]=1.[CH3:18][C:19]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:20]=1[NH2:21]>CS(C)=O>[CH2:13]([CH:12]([NH:11][C:6]1[CH:5]=[C:4]([CH3:17])[N:3]=[C:2]([NH:21][C:20]2[C:22]([CH3:27])=[CH:23][C:24]([CH3:26])=[CH:25][C:19]=2[CH3:18])[C:7]=1[N+:8]([O-:10])=[O:9])[CH2:15][CH3:16])[CH3:14]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: CCC(CC)Nc1cc(C)nc(Cl)c1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CCC(CC)Nc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1[N+](=O)[O-]
Temperature: 130 °C
Yield: 43.4 %

Procedure:
A mixture of (2-chloro-6-methyl-3-nitro-pyridin-4-yl)-(1-ethyl-propyl)-amine (250 mg, 0.97 mmol) and 2,4,6-trimethylaniline (262 mg, 1.94 mmol) in 4 ml of dry DMSO was heated at 130° C. overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give a yellow oil. The oil was purified through silica gel column chromatography to give 150 mg (43%) of the title compound as yellow solid, mp 104-107° C. 1H NMR (CDCl3) δ 10.36 (s, 1H), 9.24 (d, 1H), 6.93 (s, 2H), 5.86 (s, 1H), 3.45 (m, 1H), 2.32 (s, 3H), 2.18 (s, 6H), 2.13 (s, 3H), 1.55-1.80 (m, 4H), 0.99 (t, 6H) ppm.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:21]1[CH:26]=[CH:25][C:24](F)=[C:23]([F:28])[CH:22]=1.BrC1C=CC([O:36]C)=C(F)C=1>>[F:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:21]1[CH:26]=[CH:25][C:24]([OH:36])=[C:23]([F:28])[CH:22]=1
Reactant: CCC[C@H]1CC[C@H](c2ccc3c(F)c(-c4ccc(F)c(F)c4)ccc3c2)CC1
Reactant: COc1ccc(Br)cc1F
Product: CCC[C@H]1CC[C@H](c2ccc3c(F)c(-c4ccc(O)c(F)c4)ccc3c2)CC1

Procedure:
20 g of 1-fluoro-2(3-fluoro-4-hydroxyphenyl)-6-(trans-4-propylcyclohexyl)naphthalene (obtained in the same manner as in (5-f) except that 1-bromo-3-fluoro-4-methoxybenzene was used instead of 3,4-difluoro-1-bromobenzene to obtain 1-fluoro-2-(3-fluoro-4-methoxyphenyl)-6-(trans-4-propylcyclohexyl)naphthalene which was then demethylated with hydrobromic acid) was dissolved in 80 ml of dichloromethane. To the solution was then added dropwise 15.8 g of trifluoromethanesulfonic anhydride under cooling with ice. To the reaction mixture was then added dropwise 10 ml of pyridine in such a manner that the temperature thereof didn't exceed 5° C. After the termination of dropwise addition, the reaction mixture was stirred at the same temperature for 1 hour. To the reaction mixture was then added 20 ml of water to terminate the reaction. The resulting organic phase was washed twice with 20 ml of water, and then dehydrated and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled off. The residue was then purified through silica gel column chromatography (hexane) to obtain 24.3 g of 1-fluoro-2-(3-fluoro-4-trifluoromethanesulfonyloxyphenyl)-6-(trans-4-propylcyclohexyl) naphthalene.
Reaction SMILES: [BH4-].[Na+].[CH:3](=[N:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])[CH3:4].O>C1COCC1.CO>[CH2:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])[CH3:4]
Reactant: CC=Nc1c(C)cccc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCNc1c(C)cccc1C

Procedure:
Sodium borohydride (19.0 g, 0.5 mol) was added in small portions to a stirred solution of N-ethylidene-2,6-dimethylaniline (36.3 g, 0.247 mol) in THF (150 mL) and methanol (150 mL). The reaction was exothermic and a water/ice bath was used to cool the mixture. After addition of sodium borohydride, the bath was removed and the mixture was allowed to react for another 30 min. Then, water (150 mL) was added to the reaction mixture, while stirring and cooling the mixture with a water/ice bath. The volatiles were removed in vacuo, the aqueous layer extracted with dichloromethane (3×150 mL) and the combined organic layers were dried with sodium sulfate. Filtration and rotatory vaporation of the volatiles yielded the desired product. Yield: 36.4 g (99%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH2:10][CH2:9][C:8]([C:21]([OH:23])=[O:22])=[CH:7][C:6]=2[CH:24]=1.B([O-])([O-])O[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[CH2:37]([O:36][CH2:35][CH2:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)[CH2:10][CH2:9][C:8]([C:21]([OH:23])=[O:22])=[CH:7][C:6]=3[CH:24]=2)=[CH:32][CH:31]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: COc1ccc(CN2CCC(C(=O)O)=Cc3cc(Br)ccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccc(OC)cc2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
In toluene (20 ml), ethanol (2 ml) and water (2 ml) were suspended 7-bromo-1-(4-methoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (300 mg), 4-butoxyethoxyphenyl borate (368 mg) and potassium carbonate (534 mg), and the suspension was stirred under argon atmosphere for 30 minutes. Then, to the suspension was added tetrakistriphenylphosphinepalladium (63 mg), and the mixture was heated at 100° C. for 6 hours under argon atmosphere. After allowing to cool, water was added to the mixture, which was made acidic (pH=4) with 1N hydrochloric acid and extracted with ethyl acetate twice. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=2:1) and the resulting solid was washed with hexane to give 7-(4-butoxyethoxyphenyl)-1-(4-methoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (149 mg) as yellow crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13].[F:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[I-]>[O-2].[Zn+2].O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:6]2[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]([CH2:3][CH2:2][OH:1])[C:5]2=[O:13])=[CH:17][CH:16]=1
Reactant: Fc1ccc(I)cc1
Reactant: O=c1[nH]c2ccccc2n1CCO
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Product: O=c1n(CCO)c2ccccc2n1-c1ccc(F)cc1
Reaction time: 4.5 h
Yield: 14.5 %

Procedure:
A mixture of 1-(2-hydroxyethyl)benzimidazolone (J. Davoll, J. Chem. Soc., 1960, 308) (9 g), 4-fluoroiodobenzene (23 g), potassium carbonate (8.0 g), cupper(I) iodide (1 g), and zinc oxide (0.5 g) in N-methyl-2(3H)-pyrrolidinone (100 ml) was kept at 155° C. for 4.5 h. After cooling water (500 ml) was added followed by extraction with ethyl acetate (3×200 ml). The organic phase was washed with water and saturated calcium chloride solution and dried over magnesium sulfate. Removal of solvent in vacuo gave an oil which was purified by chromatography (silica gel, ethyl acetate) giving 1-(4-fluorophenyl)-3-(2-hydroxyethyl)-2(3H)-benzimidazolone (2 g) as a solid, mp: 124-26° C.
Reaction SMILES: [NH3:1].[C:2]([O:6][C:7]([N:9]1[CH2:12][CH:11]([C:13]2[N:17]3[CH:18]=[CH:19][N:20]=[C:21](Cl)[C:16]3=[C:15]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:25][CH:24]=3)[N:14]=2)[CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].CC(O)C>O>[C:2]([O:6][C:7]([N:9]1[CH2:12][CH:11]([C:13]2[N:17]3[CH:18]=[CH:19][N:20]=[C:21]([NH2:1])[C:16]3=[C:15]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:25][CH:24]=3)[N:14]=2)[CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(Cl)nccn23)C1
Reactant: N
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)nccn23)C1
Reaction time: 8 h

Procedure:
20 M of NH3 in H2O (3 mL) was added to a suspension of 3-[8-chloro-1-(4-phenoxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]-azetidine-1-carboxylic acid tert-butyl ester in i-PrOH (4 mL, 0.05 mol). The mixture was heated in an oil bath set at 105° C. overnight. The solvent was removed under reduced pressure and the residue was carried on to the next step without further purification. MS (ES+): m/z 467.82 (100)[MH+]. HPLC: tR=2.66 min (Open Lynx, polar—5 min).
Reaction SMILES: [NH2:1][CH:2]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:17]([O:24][CH2:25][CH:26]([NH:30][C:31]([O:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1)=[O:32])[C:27](O)=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>CN(C=O)C>[CH2:17]([O:24][CH2:25][CH:26]([NH:30][C:31]([O:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1)=[O:32])[C:27]([NH:1][CH:2]([C:9]1[CH:10]=[C:11]([Cl:16])[CH:12]=[C:13]([Cl:15])[CH:14]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)CC(N)c1cc(Cl)cc(Cl)c1
Reactant: O=C(NC(COCc1ccccc1)C(=O)O)OCCCNc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)CC(NC(=O)C(COCc1ccccc1)NC(=O)OCCCNc1ccccn1)c1cc(Cl)cc(Cl)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
119.44 mg of ethyl 3-amino-3-(3,5-dichlorophenyl)propionate, 0.164 g of 3-benzyloxy-2-[3-(pyridin-2-ylamino)propoxycarbonylamino]propionic acid, 10.00 ml of DMF, 0.084 g of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 0.097 ml of 4-methylmorpholine are reacted together with stirring firstly for 1.5 hours at 50° C. and subsequently overnight at room temperature. After removal of the DMF by distillation, the residue is taken up in ethyl acetate, washed with water, evaporated to dryness and purified by chromatography over a short silica column (eluent ethyl acetate), giving ethyl 3-{3-benzyloxy-2-[3-(pyridin-2-ylamino)propoxycarbonylamino]propanoylamino}-3-(3,5-dichlorophenyl)propionate, RT 1.552 min, FAB-MS (M+H)+ 618.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C@:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1.[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[CH2:19]>>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:18]=[CH:19][C:2]1[CH:3]=[C:4]2[CH2:10][C@:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Reactant: C=Cc1ccccn1
Product: C(=Cc1ccccn1)c1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Yield: 24 %

Procedure:
(R)-(−)-5′-Bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (150 mg, 0.5 mmol) was treated with 2-vinylpyridine (0.070 mL, 0.65 mmol) in the same way as described in example 16. Purification by flash chromatography through silica gel (eluting with ammoniated ether/methanol, 95:5 to 9:1), followed by recrystallization from acetonitrile produced the title compound (37 mg, 0.12 mmol, 23%): electrospray MS (m/z, relative intensity) 320 ([MH]+, 100).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1([C:9]#[N:10])[CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:2].[C:13]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+].NC(C1C=CC=CC=1)C1(N(C)C)CCCC1>C(OCCCC)CCC.C1COCC1.CO>[NH2:10][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]1([N:3]([CH2:1][CH3:2])[CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: [Li]c1ccccc1
Reactant: CCN(CC)C1(C#N)CCCC1
Agent: CN(C)C1(C(N)c2ccccc2)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCOCCCC
Solvent: CO
Product: CCN(CC)C1(C(N)c2ccccc2)CCCC1
Yield: 47 %

Procedure:
The title compound (0.45 g, 47%) was prepared from 1-(diethylamino)cyclopentane carbonitrile D11 (0.65 g, 3.9 mmol), and phenyllithium in dibutylether (2.4 ml of a 1.8M solution; 4.3 mmol) in THF (4 ml), followed by reaction with sodium borohydride (0.445 g, 11.7 mmol) in methanol (4 ml) in a similar manner to that described in D2. 1H NMR (CDCl3) δ: 0.42 (1H, m), 1.10 (6H, m), 1.35 (3H, m), 1.55 (1H, m), 1.66 (2H, m), 1.80-2.08 (3H, m), 2.53-2.70 (4H, m), 4.22 (1H, s), 7.20-7.31 (3H, m), 7.47 (2H, m).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Br[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH3:14][C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: CC(C)(C)CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)CCOc1ccc(C#N)cc1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
Mix 4-cyanophenol (1.2 g, 10 mmol), 1-bromo-3,3-dimethylbutane (5.3 g, 32 mmol), powdered potassium carbonate (4.14 g, 30 mmol), and powdered potassium iodide (166 mg, 1 mmol) in acetone (60 mL). Stir under inert atmosphere and heat at reflux for 48 h. Cool the reaction mixture to ambient temperature. Dilute with acetone, filter and evaporate. Purify by chromatography on silica gel eluting with hexane/EtOAc (10 and 9:1) to obtain the desired intermediate (1.8 g, 89%). MS (ES+) m/z: 221 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[CH:18]=[CH:17][C:16]4[CH2:20][CH2:21][C:22](=O)[CH2:23][C:15]=4[C:14]=3[CH:13]=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:25][CH2:26][CH:27]1[CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:27]1([CH2:26][NH:25][CH:22]2[CH2:23][C:15]3[C:14]4[CH:13]=[CH:12][N:11]([S:8]([C:5]5[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=5)(=[O:10])=[O:9])[C:19]=4[CH:18]=[CH:17][C:16]=3[CH2:20][CH2:21]2)[CH2:29][CH2:28]1
Reactant: NCC1CC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c4c(ccc32)CCC(=O)C4)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c4c(ccc32)CCC(NCC2CC2)C4)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-[(4-methylphenyl)sulfonyl]-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-one (2.0 g) in CH2Cl2 is treated sequentially with aminomethylcyclopropane ((0.630 g, 1.5 eq.) and sodium triacetoxyborohydride (1.6 g, 1.3 eq.), stirred at room temperature for 16 h, quenched with 1N NaOH and extracted with CH2Cl2. The extracts are combined, dried over MgSO4 and concentrated in vacuo to give the title product, 2.2 g, identified by NMR and mass spectral analyses.