Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[N:8]1[CH2:13][CH2:12][C:11]([C:25]#[CH:26])([O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[N+:22]([O-:24])=[O:23])[CH2:10][CH2:9]1.[C:27]1([O:33][C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl.CCOCC>[O:33]([C:34]([N:8]1[CH2:13][CH2:12][C:11]([C:25]#[CH:26])([O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[N+:22]([O-:24])=[O:23])[CH2:10][CH2:9]1)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C#CC1(Oc2ccc(F)cc2[N+](=O)[O-])CCN(C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Product: C#CC1(Oc2ccc(F)cc2[N+](=O)[O-])CCN(C(=O)Oc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.1 %

Procedure:
To a stirred suspension of 5.01 g of potassium carbonate, 50 ml of dichloromethane (dried over anhydrous magnesium sulfate) and 10.1 g of 1-N-methyl-4-ethynyl-4-(4-fluoro-2-nitrophenoxy)piperidine was added dropwise a solution of 5.66 g of phenylchloroformate in 50 ml of dichloromethane (dried over anhydrous magnesium sulfate). The mixture was stirred 12 hr at ambient temperature and 6 hr at reflux under nitrogen. The suspension was poured into ice, extracted with dichloromethane, washed with 15% sodium hydroxide solution, 1N hydrochloric acid and saturated sodium chloride solution. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered and the solvent evaporated to provide an oil. The oil was dissolved in ether, washed with water, 1N hydrochloric acid and saturated sodium chloride solution. The solution was dried over anhydrous sodium sulfate, filtered and the solvent evaporated to provide an oil. The oil was dried overnight at room temperature (1 mm) during which time it crystallized to provide 10.3 g (73.8%) of product. Recrystallization from cyclohexane/ethyl acetate provided the analytical sample, mp 82°-83°.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[CH:26]=3)[CH:22]=[CH:23][CH:24]=2)[N:4]=1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43].C([O-])(O)=O.[Na+]>ClCCl>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:42]([CH3:41])(=[O:44])=[O:43])[CH:26]=3)[CH:22]=[CH:23][CH:24]=2)[N:4]=1
Reactant: Nc1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Yield: 59.5 %

Procedure:
To a stirred and cooled (ice bath) solution of 3′-[4-trifluoromethyl-6-(4-trifluoromethylphenyl)-pyrimidin-2-yl]-biphenyl-3-ylamine (example 220) (0.23 g, 0.5 mmol) in dichloromethane (5 mL) was added triethylamine (0.21 mL) and methanesulfonyl chloride (0.06 g, 0.52 mmol), the reaction mixture was allowed to stir at room temperature for 1 h, poured into sat. NaHCO3 solution (20 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4) and evaporated. Further purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound (0.16 g, 72%) as a white solid. MS (ISP) 538.0 [(M+H)+]; mp 191° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C@H:14]2[O:26][CH3:27])(=O)=O)=CC=1.[NH3:28]>C1COCC1>[NH2:28][CH2:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C@H:14]1[O:26][CH3:27]
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1COS(=O)(=O)c1ccc(C)cc1
Reactant: N
Solvent: C1CCOC1
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1CN

Procedure:
A mixture of intermediate (23) (0.065 mol) in THF (250 ml) was treated with liquid NH3 in an autoclave at 125° C. during 16 hours. The reaction mixture was filtered and the filtrate was evaporated. The residue was partitioned between a 5% aqueous NaOH solution and DCM. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 16 g of 1,1-dimethylethyl (trans)-4-(aminomethyl)-3-methoxy-1-piperidinecarboxylate (intermediate (24).
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].CS(O[CH2:40][C:41]([F:44])([F:43])[F:42])(=O)=O>CN(C)C=O>[F:32][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH2:40][C:41]([F:44])([F:43])[F:42])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCC2)CC1
Reactant: CS(=O)(=O)OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2CC(F)(F)F)N1CCC(N2CCCC2)CC1
Yield: 46 %

Procedure:
The title compound was synthesized in analogy to example 51, from (4,4-difluoro-piperidin-1-yl)-[5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 169), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate in N,N-dimethylformamide, to give the desired product as a yellow solid (46%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].[N:15]1C=CC=CC=1>C(Cl)Cl>[NH2:15][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=1)[C:8]#[N:9]
Reactant: c1ccncc1
Reactant: N#Cc1ccnc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccnc(N)c1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
To a slurry of 2-chloro-4-cyanopyridine (10.00 g, 0.079 mol) and sodiumbicarbonate (19.92 g, 0.237 mol) in amine (0.174 mol) was added pyridine (35.0 mL) and the reaction was heated to 90° C. for 3 h. The reaction was then cooled to RT, diluted with the addition of CH2Cl2 (100 mL) and filtered. The solid was washed with EtOAc. Combined washes were concentrated in vacuo. A mixture of MeOH/hexanes was added and kept in the fridge for 12 h. The crystals that formed were filtered and washed with hexanes.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH:6]([OH:8])[CH3:7])[CH2:5][CH2:4]1.[Br:9][C:10]1[CH:15]=[CH:14][C:13](F)=[CH:12][CH:11]=1>CN(C=O)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([O:8][CH:6]([CH:3]2[CH2:5][CH2:4]2)[CH3:7])=[CH:12][CH:11]=1
Reactant: CC(O)C1CC1
Reactant: Fc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Oc1ccc(Br)cc1)C1CC1
Temperature: 100 °C
Yield: 94.6 %

Procedure:
To a 0° C. slurry of NaH (460 mg, 11.4 mmol, 60 wt % dispersion in mineral oil) in DMF (14 mL) was added 1-cyclopropylethanol (0.79 mL, 7.41 mmol) dropwise. The cold bath was removed for 30 min before the addition of 1-bromo-4-fluorobenzene (1.00 g, 5.7 mmol). The resulting reaction mixture was heated to 100° C. for 3 h. At completion, the reaction was cooled to room temperature and concentrated. The resulting oil was diluted with water (30 mL) and extracted into EtOAc (3×30 mL). The combined organics were washed with brine (20 mL), then dried over MgSO4 and concentrated to provide 1-bromo-4-(1-cyclopropylethoxy)benzene (1.30 g, 95% yield). The resulting oil was used directly without further purification.
Reaction SMILES: [Cl:1][CH:2]([Cl:9])[C:3](=O)[CH2:4][CH2:5][CH2:6][CH3:7].[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][NH2:21])(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(O)(=O)CC>>[Cl:1][CH:2]([Cl:9])/[C:3](=[N:21]/[NH:20][S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:19])/[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: CCCCC(=O)C(Cl)Cl
Solvent: CCC(=O)O
Product: CCCC/C(=N\NS(=O)(=O)c1ccc(C)cc1)C(Cl)Cl
Temperature: 60 °C
Yield: 43.4 %

Procedure:
1,1-Dichlorohexan-2-one (Intermediate 5) (45.3 mg, 0.27 mmol) and 4-methylbenzenesulfonohydrazide (50 mg, 0.27 mmol) were added to propionic acid (0.5 ml) and then heated to 60° C. for 4 hours. The reaction mixture was then heated to 100° C. for 5 minutes and allowed to cool to room temperature overnight. Hexanes (20 ml) were added and the precipitate was filtered under nitrogen to yield the title compound (39.5 mg).
Reaction SMILES: Cl.[SH:2][CH2:3][CH2:4][NH2:5].C(=O)([O-])[O-].[K+].[K+].[C:12](Cl)(=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16].ClCCl>O>[SH:2][CH2:3][CH2:4][NH:5][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCC(=O)Cl
Reactant: NCCS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCCCC(=O)NCCS
Temperature: 40 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, 22.7 g of 2-mercaptoethylamine hydrochloride (0.2 mol) and 44.3 g of potassium carbonate (0.32 mol) were introduced at room temperature in solution in 130 ml of water. The solution was warmed to 40° C. and 12.0 g of valeryl chloride (0.1 mol) were added dropwise over the course of 15 minutes. The batch was stirred at 40° C. for 3 hours and then cooled to room temperature. 70 ml of dichloromethane were added and a phase separation was carried out. The organic phase was washed with 50 ml of 20% strength ammonium chloride solution, dried over sodium sulfate and freed of its solvent under reduced pressure.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:15](=[O:23])[C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])=[CH:11][NH:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].I[CH3:25]>C1COCC1.O>[CH3:25][N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:14]=2)[C:10]([C:15](=[O:23])[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:11]1
Reactant: CI
Reactant: O=C(C(=O)N1CCCC1)c1c[nH]c2cc([N+](=O)[O-])ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(C(=O)C(=O)N2CCCC2)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.1 %

Procedure:
Add NaH (0.83 g, 20.8 mmol) to a solution of 1-(6-nitro-1H-indol-3-yl)-2-pyrrolidin-1-yl-ethane-1,2-dione (5.0 g, 17.42 mmol) in THF (60 mL). Stir at room temperature for 10 min, add iodomethane (1.18 mL, 19.2 mmol), and continue stirring for 18 h. Dilute with water and extract with EtOAc (2×). Filter the solid that formed between the layers during the extraction. Dry organic portion, concentrate, and combine the solids. Triturate the solid with ether, filter, and dry to obtain the title compound (5.20 g, 99%). 1H NMR (400 MHz, DMSO-d6): δ 8.59 (m, 2H), 8.30 (d, 1H, J=8.8 Hz), 8.17 (dd, 1H, J=8.8, 2.2 Hz), 4.01 (s, 3H), 3.48 (t, 2H, J=6.8 Hz), 3.41 (t, 2H, J=6.4 Hz), 1.85 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[CH2:20][CH2:19][C:5]2[N:6]([CH2:14][CH2:15][C:16]([OH:18])=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.CCN=C=NCCCN(C)C.[CH:32]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>ClCCl>[CH:32]1([NH:38][C:16](=[O:18])[CH2:15][CH2:14][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:20][CH2:19][C:5]2=3)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: Cc1ccc2c(c1)c1c(n2CCC(=O)O)CCN(C)C1
Reactant: NC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CCC(=O)NC2CCCCC2)CCN(C)C1
Reaction time: 16 h

Procedure:
3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoic acid was mixed with EDCI (78 mg, 0.4 mmol) and cyclohexylamine in dichloromethane and the reaction mixture was stirred for 16 h to obtain N-cyclohexyl-3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanamide after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient.
Reaction SMILES: [CH2:1]([C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6])[CH2:2][CH3:3].[C:12]([O-])([O-])=O.[K+].[K+].IC.Cl>CN(C=O)C>[CH3:12][O:11][C:10]1[C:4]([CH2:1][CH2:2][CH3:3])=[C:5]([OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: CCCc1c(O)cccc1O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCCc1c(O)cccc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 4 %

Procedure:
2-Propyl resorcinol (1.50 g, 9.86 mmol) was dissolved in DMF (anhydrous, 20 mL) and K2CO3 (681 mg, 4.93 mmol) was added. After stirring for 10 min at rt, iodomethane (0.92 mL, 14.8 mmol) was added and the reaction mixture was stirred for 6 h at 60° C. After cooling to rt, the reaction mixture was acidified with HCl (1 N aqueous solution) and concentrated under reduced pressure. Water was added and the aqueous phase was extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc/hexane (v/v) 1:15) gave 33 mg (24%) of the title compound as an oil. 1H NMR (400 MHz, CDCl3): δ 0.97 (t, 3H), 1.54 (m, 2H), 2.61 (t, 2H), 3.81 (s, 3H), 4.68 (br, 1H), 6.47 (m, 2H), 7.03 (t, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[CH3:11])[CH3:2].[Se](=O)=[O:14]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[CH:11]=[O:14])[CH3:2]
Reactant: O=[Se]=O
Reactant: CCOC(=O)c1cccnc1C
Solvent: C1COCCO1
Product: CCOC(=O)c1cccnc1C=O
Temperature: 25 °C

Procedure:
16.9 g of 2-methylnicotinic acid ethyl ester, 22.9 g of selenium (IV) oxide and 240 ml dioxane are combined and refluxed overnight under nitrogen. The mixture is cooled to RT, filtered Through celite, and evaporated. The resulting red sludge is diluted with ethylacetate, filtered twice through celite and the solvent removed by evaporation under vacuum.
Reaction SMILES: C([N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH:25](O)[CH2:26][CH3:27])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[OH:30]>>[NH:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25][C@@H:26]([OH:30])[CH3:27]
Reactant: CO
Reactant: CCC(O)c1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: C[C@H](O)Cc1ncc[nH]1

Procedure:
A solution of N-tritylimidazolylpropanol (S)-(6) (2.39 g, 6.51 mmol) in 80 ml methanol containing 4.3 ml glacial acetic acid (5%) was refluxed for about 12 hours. After that time, TLC indicated disappearance of the starting materials. The mixture was concentrated in vacuo and a white precipitate appeared upon addition of 50 ml of cold distilled water. The mixture was chilled, then filtered, and the white precipitate was washed with cold distilled water (10 ml). The filtrate was then evaporated twice, and the residual yellow oil redissolved in 50 ml dry methanol and passed through the weakly basic anion exchange resin (hydroxide form) IRA-68. The solution was then evaporated to yield a solid residue that could be recrystallized from a mixture of methanol and ethyl acetate. yield: 0.80 g, 98% of pure (S)-(7). m.p. 119-121° C.; 1H NMR (200 Mhz, CD3OD) δ 6.96 (s, 2H, NCHCHN); 3.96 (m, 1H, CHCH3); 2.4-2.65 (ABX, 3JHa-Hx =6.3Hz, 3JHb-HX =6.7Hz, 3JHa-Hb =14.5Hz, CH2); 0.87 (d, 3H, 3JH-H =6.3Hz, CH3); 13C NMR (50MHz, CD3OD) δ 145.8 (s, CH2CNH); 121.2 (d, NCH=CHNH); 67.1 (d, CHOH); 38.4 (t, CH2); 23.1 (q, CH3); MS (CI): [M+1]+. 127.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][CH2:20][O:21][CH2:22][CH3:23])[CH2:16][CH:15]2[C:24](=[O:33])[N:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=C)[CH3:26])=[O:13])[CH2:8][CH:7]1[CH:9]=C)=[O:5])[CH3:2]>ClC(Cl)C>[CH2:1]([O:3][C:4]([C:6]12[CH2:8][CH:7]1[CH:9]=[CH:31][CH2:30][CH2:29][CH2:28][CH2:27][N:25]([CH3:26])[C:24](=[O:33])[CH:15]1[CH:14]([CH2:18][CH:17]([O:19][CH2:20][O:21][CH2:22][CH3:23])[CH2:16]1)[C:12](=[O:13])[NH:11]2)=[O:5])[CH3:2]
Reactant: C=CCCCCN(C)C(=O)C1CC(OCOCC)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Solvent: CC(Cl)Cl
Product: CCOCOC1CC2C(=O)NC3(C(=O)OCC)CC3C=CCCCCN(C)C(=O)C2C1
Temperature: 95 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
The diene (1d) (1.75 g) was dissolved in dry dichloroethane (800 ml, 0.0046M solution). The solution was bubbled with argon for 10 min whereafter Hoveyda-Grubbs 1:st gen. catalyst (20 mg 3.5 mol %) was added and the reaction mixture was stirred at 95° C. overnight. Additional catalyst (25 mg) was added to the reaction mixture (at argon flow) and the reaction was stirred at 97° C. The reaction mixture was cooled to room temperature and scavenger (100 mg) was added and reaction mixture was stirred for 4 h at room temperature. The reaction mixture was filtered, the filtrate was concentrated by rotary evaporation and the residue was purified by column chromatography on silica which gave the pure title compound (1.23 g. Yield 75%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH2:19][C:20]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1.CCN(CC)CC>CC#N>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH2:19][C:20]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][N:27]([CH2:35][C:34]4[CH:37]=[CH:38][C:31]([F:30])=[CH:32][CH:33]=4)[CH2:26][CH2:25]3)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CNC(=O)OCC1c2ccccc2-c2ccccc21)NCC1CCNCC1
Reactant: Fc1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(CNC(=O)OCC1c2ccccc2-c2ccccc21)NCC1CCN(Cc2ccc(F)cc2)CC1

Procedure:
A solution of 4-[{N-(9-fluorenylmethyloxycarbonyl)glycyl}aminomethyl]piperidine (1.50 g, 3.49 mmol), 4-fluorobenzyl bromide (0.478 mL, 3.84 mmol), and Et3N (1.47 mL, 10.5 mmol) in CH3CN (200 mL) was stirred at room temperature for 13 h and concentrated. Column chromatography (SiO2, 10% CH3OH/CH2Cl2) afforded 4-[{N-(9fluorenylmethyloxycarbonyl)glycyl}aminomethyl]-1(4-fluorobenzyl)piperidine
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]([C:15]3[S:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[CH:12][C:11]3[C:6](=[C:7]([NH2:22])[N:8]=[C:9]([NH2:21])[N:10]=3)[C:5]=2[CH:4]=[CH:3]1.[H-].[Na+].I[CH3:26].O>CN(C)C=O>[CH3:1][N:2]1[C:14]2[C:13]([C:15]3[S:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[CH:12][C:11]3[C:6](=[C:7]([NH:22][CH3:26])[N:8]=[C:9]([NH2:21])[N:10]=3)[C:5]=2[CH:4]=[CH:3]1
Reactant: Cc1ccc(-c2cc3nc(N)nc(N)c3c3ccn(C)c23)s1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNc1nc(N)nc2cc(-c3ccc(C)s3)c3c(ccn3C)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 11.6 %

Procedure:
A solution of 7-methyl-6-(5-methyl-thiophen-2-yl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine (100 mg, 0.32 mmol) in N,N-dimethylformamide (5.0 mL) at 25° C. was treated with 60% sodium hydride (25 mg, 0.62 mmol) and iodomethane (0.62 mL, 0.35 mmol) and stirred at 25° C. for 15 min. The resulting mixture was poured into water and extracted with a 9/1 methylene chloride/methanol solution. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 9:1 methylene chloride/methanol) afforded 7,N1-dimethyl-6-(5-methyl-thiophen-2-yl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine (12 mg, 11.5%) as a light yellow solid; EI-HRMS m/e calcd for C17H17N5S (M+H)+ 324.1278, found 324.1280; and 7,N1,N1-trimethyl-6-(5-methyl-thiophen-2-yl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine (18 mg, 16.5%) as a dark brown solid; EI-HRMS m/e calcd for C18H19N5S (M+H)+ 338.1434, found 338.1437.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH:5]([Se]C1C=CC=CC=1)[C:6]2=[O:9].N1C=CC=CC=1.OO>C(Cl)Cl>[CH3:1][C:2]1([CH3:17])[CH:7]2[CH2:8][CH:3]1[CH:4]=[CH:5][C:6]2=[O:9]
Reactant: CC1(C)C2CC([Se]c3ccccc3)C(=O)C1C2
Agent: OO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)C2C=CC(=O)C1C2
Temperature: 0 °C
Reaction time: 5 h

Procedure:
6,6-Dimethyl-3-phenylselanyl-bicyclo[3.1.1]heptan-2-one, pyridine (8.71 mL), and methylene chloride (650 μL) were combined in a round bottom flask. The temperature of the flask was dropped to 0° C. 67.5 μL of H2O2 was added to the flask and allowed to stir at room temperature for 5 hours at 0° C. Next, the reaction was stirred at room temperature overnight. 5 mL of methylene chloride was added to the solution, and the mixture was washed with water, NaHSO3, and CuSO4, dried with NaSO4, and concentrated. The concentrate was purified via column chromatography to afford final product (70:30, Hexane: EtOAc). 1H NMR (500 MHz, CDCl3): δ (ppm) 1.485 (s, 3H), 1.517 (s, 3H), 2.145 (d, 3H), 2.2.616 (m, 1H), 2.724 (m, 1H), 2.849 (m, 1H), 5.958 (d, 1H), 7.526 (dd, 1H). (ESI, Pos) m/z 159.0 (M+23).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][C:19](O)=[O:20])[CH2:13][CH2:12]1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][CH2:19][OH:20])[CH2:13][CH2:12]1)[CH3:9])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C[C@H]1CC[C@H](CCC(=O)O)CC1)C(=O)OC(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Product: CN(C[C@H]1CC[C@H](CCCO)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.898 g (3.0 mmol) of trans-3-{4-[(tert-butoxycarbonyl-methyl-amino)-methyl]-cyclohexyl}-propionic acid dissolved in 10.0 ml of tetrahydrofuran were added slowly and at 0° C. to 4.5 ml of an 1M solution of boran-tetrahydrofuran-complex in tetrahydrofuran. The reaction mixture was then stirred at room temperature for 1 hour. Subsequently, 10 ml of methanol were added and the reaction mixture evaporated. It was then poured into 50 ml of an ice/water/aqueous sodium hydrogen carbonate mixture and extracted 3 times with 50 ml of dichloromethane. The combined dichloromethane phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 4:1 v/v mixture of dichloromethane and ether as the eluent giving 0.690 g (80.6%) trans-[4-(3-hydroxy-propyl)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester as colorless viscous oil, MS: 286 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[C:13](=[O:21])[C@H:14]([CH2:16][C:17]([O:19]C)=[O:18])[CH2:15][C:4]=2[CH:3]=1>Cl>[ClH:1].[ClH:1].[Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:22][C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[C:13](=[O:21])[C@H:14]([CH2:16][C:17]([OH:19])=[O:18])[CH2:15][C:4]=2[CH:3]=1
Reactant: COC(=O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O
Agent: Cl
Product: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O
Temperature: 50 °C
Yield: 83 %

Procedure:
(S)-Methyl 2-(4-chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino [3,4-e]indazol-7-yl)acetate (21 mg, 0.05 mmol) was dissolved in 1N hydrochloric acid (1.0 mL). Reaction was heated at 50° C. for 5 hours. Another 1 mL of 1N hydrochloric acid was added to the mixture. Reaction was heated at 50° C. for 17 hours. Mixture was concentrated in vacuo. Residue was treated with acetonitrile and then the material was concentrated. Title compound was obtained as dark yellow solid in 83% yield. MS m/e (M+H)+=385.2.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1.[OH-:9].[NH4+]>S(=O)(=O)(O)O>[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:8])=[O:9])[CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: N#CC1CCNCC1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: NC(=O)C1CCNCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-(2-methyl-phenyl-amino)-1-phenylmethyl)-4-piperidine-carbonitrile (17.89 g) was dissolved in 88 ml conc. sulfuric acid and stirred for 3 d at room temperature. The reaction mixture was poured on ice and adjusted to pH 10 by addition of 30% aqueous ammonium hydroxide and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated to yield 4-(2-methyl-phenyl-amino)-1-phenylmethyl)-4-piperidine-carboxamide (10.35 g) as a brown oil. MS: m/z=324 (M+H)+