Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)=[O:2].C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+].[CH:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([CH3:26])[CH3:25].O>>[CH:24]([N:27]1[CH2:32][CH2:31][N:30]([C:7]([C:6]2[CH:10]=[CH:11][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)=[O:8])[CH2:29][CH2:28]1)([CH3:26])[CH3:25]
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1

Procedure:
A solution of 4-formyl-benzoyl chloride (2.80, 16.65 mol) (prepared as in Example 1 above) in toluene (43.3 g, 469.39 mmol) was added slowly to a solution of NaHCO3 (0.8 g, 9.52 mmol) and 4-isopropylpiperazine (2.50 g, 18.35 mmol) in water (5 g, 277 mmol) at 0° C. The reaction mixture was vigorously stirred until the reaction was deemed complete. The layers were split and the toluene phase was concentrated to yield the title compound as a yellow oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Na+].[Cl-]>O1CCCC1.C(OCC)C.O>[C:7]1([CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:22][OH:23])=[CH:25][CH:26]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)c1ccc(OCCCCc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(OCCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
A suspension of lithium aluminium hydride (309 mg, 7.62 mmol) in anhydrous tetrahydrofuran (65 ml) was added under inert atmosphere with a solution of 4-(4-phenylbutoxy)benzoic acid (1.03 g, 3.81 mmol) in 20 ml of dry ethyl ether. The mixture was left under stirring at room temperature for 2 hours, after that was added slowly with a NaCl saturated solution in water (80 ml), the two phases were separated and the aqueous one was extracted with ethyl acetate (3×50 ml). The organic extracts were dried and the solvent was evaporated off to obtain a crude, which was digested with ethyl ether. The digestion extracts were evaporated under reduced pressure to obtain 556 mg of the title compound (57% yield).
Reaction SMILES: Cl.[O:2]1[CH:7]=[CH:6][CH2:5][CH2:4][CH2:3]1.[CH2:8]([OH:13])[CH2:9][CH2:10][CH:11]=[CH2:12]>>[CH2:8]([O:13][CH:7]1[CH2:6][CH2:5][CH2:4][CH2:3][O:2]1)[CH2:9][CH2:10][CH:11]=[CH2:12]
Reactant: C=CCCCO
Reactant: C1=COCCC1
Agent: Cl
Product: C=CCCCOC1CCCCO1
Yield: 87.1 %

Procedure:
Concentrated HCl (0.03 ml) was added dropwise over 25 minutes (slightly exothermic) to a solution of dihydropyran (5.37 g, 64 mmol) and 4-penten-1-ol (5.0 g, 58 mmol) while stirring. At RT the reaction mixture was stirred for two hours. The solution was washed with a saturated sodium carbonate solution and dried over anhydrous potassium carbonate, thus affording 8.6 g (87% yield) of a light yellow oil.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][N:7]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:5][C:6]1[CH:11]=[C:10]([CH2:12][Br:13])[CH:9]=[CH:8][N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccnc(F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: Fc1cc(CBr)ccn1
Temperature: 50 °C
Reaction time: 16 h
Yield: 33.2 %

Procedure:
0.073 ml of acetic acid is added to a solution of 0.111 g of 2-fluoro-4-methylpyridine in 2.5 ml of carbon tetrachloride, under an inert atmosphere of argon at a temperature in the region of 20° C. The mixture is brought, with stirring, to a temperature of 50° C. 0.356 g of N-bromosuccinimide and 0.048 g of benzoyl peroxide are successively added at this temperature. The mixture is brought to 80° C. over about 16 hours. After cooling, the reaction medium is placed on a cartridge 20 mm in diameter packed with 10 g of 20-40 μm silica not conditioned beforehand, and then eluted with dichloromethane at a flow rate of 5 ml/minute. The fractions between 28 and 38 ml are concentrated to dryness under reduced pressure. 0.063 g of 2-fluoro-4-(bromomethyl)pyridine is thus obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[N:6]=[C:7]([F:29])[N:8]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=1.[F:30][C:31]([F:37])([F:36])[CH2:32][N:33]=[C:34]=[S:35]>C1COCC1>[F:29][C:7]1[N:8]([C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=[C:5]([CH2:4][CH2:3][CH2:2][NH:1][C:34]([NH:33][CH2:32][C:31]([F:37])([F:36])[F:30])=[S:35])[N:6]=1
Reactant: NCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: FC(F)(F)CN=C=S
Solvent: C1CCOC1
Product: Fc1nc(CCCNC(=S)NCC(F)(F)F)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
4-(3-Aminopropyl)-2-fluoro-1-triphenylmethylimidazole was reacted in THF with 2,2,2-trifluoroethyl isothiocyanate for 2 hours. Extractive work-up and chromatography gave 2-fluoro-4-[3-(3-[2,2,2-trifluoroethyl]thioureido)propyl]-1-triphenylmethylimidazole having the following n.m.r. in CDCl3 : 1.78 (quintet, 2H); 2.43 (t, 2H); 3.5 (q, 2H); 4.25 (m, 2H); 6.24 (s, 1H); 7.0-7.35 (m, 15H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[H-].[Na+].[CH3:14]I>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:14])[CH:7]=[CH:6]2
Reactant: CI
Reactant: COc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2C)c1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 5-methoxyindole (200 mg, 1.36 mmol) in 1.5 mL of dry N,N-dimethylformamide was added sodium hydride (55%, 66 mg, 1.5 mmol) at 0° C. After the reaction mixture was stirred at the same temperature for 30 min, methyl iodide (0.10 mL, 1.6 mmol) was added with additional stirring at room temperature overnight. After the reaction mixture was quenched with water (5 mL) at 0° C., the solution was extracted with diethyl ether (20 mL) twice. The combined extracts were washed with brine (5 mL), and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 80/20) to obtain 5-methoxy-1-methylindole (182 mg, 83%).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH2:14][CH:15]=[CH2:16])[CH:8]=2)=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH2:14][CH2:15][CH3:16])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: C=CCc1cc(Oc2ccc(F)cc2)ccc1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1cc(Oc2ccc(F)cc2)ccc1O

Procedure:
A solution of 4-(4-fluorophenoxy)-2-allylphenol (2.30 g, 9.42 mmol) and 5% Pd/C (0.90 g) in ethyl acetate (30 mL) was stirred under H2 atmosphere for 3 h at room temperature. The reaction mixture was filtered through a short pad of silica gel and concentrated in vacuo to afford the title compound which was used as is.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:6][C:5]=1[C:19]1[NH:28][C:27](=[O:29])[C:26]2[C:21](=[C:22]([CH3:30])[CH:23]=[CH:24][CH:25]=2)[N:20]=1)[CH3:2].[BH4-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:18])[CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:6][C:5]=1[C:19]1[NH:28][C:27](=[O:29])[C:26]2[C:21](=[C:22]([CH3:30])[CH:23]=[CH:24][CH:25]=2)[N:20]=1)[CH3:2]
Reactant: CCOc1ccc(C(=O)CN2CCOCC2)cc1-c1nc2c(C)cccc2c(=O)[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccc(C(O)CN2CCOCC2)cc1-c1nc2c(C)cccc2c(=O)[nH]1
Reaction time: 18 h

Procedure:
2-(2-Ethoxy-5-morpholinoacetylphenyl)-8-methylquinazolin-4(3H)-one (Example 16; 0.2 g, 0.00049 mol) was suspended in stirred ethanol (30 ml) and the mixture treated with sodium borohydride (0.0018 g, 0.00049 mol). After 18 hours at room temperature, the solvent was evaporated under vacuum. The residue was suspended in saturated aqueous sodium carbonate solution (30 ml) and the suspension extracted with ethyl acetate (3×20 ml). The extracts were combined, dried (Na2SO4) and evaporated under vacuum, then the residue crystallized from ethyl acetate-hexane to give the title compound as colorless plates (0.14 g, 70%), m.p. 145-147° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2C(Cl)=C[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][C:22]([F:25])([F:24])[F:23].C(O)C.CC(C)([O-])C.[Na+].CCCCCCC.[C:42]([O:45][CH2:46][CH3:47])(=O)[CH3:43]>CN(C)C=O.[Cu]Br.O>[NH2:1][C:2]1[N:6]([C:7]2[C:42]([O:45][CH2:46][CH3:47])=[CH:43][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][C:22]([F:25])([F:24])[F:23]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Reactant: CCOC(C)=O
Agent: [Cu]Br
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOc1cc(C(F)(F)F)cc(Cl)c1-n1nc(C#N)c(SC(F)(F)F)c1N
Temperature: 90 °C

Procedure:
To a mixture of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthiopyrazole (4.5 g, 10.7 mmol) and ethanol (0.73 g, 16.0 mmol) in N,N-dimethylformamide (25 ml), was added sodium tert-butoxide (1.54 g, 16.0 mmol) and copper(I)bromide (0.08 g, 0.5 mmol). The mixture was heated at 90° C. for 7 hours under nitrogen. After extractive workup (heptane-ethyl acetate, water) and column chromatography the title product was obtained (2.17 g), mp 166° C., 1H-NMR: 1.34 (3H), 4.14 (2H), 4.35 (2H), 7.20 and 7.45; 19F-NMR: −45.2, −63.9.
Reaction SMILES: C1(OC)C=CC=CC=1.COC1C=CC(C[O:16][C:17](=[O:64])[CH:18]([NH:33][C:34]([NH:36][CH:37]([C:52]([O:54]CC2C=CC(OC)=CC=2)=[O:53])[CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:43](=[O:51])[C:44]2[CH:49]=[CH:48][C:47]([I:50])=[CH:46][CH:45]=2)=[O:35])[CH2:19][CH2:20][C:21]([O:23]CC2C=CC(OC)=CC=2)=[O:22])=CC=1>C(O)(C(F)(F)F)=O>[C:52]([CH:37]([NH:36][C:34](=[O:35])[NH:33][CH:18]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:17]([OH:64])=[O:16])[CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:43](=[O:51])[C:44]1[CH:45]=[CH:46][C:47]([I:50])=[CH:48][CH:49]=1)([OH:54])=[O:53]
Reactant: COc1ccc(COC(=O)CCC(NC(=O)NC(CCCCNC(=O)c2ccc(I)cc2)C(=O)OCc2ccc(OC)cc2)C(=O)OCc2ccc(OC)cc2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCC(NC(=O)NC(CCCCNC(=O)c1ccc(I)cc1)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.4 %

Procedure:
A solution of 3% anisole in TFA (15 mL) was added to 2 (0.117 g, 0.129 mmol) at 0° C. The mixture was stirred at room temperature for 30 min then concentrated on a rotary evaporator. The crude material was purified by HPLC (Econosil C18 10μ, 250×10 mm, H2O/CH3CN/TFA (70/30/0.1), 4 mL/min, 3 eluting at 11 min) to afford 0.040 g (57%) of 3. 1H NMR (400 MHz, D2O:CD3CN=1:1 (v/v)) δ 7.79 (d, J=8.0 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 4.08-4.16 (m, 2H), 3.26 (m, 2H), 2.35 (m, 2H), 2.00-2.03 (m, 1H), 1.72-1.84 (m, 2H), 1.52-1.62 (m, 3H), 1.34-1.36 (m, 2H). ESI-Mass calcd for C19H24IN3O8Na [M+Na]+ 572.1. found 572.0. FAB-HRMS calcd for C19H25IN3O8 [M+H]+ 550.0686. found 550.0648.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@:10]1([CH3:19])[S:16][CH2:15][CH2:14][N:13]=[C:12](SC)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([C:30]([NH:32][NH2:33])=O)[CH2:29][CH2:28]2)=[CH:23][CH:22]=1>C(O)CCC>[Si:1]([O:8][CH2:9][C@:10]1([CH3:19])[S:16][CH2:15][CH2:14][N:13]2[C:30]([C:27]3([C:24]4[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=4)[CH2:29][CH2:28]3)=[N:32][N:33]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CSC1=NCCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C1
Reactant: NNC(=O)C1(c2ccc(Cl)cc2)CC1
Solvent: CCCCO
Product: CC(C)(C)[Si](C)(C)OC[C@@]1(C)Cc2nnc(C3(c4ccc(Cl)cc4)CC3)n2CCS1
Temperature: 140 °C
Reaction time: 6 h
Yield: 86.6 %

Procedure:
The compound (2.09 g, 6.54 mmol) obtained in Example 4-1) and the compound (1.38 g, 6.54 mmol) obtained in Example 1-1) were dissolved in 1-butanol (10 mL), and the mixture was stirred at 140° C. for 6 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, then the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=30% to 90%) to obtain the title compound (2.63 g, 87%) in a white solid form.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH:15]([CH3:17])[CH3:16])=[C:8]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:7]=1.[Br:26]Br>C(Cl)(Cl)Cl>[OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([Br:26])[N:12]2[CH:15]([CH3:17])[CH3:16])=[C:8]([NH:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:7]=1
Reactant: BrBr
Reactant: CC(C)n1cnc2c(NCc3ccccc3)nc(NCCCO)nc21
Solvent: ClC(Cl)Cl
Product: CC(C)n1c(Br)nc2c(NCc3ccccc3)nc(NCCCO)nc21
Yield: 90 %

Procedure:
1 mmol of 2-(3-hydroxypropylamino)-6-benzylamino-9-isopropylpurine was dissolved in chloroform and 1.1 mmol of bromine was added. The 8-bromo derivative hydrobromide was removed by filtration and crystallized from n-propanol-ether. M.p. 156-161° C. Yield 90%. TLC: chloroform-methanol (96:4), single spot. MS-ESI(+)m/z: 420, 422 [M+H]+
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[F:9][C:10]1[CH:27]=[CH:26][C:13]([O:14][CH2:15][C@H:16]2[CH2:25][N:20]3[CH2:21][CH2:22][NH:23][CH2:24][C@@H:19]3[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.Cl>>[F:9][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][C@H:16]2[CH2:25][N:20]3[CH2:21][CH2:22][N:23]([C:2]4[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=4)[CH2:24][C@@H:19]3[CH2:18][CH2:17]2)=[CH:26][CH:27]=1
Reactant: Fc1ccc(OC[C@@H]2CC[C@H]3CNCCN3C2)cc1
Reactant: Clc1ccc(Cl)nc1
Agent: Cl
Product: Fc1ccc(OC[C@@H]2CC[C@H]3CN(c4ccc(Cl)cn4)CCN3C2)cc1

Procedure:
The title compound was prepared according to Preparation 11 using 2,5-dichloropyridine and (7R,9aS)-7-(4-fluorophenoxy)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Preparation 8). mp (—HCl) 237-238° C. 13C NMR (base, CDCl3): δ27.0, 29.1, 36.4, 45.3, 50.9, 54.6, 58.7, 60.5, 71.6, 107.7, 115.36, 115.47, 115.60, 115.90, 120.1, 137.1, 146.3, 155.1, 155.6, 157.6, 158.8. HRMS calcd for C20H23ClFN3O: 375.1514; found, 375.1544.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14]C)[C:9]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[C:9]1=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccn(Cc2ccccc2)c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1c(O)cccn1Cc1ccccc1
Yield: 117.5 %

Procedure:
Reaction of 141b (0.15 g, 0.55 mmol) with 1M BBr3 (0.66 mL) in dry CH2Cl2 (5 mL) within 48 h according to procedure 142a afforded pure 142b (0.13 g, 90%) as slightly brownish solid. 1H NMR (400 MHz, CDCl3) δ 7.3.1 (m, 5H), 6.83 (m, 3H), 6.14 (t, J=7.1 Hz, 1H), 5.19 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 158.62, 146.78, 135.82, 128.74, 127.97, 126.53, 113.94, 106.95, 52.18. HRMS (EI) calcd for C12H11NO2 [M]+ 201.0792. found 201.0790.
Reaction SMILES: [NH2:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4].C([O-])([O-])=O.[K+].[K+].[N:18]#[C:19]Br>C1COCC1>[CH3:5][C:2]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3][O:4][C:19]([NH2:18])=[N:1]1
Reactant: CC(N)(CO)c1ccccc1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(c2ccccc2)COC(N)=N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.8 %

Procedure:
To a stirred, cooled (0° C.) mixture of 2-amino-2-phenyl-propan-1-ol (266 mg) and K2CO3 (292 mg) in THF (5 ml) under an argon atmosphere was added a solution of cyanogen bromide (292 mg) in THF (5 ml). The ice bath was removed and stirring at r.t. was continued for 18 h. The mixture (white suspension) was taken up in EtOAc/H2O 1:1. The aqueous phase was back extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2->CH2Cl2/MeOH 9:1) to give 4-methyl-4-phenyl-4,5-dihydro-oxazol-2-ylamine (204 mg) as white solid. MS (ISP): 177.1 ([M+H]+)
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[CH:4]=1.Cl>CCO.[Fe]>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[NH2:9]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: Nc1cccc(CBr)c1
Temperature: 85 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a stirred suspension of 1-(bromomethyl)-3-nitrobenzene (40 g; 0.18 mol) and iron powder (31 g; 0.55 mol) in EtOH (1000 mL) was added concentrated HCl (33.8 g, 0.93 mol) at r.t. The mixture was stirred at 85° C. for 2 hrs, cooling to r.t. and filtered. The filtrate was evaporated and the residue was solved in EtOAc and washed with brine, dried (Na2SO4) and concentrated to give the 3-(bromomethyl)aniline (30 g, 87% yield) as a yellow solid. 1H NMR: (400 MHz, MeOD) δ 7.59-7.56 (m, 1H), 7.54 (t, 1H), 7.39 (d, 1H), 7.38-7.34 (m, 1H), 4.73 (s, 2H).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][O:4][C:3]1=[O:8].C(COC)OC.[C:15]1([N:21]=[C:22]=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCCCCC>[O:8]=[C:3]1[N:2]([NH:1][C:22]([NH:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:23])[CH2:7][CH2:6][CH2:5][O:4]1
Reactant: NN1CCCOC1=O
Reactant: O=C=Nc1ccccc1
Solvent: COCCOC
Solvent: CCCCCC
Product: O=C(Nc1ccccc1)NN1CCCOC1=O
Yield: 53 %

Procedure:
To a mixture of 5.4 g of 3-amino-tetrahydro-1,3-oxazine-2-one and 50 ml glyme was added 5.0 ml of phenyl isocyanate. After an exothermic reaction a white solid formed. The mixture was refluxed for 1 hr; cooled; diluted with hexane and filtered. The solid product was crystallized from 200 ml of ethanol to give 5.8 g (53% yield) of white cotton-like needles of 1-(tetrahydro-2-oxo-1,3-oxazin-3-yl)-3-phenylurea, mp 204°-207°.
Reaction SMILES: [C:1]1([CH:14]=O)[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH:4]=[CH:3][N:2]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[N:16]1[C:25]2[CH:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:23][CH2:22][CH2:21][C:20]=2[CH:19]=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(O)(=O)C>[C:1]1([CH2:14][N:26]([CH:24]2[C:25]3[N:16]=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:21][CH2:22][CH2:23]2)[CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH:4]=[CH:3][N:2]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: CC(C)(C)OC(=O)NCCCCNC1CCCc2cccnc21
Reactant: O=Cc1nccc2c1[nH]c1ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCCCN(Cc1nccc2c1[nH]c1ccccc12)C1CCCc2cccnc21
Yield: 24 %

Procedure:
A heavy-walled Pyrex tube was charged with a solution of 9H-pyrido[3,4-b]indole-1-carbaldehyde, 2, (0.20 g, 1.02 mmol) in 1,2-dichloroethane (5 mL). This solution was treated with tert-butyl 4-(5,6,7,8-tetrahydroquinolin-8-ylamino)butylcarbamate, 3, (0.36 g, 1.12 mmol), sodium triacetoxyborohydride (0.43 g, 2.04 mmol), 4 A molecular sieves and a catalytic amount of acetic acid (2 drops). The reaction mixture was exposed to microwave irradiation for 10 min at a temperature of 100° C. After the irradiation, the reaction mixture was cooled with high-pressure air until the temperature had fallen below 40° C. The crude reaction mixture was poured onto a saturated aqueous solution of sodium bicarbonate. The product was extracted with dichloromethane. The combined organic layers were washed with brine, dried over potassium carbonate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-5% methanol/CH2Cl2) to afford 0.12 g (24% yield) of desired product 4: 1H NMR (400 MHz, CDCl3) δ 13.43 (bs, 1H), 8.67 (d, J=3.6 Hz, 1H), 8.24 (d, J=5.6 Hz, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.82 (d, J=5.2 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.54 (dt, J=1.2, 7.4 Hz, 1H), 7.41 (d, J=7.2 Hz, 1H), 7.21 (dt, J=0.8, 7.2 Hz, 1H), 7.14 (dd, J=4.8, 7.6 Hz, 1H), 4.28-4.02 (m, 4H), 2.90-2.60 (m, 5H), 2.44-2.26 (m, 2H), 2.12-2.04 (m, 1H), 1.96-1.84 (m, 1H), 1.80-1.65 (m, 1H), 1.44-1.25 (m, 1H), 1.33 (s, 9H), 1.22-1.12 (m, 1H); ESI+ MS: m/z (rel intensity) 500.2 (100, [M+H]+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][CH2:11][OH:12].O=O>O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: Clc1ccccn1
Reactant: NCCCO
Agent: O=O
Solvent: O
Product: OCCCNc1ccccn1
Temperature: 150 °C
Reaction time: 14.5 h

Procedure:
Charge 2-chloropyridine (1.0 equiv) and 3-aminopropan-1-ol (2.2 equiv, 1.5 volumes, 1.5 wt equiv) and mix thoroughly. Purge oxygen from the system by applying vacuum (ca −10 psi) to the system and backfilling with nitrogen three times. Heat the solution to 150° C. and hold for 13-16 h under a nitrogen atmosphere. The light yellow to yellow reaction mixture is then cooled to 18-23° C. and water (1.0 volume, 1.0 wt equiv) is added. Extract the mixture three times with i-PrOAc (3×5.0 volumes, 3×4.4 wt equiv). Combine the organic extracts and wash with water (0.5 volumes, 0.5 wt equiv). Concentrate the i-PrOAc solution in vacuo to minimum stir. Tert-butyl methyl ether (5.0 volumes, 3.7 wt equiv) is used to dissolve the residual oil. Add seed crystals (0.1 wt %) of the pure product and hold at 18-23 for 5 h. Cool the mixture to 0-5° C. and hold for 1-2 h. Isolate the crystalline product by filtration and wash twice with tent-butyl methyl ether (2×2 volumes, 2×1.5 wt equiv) at 5-10° C. Dry 3-(2-pyridinylamino)-1-propanol at 25-30° C. under reduced pressure. Percent yield range observed: 60-70%.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:11]=2)=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.[S:40]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41]1>O1CCCC1.O>[F:3][C:4]1[C:9]([C:10]2[N:14]([S:45]([C:42]3[CH:43]=[CH:44][S:40][CH:41]=3)(=[O:47])=[O:46])[CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH:11]=2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccsc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccsc2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
To a suspension of sodium hydride (97.9 mg, 60% in oil) in tetrahydrofuran (10 mL) were added a solution of tert-butyl {[5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (311 mg) in tetrahydrofuran (3 mL), 15-crown-5 (449 mg), and thiophene-3-sulfonyl chloride (280 mg) under ice-cooling. The mixture was stirred at room temperature for 30 min, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→3:1) to give the title compound as a pale-yellow oil (yield 433 mg, 94%).