Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1([C:8]([C:10]2[C:11]3[CH2:28][S:27](=[O:30])(=[O:29])[C:26]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:12]=3[N:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[N:14]=2)=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[Cl:31][CH2:32][CH:33]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[Cl:31][CH2:32][CH2:33][N:18]1[CH2:19][CH2:20][CH:15]([N:13]2[C:12]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[S:27](=[O:30])(=[O:29])[CH2:28][C:11]=3[C:10]([C:8]([N:2]3[CH2:3][CH2:4][O:5][CH2:6][CH2:7]3)=[O:9])=[N:14]2)[CH2:16][CH2:17]1
Reactant: O=CCCl
Reactant: O=C(c1nn(C2CCNCC2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(c1nn(C2CCN(CCCl)CC2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A suspension of 3-(morpholin-4-ylcarbonyl)-1-piperidin-4-yl-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide hydrochloride (100 mg; 0.23 mmol; 1 eq.), chloroacetaldehyde (31.13 mg; 0.24 mmol; 1.1 eq.) in DCE (4.2 ml) is added sodium triacetoxyborohydride (229.27 mg; 1.08 mmol; 1.4 eq) and the reaction mixture is stirred at 65° C. overnight. The reaction mixture is diluted with DCM and the organic phase is washed with a saturated aqueous solution of NaHCO3 then dried on MgSO4 and concentrated. The residue is purified by flash chromatography eluting from 100% to 30% AcOEt and MeOH to afford after concentration of the desired fractions of the title compound as a brown oil. HPLC (max plot) 89.6%; Rt 2.33 min.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][C:22](=O)[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH:22]([N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)[CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(c3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.3 %

Procedure:
To a suspension of 4-phenylpiperidine (2.12 g, 13.1 mmol) and 3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (2.43 g, 13.1 mmol) in MeOH (60 mL) was added NaBH(OAc)3 (8.32 g, 39.3 mmol) and the reaction mixture was stirred at ambient temperature for about 16 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in DCM (50 mL) and stirred with saturated aqueous NaHCO3 (50 mL) for about 1 h. The organic portion was separated, dried over MgSO4, filtered, and concentrated in vacuo to give 3-(4-phenyl-piperidin-1-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (4.3 g,) as a yellow oil which was used in subsequent reactions without further purification. RP-HPLC (Table 1, Method d) Rt 2.73 min; m/z: (M+H)+ 331.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([O:44][CH2:45][CH2:46][C:47]([CH3:62])([CH3:61])[CH2:48][CH2:49]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:43])=[O:42])=[CH:37][CH:36]=1>CN(C=O)C.O>[CH3:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([O:44][CH2:45][CH2:46][C:47]([CH3:61])([CH3:62])[CH2:48][CH2:49][O:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:23]2[N:22]=[CH:21][N:20]([C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:24]=2)(=[O:43])=[O:42])=[CH:37][CH:36]=1
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(C)CCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: Oc1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCC(C)(C)CCOc2ccccc2-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
To a stirred solution of 2-(1-trityl-1H-imidazol-4-yl)phenol (1.50 g, 3.73 mmol) in anhydrous DMF (10 mL) was added NaH (4.10 mmol) portion wise at 0° C. The resulting suspension was allowed to stir for 15 min. To the resulting suspension was added a solution of 3,3-dimethylpentane-1,5-diyl bis(4-methylbenzenesulfonate) (3.28 g, 7.45 mmol) in DMF (8 mL) and the mixture was allowed to stir overnight at rt. The reaction mixture was diluted with water (50 mL) and the aqueous phase was extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to afford a yellow oil which was purified by flash column chromatography on silica gel to afford the desired product (1.60 g, 64% yield). 1H NMR (A): 0.84 (s, 6H), 1.34 (t, 2H, J=7.32 Hz), 1.52 (t, 2H, J=7.20 Hz), 2.38 (s, 3H), 3.85 (t, 2H, J=7.32 Hz), 4.02 (t, 2H, J=7.32 Hz), 6.79 (d, 1H, J=8.19 Hz), 7.03 (t, 1H, J=7.47 Hz, 7.14-7.35 (m, 18H), 7.44 (s, 1H), 7.50 (s, 1H), 7.72-7.77 (m, 2H), 8.23 (d, 1H, J=5.64 Hz). 1H NMR (B): 1.08 (s, 6H), 1.95 (t, 4H, J=7.08 Hz), 4.16 (t, 4H, J=6.96 Hz), 6.92-7.02 (m, 4H), 7.20 (m, 2H), 7.45 (s, 2H), 7.65 (s, 2H), 7.86 (d, 2H, J=6.12 Hz), 8.19 (br s, 2H)
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([OH:12])=[CH:4][CH:3]=1.[O:13]([CH2:20][CH2:21]O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][CH2:21][CH2:20][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(Br)ccc1O
Reactant: OCCOc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: ClCCl
Product: COC(=O)c1nc(Br)ccc1OCCOc1ccccc1
Reaction time: 48 h
Yield: 71.3 %

Procedure:
A mixture of methyl 6-bromo-3-hydroxypicolinate (26B) (308 mg, 1.33 mmol) and 2-phenoxyethanol (183 mg, 1.33 mmol) were stirred in dry DCM (10 mL). PPh3-polystyrene bound (665 mg, 2.0 mmol) was added, followed by the dropwise addition of DIAD (0.387 mL, 2.0 mmol). The mixture was stirred for 48 hours, then filtered through Celite and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel eluting with a gradient of PE/EtOAc 9:1-7:3 to provide 334 mg (72%) of the desired compound methyl 6-bromo-3-(2-phenoxyethoxy)picolinate (27A): 1H NMR (300 MHz, CDCl3) δ7.58-6.90 (7H, m), 4.43 (2H, m), 4.34 (2H, m), 3.91 (3H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].CC1C=CC(S(O[CH2:31][CH2:32][F:33])(=O)=O)=CC=1.CCOC(C)=O>CN(C)C1C=CN=CC=1.C1COCC1>[F:33][CH2:32][CH2:31][N:17]1[CH2:18][CH2:19][N:14]([C:6]2[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:15][CH2:16]1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: O=[N+]([O-])c1cc(N2CCNCC2)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(N2CCN(CCF)CC2)cc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 51.2 %

Procedure:
Mix (3-nitro-5-(trifluoromethyl)phenyl)piperazine (200 mg, 0.73 mmol), 2-fluoroethyl 4-methylbenzenesulfonate (320 mg, 1.46 mmol) and 4-dimethylaminopyridine (50 mg, 0.37 mmol) in THF (15 mL), stir at 90° C. overnight. TLC (EtOAc:PE=1:1) shows the reaction is complete. Concentrate under reduced pressure to give a residue, purify the residue by flash chromatography (silica gel, PE:EtOAc=1:1) to yield a white solid as the target compound (120 mg, 51%).
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)=[O:2].[C:12]1([N:18]=[C:19]=[S:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(#N)C>[CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:19]([NH:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[S:20])=[CH:7][CH:6]=1)=[O:2]
Reactant: S=C=Nc1ccccc1
Reactant: Nc1ccc(NNC=O)cc1
Solvent: CC#N
Product: O=CNNc1ccc(NC(=S)Nc2ccccc2)cc1

Procedure:
1-Formyl-2-(4-aminophenyl)hydrazine (30 g, 0.20 mole) was dissolved in acetonitrile (550 ml) with heat. Phenyl isothiocyanate (28 g, 0.22 mole) was added in one portion. The mixture was refluxed for 5 minutes and then chilled. The solid was filtered off, washed with acetonitrile and dried at 75° C. Yield 52 g (91%), m.p. 188°-188.5° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11].[C:17](Cl)([Cl:19])=[O:18].O>C1(C)C=CC=CC=1>[Cl:19][C:17]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11])=[O:18]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1CO
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CO/C=C(/C(=O)OC)c1ccccc1COC(=O)Cl
Reaction time: 3 h
Yield: 13 %

Procedure:
A solution of (E)-methyl 2-[2-(hydroxymethyl)phenyl]-3-methoxypropenoate (1 g) in toluene (10 ml) was added slowly to a solution of phosgene in toluene (12.5% w/w, 6.5 ml). After stirring for 3 hours, water (70 ml) was added and the resulting mixture was extracted with diethyl ether. The diethyl ether extract was washed with brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure to leave an oil. The oil was purified by chromatography on silica gel, eluting with 30% ethyl acetate/hexane to give (E)-methyl 2-[2-(chloroformyloxy-methyl)phenyl]-3-methoxypropenoate (0.163 g, 13%). 1H NMR (CDCl3): 3.7(s,3H), 3.8(s,3H), 4.5(s,2H), 7.1-7.5(m,4H), 7.6(s,1H) ppm. IR (film): 1631, 1707, 1774 cm−1.
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@H:25]4[CH3:30])[C:18]4[CH2:23][NH:22][CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:40]([O:42][CH2:43][CH3:44])=[O:41]>CN(C=O)C>[CH:2]1([NH:5][C:6](=[O:7])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@H:25]4[CH3:30])[C:18]4[CH2:23][N:22]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)[CH2:3][CH2:4]1
Reactant: C[C@@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CNC2
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3F)nc(N3CCOC[C@H]3C)c2C1
Reaction time: 8 h
Yield: 26.8 %

Procedure:
A solution of (R)-1-cyclopropyl-3-(3-fluoro-4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride (intermediate 33) (121 mg, 0.270 mmol) and triethylamine (75 μL, 0.534 mmol) in anhydrous DMF (2 ml) was stirred at RT for 40 minutes. After this time, ethyl chloroformate (30 μl, 0.322 mmol) was added and stirring was continued at RT overnight. The reaction was partitioned between H2O and EtOAc and the aqueous phase was extracted into EtOAc. The organic extracts were combined, dried over magnesium sulphate and concentrated in vacuo. The sample was then purified via preparative HPLC at low pH to yield the title compound (35 mg, 27%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Sn](Cl)(Cl)(Cl)Cl.[C:23](Cl)(=[O:25])[CH3:24].O>C(Cl)Cl>[C:23]([C:8]1[C:7]([O:9][CH3:10])=[CH:6][C:5]([NH:11][C:12](=[O:17])[C:13]([F:14])([F:16])[F:15])=[CH:4][C:3]=1[O:2][CH3:1])(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: COc1cc(NC(=O)C(F)(F)F)cc(OC)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1cc(NC(=O)C(F)(F)F)cc(OC)c1C(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.7 %

Procedure:
To a solution of N-(3,5-dimethoxyphenyl)-2,2,2-trifluoroacetamide (31.8 g, 130 mmol) in anhydrous methylene chloride (450 mL), cooled in an ice bath, is added a solution of tin (IV) chloride (29.9 mL, 260 mmol dissolved in 30 mL anhydrous methylene chloride) dropwise over 10 minutes. Acetyl chloride (9.1 mL, 130 mmol) is added slowly, maintaining the temperature of the reaction below 5° C. After stirring 3 hours at room temperature, the reaction is cooled in an ice bath. Water (300 mL) is added, maintaining the temperature of the reaction below 25° C., and the reaction is stirred at room temperature for 18 hours. The reaction mixture is extracted with methylene chloride, and the organic layer is separated, washed with water, dried, filtered and evaporated under reduced pressure. The residue is purified by silica gel column chromatography eluting with 20% to 30% hexanes/ethyl acetate to yield N-(4-acetyl-3,5-dimethoxyphenyl)-2,2,2-trifluoroacetamide (4.8 g, 13%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:47]([C:49]1[CH:57]=[CH:56][C:52]([CH2:53][CH2:54]O)=[CH:51][CH:50]=1)#[N:48]>ClCCl.CCCCCCC>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:54][CH2:53][C:52]2[CH:56]=[CH:57][C:49]([C:47]#[N:48])=[CH:50][CH:51]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: N#Cc1ccc(CCO)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: N#Cc1ccc(CCOc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 35.1 %

Procedure:
p-Hydroxybenzaldehyde (24.9 g; 203.8 mmole) was dissolved in dichloromethane (dry). ADDP (47.2 g; 187 mmole) was added followed by addition of triphenylphosphine (49 g; 187 mmole). The reaction mixture was stirred at room temperature for 45 minutes and then p-cyanophenethyl alcohol (25 g; 110 mmole) dissolved in a small amount of dichloromethane (dry) was added in portions during one hour. The reaction mixture was stirred at room temperature over night, filtered and evaporated. Chromatography of the residue on silica gel using ethyl acetate:heptane as eluant gave 9.7 g (22.7% yield) of 4-[2-(4-formylphenoxy)ethyl]benzonitrile.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]1[N:12]2[CH:13]=[C:14]([O:17][C@H:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C@@H:21]([NH2:28])[CH2:20][CH2:19]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1)[CH3:2].CCN(C(C)C)C(C)C.ClC(Cl)(Cl)C[O:41][C:42](=O)[NH:43][C:44]1[N:45]([C:53]2[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][CH:54]=2)[N:46]=[C:47]([C:49]([CH3:52])([CH3:51])[CH3:50])[CH:48]=1>O1CCOCC1>[C:49]([C:47]1[CH:48]=[C:44]([NH:43][C:42]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([C@@H:4]5[CH2:5][CH2:6][CH2:7][N:3]5[CH2:1][CH3:2])=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:41])[N:45]([C:53]2[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][CH:54]=2)[N:46]=1)([CH3:52])([CH3:50])[CH3:51]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CCN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C)cc4)c4ccccc43)cn12
Temperature: 60 °C

Procedure:
To a solution of Intermediate 61c (72.0 mg, 0.19 mmol) in 1,4-dioxane (2.00 mL) was added DIPEA (66 μL, 0.38 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 77.0 mg, 0.19 mmol). The reaction was heated to 60° C. overnight then cooled and partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-7.5% MeOH in DCM. Further purification by HPLC (C18 X-select column, 20-70% MeCN in H2O, 0.1% HCO2H) gave the title compound as a white powder after freeze-drying (37 mg, 31%). LCMS (Method 5): Rt 3.73 min, m/z 633.2 [MH+]. 1H NMR (400 MHz, d4-MeOD): 0.94 (3H, t, J 7.2), 1.30 (9H, s), 1.89-2.16 (6H, m), 2.22-2.31 (2H, m), 2.31-2.38 (2H, m), 2.38 (3H, s), 2.49 (1H, m), 3.32 (1H, m), 4.11 (1H, t, J 8.0), 4.90 (1H, dd, J 9.0, 5.6), 5.28 (1H, t, J 4.1), 6.33 (1H, s), 7.19-7.36 (9H, m), 7.65 (1H, dd, J 10.0, 0.7), 8.37 (1H, d, J 1.9).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:21]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH:18]([CH3:19])[CH3:20])=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(C)OC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CC(C)OC(=NC(=O)c1ccc(F)cc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from isopropyl 5,7-dihydro-6H-dibenz[c,e]-azepine-6-carboximidate and p-fluorobenzoyl chloride, there is obtained isopropyl N-(p-fluorobenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 90°-93° C.;
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[N+:11]([C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)[NH2:17])([O-:13])=[O:12]>O>[N+:11]([C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)[NH:17][CH:5]=[O:7])([O-:13])=[O:12]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: O
Solvent: O=CO
Product: O=CNc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (6.0 ml.) was added to formic acid (98- 100% w/v; 24.0 ml.) with swirling and cooling and the mixture was allowed to stand at room temperature for 30 minutes. 3,5-Dinitroaniline (6.0 g.) was then added. The reaction mixture was warmed for 5 minutes on the steam bath and allowed to stand for 40 minutes, allowing it to cool to room temperature. Water (100 ml.) was added, and the precipitate was filtered off and dried. Crystallisation from a mixture of petroleum ether (b.p. 60°-80°C.) and ethyl acetate (2:1 by volume) gave 3',5'-dinitroformanilide (4.1 g.), m.p. 121°-123°C.
Reaction SMILES: [C:1]1([CH:7](Cl)[C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH:21]([CH3:34])[CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])[CH2:17][CH2:16]1.OC1CCN(CCCOC2C=CC=CC=2[N+]([O-])=O)CC1>>[C:1]1([CH:7]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[O:14][CH:15]2[CH2:16][CH2:17][N:18]([CH:21]([CH3:34])[CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N+:31]([O-:33])=[O:32])[CH2:19][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(c1ccccc1)c1cccs1
Reactant: CC(CCOc1ccccc1[N+](=O)[O-])N1CCC(O)CC1
Agent: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: CC(CCOc1ccccc1[N+](=O)[O-])N1CCC(OC(c2ccccc2)c2cccs2)CC1

Procedure:
The procedure of Example 36 (a) was repeated except for using phenyl-2-thienylmethyl chloride and 4-hydroxy-1-[1-methyl-3-(2-nitrophenoxy)propyl]piperidine instead of phenyl-2-thienylmethyl chloride and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-(phenyl-2-thienylmethoxy)-1-[3-(2-nitrophenoxy)-1-methylpropyl]piperidine.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:13]>>[CH:1]1([CH2:7][C:8]([Cl:13])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CC1CCCCC1
Product: O=C(Cl)CC1CCCCC1
Reaction time: 1.5 h

Procedure:
Cyclohexyl acetic acid (2.5 g; 0.02 moles) was mixed with SOCl2 (3.7 cc; 0.05 moles) and the resulting solution was kept at 80° C. for 1.5 hours. The mixture was concentrated under vacuum and some washings were carried out with anhydrous toluene to remove SOCl2. The mixture was then dried under vacuum and the title product was obtained as a raw material which was used as such in the next step (b).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11]O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.P(Br)(Br)[Br:30]>C1COCC1>[Br:30][CH2:11][C:10]1[N:2]([CH3:1])[C:3]2[C:8]([N:9]=1)=[C:7]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[N:6]=[C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])[N:4]=2
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CO)n(C)c2n1
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1

Procedure:
To crude (9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purin-8-yl)methanol (6 g) in anhydrous THF (400 mL) was added phosphorus tribromide (2.7 mL). The reaction was monitored by LC/MS until complete. The heterogeneous reaction mixture was passed thru a Buchner funnel and the solid was collected and rinsed with thrice with water and twice with MeOH to get 2 g of crude 4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine of which 50 mg was reacted with bicyclo[2.2.2]octan-1-amine (1-adamantyl amine) via General Procedure E to give 5.7 mg of 270 following reverse phase purification. MS (Q1) 513.3 (M)+
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][CH:8]=1.C(N(C(C)C)CC)(C)C.CS([Cl:30])(=O)=O>C1COCC1>[Cl:30][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CO)cn1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(CCl)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.6 %

Procedure:
To a solution of tert-butyl 5-(hydroxymethyl)pyridin-2-ylcarbamate 116 (85.0 g, 379 mmol) and diisopropylethylamine (296 g, 2.27 mol) in THF (850 mL) was added methanesulfonyl chloride (130 g, 1.14 mol) over a period of 30 min at 0° C. The mixture was stirred for 12 h at room temperature then washed with H2O (2×100 mL) and dried over Na2SO4. The mixture was concentrated and the crude residue was purified by flash chromatography (petroleum ether: ethyl acetate=10:1) to give 117 (30 g, 63% yield).
Reaction SMILES: [CH3:1][NH:2][NH2:3].C(N(CC)CC)C.[CH2:11]([O:18][C:19](Cl)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1>[C:12]1([CH2:11][O:18][C:19]([N:2]([CH3:1])[NH2:3])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(N)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cold, stirred solution of 36.8 (0.8 mol; 42.49 ml) methylhydrazine and 161.6 g (1.6 mol, 224 ml) triethylamine in 700 ml tetrahydrofuran were added dropwise 136.5 g (0.8 mol, 113.6 ml) benzylchloroformate. After stirring at room temperature overnight, the tetrahydrofuran was evaporated and the residue was worked up with ethylacetate/water (pH=9.0. Insoluble material was removed by filtration and the organic phase was washed (H2O), dried (MgSO4) and evaporated. The oily residue was stirred with 1 1. of ether, the etherial solution was decanted from insoluble material and evaporated to give 61 g of an oil which was dissolved in 200 ml MeOH containing 25 ml conc. HCl. After evaporation to dryness, the residue was recrystallized from EtOH/ ethylacetate to give 22.0 g of the hydrochloride of 2 as colorless crystals. This material was dissolved in water and the pH was adjusted to 9.0. Extraction with ethylacetate, drying of the organic phase (MgSO4) and evaporation yielded 19.0 g of the title compound as a colorless oil.