Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8]2)=[CH:4][CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].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.C(O)C>[C:13]1([CH:9]2[O:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:19]=[CH:20][C:2]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[C:22]([F:33])([F:32])[F:21])=[CH:3][CH:4]=3)[CH2:8]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccc(CN2CCOC(c3ccccc3)C2)cc1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: FC(F)(F)c1ccccc1-c1ccc(CN2CCOC(c3ccccc3)C2)cc1
Temperature: 120 °C
Yield: 69.6 %

Procedure:
106 mg of 4-(4-Bromo-benzyl)-2-phenyl-morpholine was combined with 91 mg of 2-(Trifluoromethyl)phenyl boronic acid, 18 mg of tetrakis(triphenylphosphine)palladium(0), 1.1 mL of 2M sodium carbonate solution, 2.9 mL toluene and 1.4 mL ethanol. The reaction mixture was heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography eluting in a 10 to 40% ethyl acetate/hexanes gradient. The product fractions were pooled and concentrated to afford 88.3 mg of product. ES MS (+) m/z 398
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:12]2[N:13]=[CH:14][N:15](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:16]=2)([OH:11])[CH3:10])=[CH:5][C:4]=1[F:36])#[N:2].[C:37]([O:41][CH3:42])(=[O:40])[CH2:38]O.C(N(CC)C(C)C)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[CH3:42][O:41][C:37](=[O:40])[CH2:38][N:13]1[C:12]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:36])[CH:5]=2)([OH:11])[CH3:10])=[CH:16][N:15]=[CH:14]1
Reactant: COC(=O)CO
Reactant: CC(O)(c1ccc(C#N)c(F)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Cn1cncc1C(C)(O)c1ccc(C#N)c(F)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 1-(4-cyano-3-fluorophenyl)-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol, as described above in Step C, (200 mg, 0.42 mmol), methyl glycolate (35 mg, 0.39 mmol), and N,N-diisopropylethylamine (65 mg, 0.51 mmol) in dry CH2Cl2 (10 mL), under argon, at −78° C., was added trifluoromethanesulfonic anhydride (110 mg, 0.39 mmol) dropwise. The mixture was allowed to warm slowly to ambient temperature, then the solvent was removed in vacuo. The residue was dissolved in MeOH (10 mL) and the solution was heated to reflux for 1 hour, then concentrated to dryness. The residue was purified by silica gel chromatography, eluting with 4% MeOH—0.4% NH4OH in CHCl3, to yield the titled product as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][C@@H:4]([O:7][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@:3]1([CH3:26])[OH:25].[Cl:27][C:28]1[C:35]([CH2:36][CH3:37])=[C:34](F)[CH:33]=[CH:32][C:29]=1[C:30]#[N:31]>>[Cl:27][C:28]1[C:35]([CH2:36][CH3:37])=[C:34]([NH:1][C@@H:2]2[CH2:6][CH2:5][C@@H:4]([OH:7])[C@:3]2([OH:25])[CH3:26])[CH:33]=[CH:32][C:29]=1[C:30]#[N:31]
Reactant: CCc1c(F)ccc(C#N)c1Cl
Reactant: CC(C)(C)[Si](O[C@@H]1CC[C@@H](N)[C@]1(C)O)(c1ccccc1)c1ccccc1
Product: CCc1c(N[C@@H]2CC[C@@H](O)[C@@]2(C)O)ccc(C#N)c1Cl

Procedure:
The title compound is prepared by essentially following the procedure described in Example 20, using rel-(1S,2R,5R)-2-amino-5-(tert-butyl(diphenyl)silyl)oxy-1-methyl-cyclopentanol and 2-chloro-3-ethyl-4-fluoro-benzonitrile for the substitution reaction followed by TBDPS removal with TBAF. 1H-NMR (400 MHz, DMSO-d6) δ 7.44 (d, J=8.7 Hz, 1H), 6.87 (d, J=9.0 Hz, 1H), 5.74-5.70 (m, 1H), 4.74 (d, J=5.4 Hz, 1H), 4.27 (s, 1H), 3.82-3.79 (m, 1H), 3.58-3.51 (m, 1H), 2.80-2.78 (m, 2H), 2.03-2.02 (m, 1H), 1.88-1.86 (m, 1H), 1.69-1.68 (m, 1H), 1.52-1.51 (m, 1H), 1.01-0.97 (m, 3H), 0.93 (s, 3H). LC-ES/MS m/z 295 (M+1).
Reaction SMILES: [CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([O:10][CH:4]([O:5]3)[C:3](=[O:12])[O:2]1)[CH2:9]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>COCCOC>[OH:12][CH2:3][CH:4]1[O:10][CH:8]2[CH2:7][CH:6]([CH2:11][CH:1]([OH:2])[CH2:9]2)[O:5]1
Reactant: O=C1OC2CC3CC(C2)OC1O3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: OCC1OC2CC(O)CC(C2)O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 8.50 g (0.05 mols) of 2,5,11-trioxatricyclo[4,3,1,14,8 ]undecan-3-one of the formula Ia in 90 ml of ethylene glycol dimethyl ether is added dropwise within 15 minutes, while stirring and cooling with ice, to a suspension of 2.0 g (0.05 mols) of lithium aluminium hydride in 60 ml of ethylene glycol dimethyl ether. The reaction mixture is boiled for 15 minutes under reflux, cooled to room temperature and carefully treated with 10 ml of ethyl acetate to destroy excess lithium aluminium hydride. Then, while stirring, 2.0 ml of water, 2.0 ml of 15% sodium hydroxide solution, and finally 6 ml of water, are added to the reaction mixture. The precipitated salts are filtered off, stirred with 100 ml of methylene chloride and filtered again. The combined filtrates are concentrated in a water jet vacuum. The crystalline residue is recrystallised from methylene chloride to give 3-hydroxymethyl-2,4-dioxabicyclo[3,3,1]nonan-7-ol of the formula IIa ##SPC9##
Reaction SMILES: [Si]([O:18][C:19]1[CH:56]=[CH:55][C:22]([O:23][CH2:24][C@@H:25]([OH:54])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:53]=[CH:52][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([C:43]4[C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[NH:45][N:44]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[OH:54][C@H:25]([CH2:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([OH:18])=[CH:56][CH:55]=1)[CH2:26][NH:27][CH2:28][CH2:29][C:30]1[CH:53]=[CH:52][C:33]([NH:34][CH:35]2[CH2:40][CH2:39][N:38]([C:41]([C:43]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[NH:45][N:44]=3)=[O:42])[CH2:37][CH2:36]2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)c4n[nH]c5ccccc45)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(c1n[nH]c2ccccc12)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 63.1 %

Procedure:
{4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-1-piperidinyl}(1H-indazol-3-yl)methanone (0.093 g, 0.176 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol) to give the title compound (0.059 g, 0.111 mmol).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O-:14].[Na+].[CH3:16][OH:17]>O>[CH3:13][O:14][C:2]1[CH:11]=[C:10]([O:17][CH3:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1cc(Cl)c2ccccc2n1
Reactant: C[O-]
Reactant: CO
Agent: [Na+]
Solvent: O
Product: COc1cc(OC)c2ccccc2n1

Procedure:
To a suspension of 2,4-dichloroquinoline in MeOH (100 mL) was added sodium methoxide (50 g). The mixture was heated at reflux for 2 days. After cooling, the mixture was filtered. The filtrate was concentrated under reduced pressure to yield a residue that was dissolved in water and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated to give 2,4-dimethoxyquinoline as a white solid (13 g, 74% over 2 steps).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]([CH3:23])[CH2:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][NH:18][CH2:19][CH2:20][CH2:21][OH:22])[CH2:13][CH2:12]2)=[N:6][CH:7]=1.[CH2:24]=O.P(O)(O)O>O1CCOCC1>[Br:1][C:2]1[CH:7]=[N:6][C:5]([N:8]([CH3:23])[CH2:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][N:18]([CH3:24])[CH2:19][CH2:20][CH2:21][OH:22])[CH2:13][CH2:12]2)=[N:4][CH:3]=1
Reactant: C=O
Reactant: CN(CC[C@H]1CC[C@H](CNCCCO)CC1)c1ncc(Br)cn1
Agent: OP(O)O
Solvent: C1COCCO1
Product: CN(CCCO)C[C@H]1CC[C@H](CCN(C)c2ncc(Br)cn2)CC1
Temperature: 60 °C

Procedure:
A solution of 0.21 g (0.6 mmol) trans-3-[(4-{2-[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-ethyl}-cyclohexylmethyl)-amino]-propan-1-ol was taken up in 3 ml of dioxan, treated with 3 ml of a aqueous 1N NaH2PO3 solution and 3 ml of a 36% aqueous formaldehyde solution (Loibner, H., A. Pruckner, et al. (1984). “Reductive methylation of primary and secondary amines with formaldehyde and phosphorous acid salts.” Tetrahedron Lett. 25(24): 2535–6). The mixture was heated to 60° C. for 30 min. The mixture was cooled and extracted with 2N NaOH/ether (3×). The organic phase was washed with aqueous 10% NaCl, dried (NaSO4) and evaporated. Purification by flash silica gel column (CH2Cl2/MeOH 98:2 to 9:1) gave 0.17 g (76%) of trans-3-[(4-{2-[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-ethyl}-cyclohexylmethyl)-methyl-amino]-propan-1-ol, MS: 399 (MH+, 1Br).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[C:5]([O:33][CH3:34])=[CH:4][C:3]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1.[S:42]1[C:46]([NH2:47])=[N:45][CH:44]=[N:43]1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:47][C:46]4[S:42][N:43]=[CH:44][N:45]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[C:5]([O:33][CH3:34])=[CH:4][C:3]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1
Reactant: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Nc1ncns1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1nccc2cc(S(=O)(=O)Nc3ncns3)ccc12
Reaction time: 2 h
Yield: 64.4 %

Procedure:
A vial was charged with perfluorophenyl 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)isoquinoline-6-sulfonate (INTERMEDIATE TTTT; 71.85 mg, 0.118 mmol), 1,2,4-thiadiazol-5-amine (13.10 mg, 0.130 mmol), and cesium carbonate (115 mg, 0.353 mmol). The vial was flushed with Ar (g), and then acetonitrile (589 μl) was added. After 2 h, the mixture was diluted with EtOAc and 0.5 N aq. HCl. The layers were separated, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was concentrated from DCM/MeOH. The residue was then taken up in MeOH and filtered. The collected solid was washed with MeOH (1×), dried under a stream of N2 (g), then dried under vacuum to give 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (40 mg, 0.076 mmol, 64.4% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.72 (d, J=5.7 Hz, 1H), 8.60 (d, J=1.7 Hz, 1H), 8.48 (s, 1H), 8.16 (d, J=5.7 Hz, 1H), 7.95-7.90 (m, 1H), 7.88-7.81 (m, 1H), 7.63-7.54 (m, 2H), 7.50-7.41 (m, 2H), 7.36-7.29 (m, 1H), 7.27 (s, 1H), 3.71 (s, 3H). m/z (ESI) 527.2 (M+H)+.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>>[CH:23]1([NH:26][C:2]2[C:3]([CH3:22])=[N:4][C:5]3[C:10]([N:11]=2)=[C:9]([C:12]2[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=2)[CH:8]=[CH:7][CH:6]=3)[CH2:25][CH2:24]1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: NC1CC1
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1CC1
Temperature: 100 °C
Yield: 78 %

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 55 mg, 0.186 mmol) and cyclopropanamine (25.7 μl, 0.371 mmol, Aldrich), heating at 100° C. for 30 min. Purification by silica gel (100% DCM to 4% MeOH/DCM) provided 2-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (78% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.70-0.75 (m, 2H) 0.96 (dd, J=6.65, 1.96 Hz, 2H) 2.56 (s, 3H) 2.86-2.96 (m, 3H) 3.44 (td, J=6.80, 2.25 Hz, 2H) 6.98 (br. s., 1H) 7.16 (d, J=2.15 Hz, 1H) 7.37 (t, J=7.82 Hz, 1H) 7.58 (d, J=1.17 Hz, 2H) 7.99 (dd, J=7.63, 1.17 Hz, 1H) 12.83 (br. s., 1H). MS (ESI, pos. ion) m/z: 334.2 (M+1).
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH2:7][CH:6]([C:8]([OH:10])=O)[CH2:5]1)#[N:2].C(Cl)(=O)C([Cl:14])=O>ClCCl.CN(C)C=O>[C:1]([CH2:3][CH:4]1[CH2:7][CH:6]([C:8]([Cl:14])=[O:10])[CH2:5]1)#[N:2]
Reactant: N#CCC1CC(C(=O)O)C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#CCC1CC(C(=O)Cl)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-cyanomethylcyclobutane carboxylic acid (4.0 g, 28.8 mmol) in dichloromethane (50 ml) was added two drops of dimethylformamide followed by oxalyl chloride (12 ml). The mixture was stirred overnight at room temperature followed by removal of the solvent and excess reagent in vacuo. The resulting oil was dissolved in dry dichloromethane and the solvent evaporated to give the title compound as an oil.
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.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[Cl-].[Li+].C([Sn](CCCC)(CCCC)[C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1)CCC>COCCOC.C(Cl)(Cl)Cl.CO>[N:49]1[CH:50]=[CH:51][CH:52]=[C:47]([C:2]2[CH:3]=[C:4]3[CH2:10][C:9]4([CH:15]5[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]5)[CH2:11]4)[O:8][C:5]3=[N:6][CH:7]=2)[CH:48]=1
Reactant: Brc1cnc2c(c1)CC1(CN3CCC1CC3)O2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: c1cncc(-c2cnc3c(c2)CC2(CN4CCC2CC4)O3)c1
Yield: 37 %

Procedure:
A solution containing 5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (158 mg, 0.535 mmol), tris(dibenzylidineacetone)dipalladium (0) (23 mg, 0.025 mmol), tri(o-tolyl)phosphine (66 mg, 0.217 mmol), lithium chloride (99 mg, 2.34 mmol), and 3-(tri-n-butylstannyl)pyridine (0.3 ml, approx. 0.3 g, approx. 0.82 mmol) in 1,2-dimethoxyethane (2 ml) was heated under reflux for 6 h. The solution was evaporated, and the residue was taken up in chloroform and filtered. The filtrate was evaporated then purified by HPLC using a gradient of 0-20% 1:1:2 7M methanolic ammonia:methanol:chloroform and chloroform to obtain the title compound (58 mg, 0.198 mmol, 37%) as a pale solid: electrospray MS (m/z, relative intensity) 294 ([MH]+, 80), 273 (100).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20]N)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:22]=O.[C:24]([BH3-])#[N:25].[Na+]>CC#N>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][N:25]([CH3:24])[CH3:22])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: [BH3-]C#N
Reactant: C=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2CN)CC1
Agent: [Na+]
Solvent: CC#N
Product: CN(C)Cc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
1-Boc-4-(2-aminomethyl-phenyl)-piperazine (2.0 g, 6.86 mmol) was dissolved in CH3CN (15 mL) and cooled to about 0° C. Aqueous formaldehyde (37% wt. in H2O) (7.56 mL) was added to the cold solution followed by the addition of sodium cyanoborohydride (2.15 g, 34.32 mmol). The reaction mixture was allowed to stir at 0° C. for about 5 minutes and then allowed to naturally warm to room temperature. The mixture was then concentrated to dryness. The resulting residue was taken up in EtOAc (100 mL) and washed with saturated NaHCO3 solution (100 mL) and brine (100 mL). The organic phase was concentrated to dryness to afford about 2.2 g of crude material. MS (ESI+) 320.2 [M+1]
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9]([NH:11][CH:12]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=3[N:14](C)[C:13]2=S)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:32][OH:33].C(N(CC)CC)C.C1COCC1>CO>[CH:1]1([CH2:7][CH2:8][C:9]([NH:11][CH:12]2[C:13](=[N:32][OH:33])[NH:14][C:15]3[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=3[C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:18]2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN1C(=S)C(NC(=O)CCC2CCCCC2)N=C(c2ccccc2)c2ccccc21
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCC1CCCCC1)NC1N=C(c2ccccc2)c2ccccc2NC1=NO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-cyclohexyl-N-(2,3-dihydro-1-methyl-5-phenyl-2-thioxo-1H-1,4-benzodiazepin-3-yl)propanamide (740 mg, 1.83 mmol), hydroxylamine hydrochloride (140 mg, 2 mmol) and triethylamine (280 μL, 203 mg, 2 mmol) in methanol (15 mL)/THF (15 mL) was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2 /MeOH (98:2). The residue recrystallized from ethyl acetate. The first isomer to crystallize was recrystallized from ethyl acetate to give (E)-3-cyclohexyl-N-(2,3-dihydro-2-hydroxyimino-5-phenyl-1H-1,4-benzodiazepin-3-yl)propanamide as a solid, m.p. 196° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[N+:6]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1O)=[N:16][CH:15]=[CH:14][CH:13]=2)([O-:8])=[O:7].O[NH:21][CH2:22][CH:23]([CH3:25])[CH3:24].[OH2:26]>CN(C)C=O>[CH3:24][C:23]([CH3:25])([OH:26])[CH2:22][NH:21][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[N:11]=[CH:10][C:9]=1[N+:6]([O-:8])=[O:7]
Reactant: O=[N+]([O-])c1cnc2cccnc2c1O
Reactant: O
Reactant: CC(C)CNO
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cccnc12
Temperature: 60 °C

Procedure:
Phosphorus oxychloride (4 mL, 43 mmol) was reacted with N,N-dimethylformamide (15 mL) while chilling in an ice bath. This mixture was added to a solution of 3-nitro[1,5]naphthyridin-4-ol (6.9 g, 36.1 mmol) in N,N-dimethylformamide (60 mL). The reaction mixture was warmed in an oil bath to 60° C. After 3 hours the reaction mixture was poured into ice water. The resulting precipitate was isolated by filtration and then washed with water. The wet crude 5-chloro-3-nitro[1,5]naphthyridine was suspended in dichloromethane (150 mL). Diisopropylethylamine was added followed by the slow addition of hydroxyisobutylamine (3.4 g, 40 mmol). The reaction mixture was refluxed for 2 hours and then combined with water (˜100 mL). The resulting precipitate was isolated by filtration to provide 7.2 g of 1,1-dimethyl-2-[(3-nitro[1,5]naphthyridin-4-yl)amino]ethanol. A small sample was recrystallized from isopropanol to provide a pure sample, m.p. 184.5-186° C. Analysis: Calculated for C12H14N4O3: % C, 54.96; % H, 5.38; % N, 21.36; Found: % C, 54.63; % H, 5.36: % N, 21.51.
Reaction SMILES: C1(N2CC[O:9]CC2)CCCC=1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.Cl.[CH:23]1[CH:28]=[CH:27][CH:26]=[CH:25]C=1>>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[C:25]2[CH2:26][CH2:27][CH2:28][C:23]2=[O:9])=[CH:16][CH:15]=1
Reactant: COc1ccc(C=O)cc1
Reactant: c1ccccc1
Reactant: C1=C(N2CCOCC2)CCC1
Agent: Cl
Product: COc1ccc(C=C2CCCC2=O)cc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
With reflux device installed, 36.8 g (0.24 mol) of N-cyclopentenyl morpholine, 27.2 g (0.20 mol) of 4-methoxybenzaldehyde and 200 mL of benzene were added to a round bottom flask and heated under reflux for 20 h. The resulting solution was cooled to 30° C., and slowly stirred while 62 mL of hydrochloric acid (6 mol/L) was added. After stirring for 2 h at room temperature, the benzene layer was separated and washed with water to neutral, and dried over anhydrous sodium sulfate overnight. Then the mixture was filtered and benzene was recovered by evaporation under reduced pressure. The residue was cooled and solidified, then recrystallized in cyclohexane/ethanol to yield light yellow flaky crystal product with a yield of 76.3%.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:11][CH:10]=[C:9]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]2[CH:7]=[C:6]([C:19]([O:21]C)=[O:20])[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CCO.C1COCC1>[CH3:1][C:2]1([CH3:23])[CH2:11][CH:10]=[C:9]([S:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]2[CH:7]=[C:6]([C:19]([OH:21])=[O:20])[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc2c(c1)C(Sc1ccccc1)=CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC=C(Sc2ccccc2)c2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5,5-dimethyl-5,6-dihydro-8-(phenylthio)-naphthalene-2-carboxylate (Compound E18, 300.0 mg, 0.926 mmol) in 4.0 mL of EtOH and 2.0 mL THF was added NaOH (200.0 mg, 5.00 mmol; 5.0 mL of a 1N aqueous solution). After stirring overnight at room temperature the reaction was quenched by the addition of 10% aqueous HCl. The mixture was extracted with EtOAc and the combined organic layers washed with H2O and saturated aqueous NaCl before being dried over Na2SO4. Removal of the solvents under pressure afforded the title compound as a yellow solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Al+3].[Cl-].[Cl-].[Cl-].ClC[CH2:16][C:17](Cl)=[O:18].Cl[CH2:21][Cl:22]>>[Cl:22][CH2:21][C:17](=[O:18])[CH2:16][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH:2]=1
Reactant: ClCCl
Reactant: c1ccc2sccc2c1
Reactant: O=C(Cl)CCCl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCl)Cc1csc2ccccc12
Yield: 85.3 %

Procedure:
To the solution of benzothiophene (0.05 mol) dissolved in dichloromethane (30 mL), AlCl3 (0.10 mol) is added batch by batch and 3-chloropropionyl chloride (0.055 mol) is added dropwise, while the internal temperature is maintained below 5° C. Following procedures described in General Method One—Method A, 3-chloro-1-(benzothiophen-3- yl)-acetone is obtained as a white solid (9.6 g). The yield is 85.3%. MS(m/z): 225.0 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.OO.NC(N)=[O:14].FC(F)(F)C(OC(=O)C(F)(F)F)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N+:3]=1[O-:14]
Reactant: NC(N)=O
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: N#Cc1ccc(Cl)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Chloropyridine-5-carbonitrile (7.01 g) was dissolved in acetonitrile (70 mL), and urea hydrogen peroxide addition compound (10 g) was added. Trifluoroacetic anhydride was added dropwise to the reaction mixture under ice-cooling and the mixture was stirred at room temperature for 18 hr. The reaction mixture was added to aqueous sodium thiosulfate solution and the mixture was extracted with chloroform. The extract was washed successively with saturated aqueous sodium hydrogencarbonate solution and brine and dried. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography to give 2-chloro-5-cyanopyridine 1-oxide (0.779 g) as a white solid.