Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[C:33](Cl)[N:32]=[CH:31][N:30]=4)[CH2:25][CH2:24]3)=[O:22])[N:9]=2)=[CH:4][CH:3]=1.[CH2:36]([OH:39])[CH2:37][OH:38].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[C:33]([O:38][CH2:37][CH2:36][OH:39])[N:32]=[CH:31][N:30]=4)[CH2:25][CH2:24]3)=[O:22])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1)N1CCN(c2cc(Cl)ncn2)CC1
Reactant: OCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1)N1CCN(c2cc(OCCO)ncn2)CC1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
50 mg 2-(3,5-Bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-1-(4-(6-chloro-pyrimidin-4-yl)-piperazin-1-yl)-ethanone and 3 mL ethane-1,2-diol were added to 10 mg potassiumcarbonate in 3 mL ethanol. The reaction was stirred 30 min at 150° C. under microwave conditions. The solvent was removed and the precipate was purified by HPLC to give 29 mg of the desired product. Rt: 1.87 min (method C), (M+H)+: 522
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([CH:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[NH:21][C:22]([NH:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:23])[C:12]2=O)=O)=[CH:7][CH:6]=1.O.[NH2:35][NH2:36].CC(O)=O>CCO>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]2[NH:36][N:35]=[C:12]3[C:13]4[C:18]([C:19](=[O:20])[C:11]=23)=[C:17]([NH:21][C:22]([NH:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:23])[CH:16]=[CH:15][CH:14]=4)=[CH:7][CH:6]=1
Reactant: NN
Reactant: O=C(Nc1cccc2c1C(=O)C(C(=O)c1ccc(OCCCl)cc1)C2=O)NN1CCOCC1
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: O=C(Nc1cccc2c1C(=O)c1c-2n[nH]c1-c1ccc(OCCCl)cc1)NN1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.8 %

Procedure:
To a suspension of 1-{2-[4-(2-chloroethoxy)benzoyl]-1,3-dioxo-indan-4-yl}-3-morpholin-4-yl-urea (39 g, 82.6 mmol) in EtOH (425 mL) was added hydrazine monohydrate (20.7 g, 413 mmol) followed by AcOH (9.9 g, 165.3 mmol). The reaction mixture was heated at reflux for 48 h. The reaction mixture was cooled to room temp. The yellow solid was collected by filtration, rinsed with EtOH and dried under vacuum. The solid was suspended in THF (1000 mL) and 1N HCl (500 mL) was added. The resulting suspension was stirred for 90 min. Brine (500 mL) was added and the pH was adjusted to 13 with 50% NaOH. The layers were separated and the aqueous layer was washed with THF (2×300 mL). The combined organic layers were washed with 1N HCl/brine (1×250 mL, 1:1), then brine (1×250 mL), dried (MgSO4), and concentrated under reduced pressure. The yellow solid was triturated with Et2O then dried under vacuum to give the desired pyrazole (23.5 g, 61% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8]O)=[N:4][CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.CS(Cl)(=O)=O.C(OC(=O)[NH:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][CH2:34][C:35]1[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][N:36]=1)(C)(C)C>C(Cl)Cl.CC#N>[Cl:1][C:2]1[C:3]([CH2:8][N:33]([CH2:34][C:35]2[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][N:36]=2)[CH2:32][CH2:31][CH2:30][CH2:29][NH2:28])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCCCNCc1ncccc1Cl
Reactant: OCc1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NCCCCN(Cc1ncccc1Cl)Cc1ncccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
Using General Procedure C: (3-Chloro-pyridin-2-yl)-methanol (167 mg, 1.17 mmol) (Iqbal, N. et al. J. Med. Chem. 1998, 41, 1827-1837) was dissolved in CH2Cl2 (10 mL) at 0° C. Et3N (212 μL, 1.52 mmol) was added to the colorless solution followed by subsequent addition of MsCl (90 μL, 1.17 mmol). The reaction mixture was stirred at 0° C. for one hour and then the solvent was removed under reduced pressure. The resulting crude mesylate mixture was dissolved in CH3CN (5 mL) and added to a mixture of {4-[(3-chloro-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester (265 mg, 0.88 mmol) and Et3N (169 μL, 1.21 mmol) in CH3CN (10 mL). The reaction mixture was stirred at 50° C. for 16 hours. The solvent was removed under reduced pressure and the brown oil was purified via column chromatography on silica gel (CH2Cl2:MeOH, 95:5, v/v) to give the product as a pale yellow oil (205 mg, 52%). 1H NMR (CDCl3) δ 1.35 (m, 2H), 1.43 (s, 9H), 1.55 (m, 2H), 2.67 (t, 2H, J=7.5 Hz), 2.98 (m, 2H), 3.98 (s, 4H), 4.86 (s, 1H), 7.11 (dd, 2H, J=9.0, 6.0 Hz), 7.61 (d, 2H, J=9.0 Hz), 8.45 (m, 2H). Conversion to the HBr salt using General Procedure D gave COMPOUND 235 as a white solid. 1H NMR (D2O) δ 1.75 (m, 2H), 1.97 (m, 2H), 3.02 (t, 2H, J=7.5 Hz), 3.52 (t, 2H, J=8.1 Hz), 4.80 (s, 2H), 4.82 (s, 2H), 7.42 (dd, 2H, J=8.4, 4.8 Hz), 7.92 (d, 2H, J=8.1 Hz), 8.45 (m, 2H). 13C NMR (D2O) δ 21.51, 24.37, 39.25, 48.71, 55.98, 126.19, 131.75, 139.55, 147.09, 147.26. ES-MS m/z 339 [M+H]+. Anal. Calcd. for C16H20N4Cl2−.3.5HBr.0.8H2O: C, 30.18, H, 3.97; N, 8.80; Cl, 11.13; Br, 43.91. Found: C, 30.18; H, 4.04; N, 8.72; Cl, 10.77; Br, 44.05.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[C:11]([C:13](O)=[O:14])[CH:10]=[C:9]([O:16][C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[C:7]=2[CH:8]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:60][C:61]1[CH:66]=[CH:65][C:64]([CH3:67])=[CH:63][N:62]=1>CN(C=O)C>[CH3:1][O:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[C:11]([C:13]([NH:60][C:61]3[CH:66]=[CH:65][C:64]([CH3:67])=[CH:63][N:62]=3)=[O:14])[CH:10]=[C:9]([O:16][C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=3)[C:7]=2[CH:8]=1
Reactant: Cc1ccc(N)nc1
Reactant: COCc1cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)O)cc2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCc1cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)Nc3ccc(C)cn3)cc2o1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54.7 %

Procedure:
To a solution of 2-(methoxymethyl)-4-(4-(methylsulfonyl)phenoxy)benzofuran-6-carboxylic acid (130 mg, 0.345 mmol) in DMF (5 mL) was added HATU (263 mg, 0.691 mmol) and DIEA (89.3 mg, 0.691 mmol). After stirring the solution at 0° C. for 15 minutes, 2-amino-5-methylpyridine (74.7 mg, 0.691 mmol) was added. The solution was warmed gradually to room temperature and stirred for 14 h. The reaction was concentrated under high vacuum, and the product was purified by reverse phase HPLC to give the title compound (88 mg, 55%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.36 (s, 3 H) 3.07 (s, 3 H) 3.46 (s, 3 H) 4.56 (s, 2 H) 6.59 (s, 1 H) 7.07-7.18 (m, 2 H) 7.53 (d, J=1.32 Hz, 1 H) 7.74 (dd, J=8.67, 1.32 Hz, 1 H) 7.85-7.95 (m, 2 H) 8.00 (s, 1 H) 8.09 (s, 1 H) 8.22 (d, J=8.67 Hz, 1 H) 9.10 (s, 1 H). LCMS m/z 467.20 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=[O:21])=[C:15]2[C:10]([C:11]([C:25]([F:28])([F:27])[F:26])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[NH4+].[Cl-].ClCCl>CO>[CH2:1]([N:8]1[C:16]([C:17]2[CH:18]=[C:19]([CH2:20][OH:21])[CH:22]=[CH:23][CH:24]=2)=[C:15]2[C:10]([C:11]([C:25]([F:27])([F:28])[F:26])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2ccccc2)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: OCc1cccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2ccccc2)c1
Reaction time: 1 h

Procedure:
To a solution of 116 mg (0.305 mmol) of 3-[2-benzyl-7-(trifluoromethyl)-2H-indazol-3-yl]benzaldehyde (compound of Formula (I)), prepared in a same way as Example 1, in 2 ml of methanol, 23 mg (0.71 mmol) of NaBH4 was added at 0° C. The reaction mixture was stirred at this temperature for 1 hr. Saturated NH4Cl-solution and dichloromethane were added, and the phases were separated. The product was obtained after flash chromatographic purification using dichloromethane as eluant. Yield: 111 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([NH2:11])[C:4]=1[NH2:12].CO[C:15]1C(OC)=C[C:18]2[NH:19][C:20](CCCNC)=N[C:17]=2[CH:16]=1>>[CH3:10][O:9][C:6]1[C:5]2[N:11]=[C:15]([CH2:16][CH2:17][CH2:18][NH:19][CH3:20])[NH:12][C:4]=2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: CNCCCc1nc2cc(OC)c(OC)cc2[nH]1
Reactant: COc1ccc(OC)c(N)c1N
Product: CNCCCc1nc2c(OC)ccc(OC)c2[nH]1

Procedure:
Prepared from 3,6-dimethoxy-benzene-1,2-diamine in analogy to the methods described for [3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amine.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])([CH3:5])[CH3:4])#N.[O:15]1CCCC1.[H-].C([Al+]CC(C)C)C(C)C.Cl>C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH3:5][C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])([CH3:4])[CH:1]=[O:15]
Reactant: C1CCOC1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C=O)c1cccc(C(=O)O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)benzoic acid (8.60 g, 45.5 mmol) produced in Example C6(ii) in toluene (60 mL)/tetrahydrofuran (40 mL) was added dropwise a 1.0M solution (100 mL, 100 mmol) of diisobutylaluminum hydride in hexane at −78° C. for 1 hr. After the completion of the dropwise addition, the mixture was stirred at −78° C. for 1 hr and at 0° C. for 1 hr. The reaction mixture was poured into a mixture of ethyl acetate (200 mL) and 3N hydrochloric acid (300 mL), the organic layer and the aqueous layer were separated, and the aqueous layer was extracted with ethyl acetate (2×100 ml). The combined organic layer was washed with saturated brine (50 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (6.39 g, 73%) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([CH2:16][CH2:17][O:18][CH2:19][CH3:20])[C:9]([O:11]C(C)(C)C)=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>O1CCOCC1.O>[C:1]([O:5][C:6]([CH:8]([CH2:16][CH2:17][O:18][CH2:19][CH3:20])[C:9]([OH:11])=[O:10])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOCCC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCOCCC(C(=O)O)C(=O)OC(C)(C)C
Yield: 26.3 %

Procedure:
To a solution of the product from step (a) (5 g) in dioxane (25 ml) was added a solution of potassium hydroxide (1 g) in water (20 ml). The cloudy reaction mixture was heated to reflux for 5.5 hours and then evaporated to dryness. The residue was dissolved in water, washed with ether, and acidified to pH 4 with conc. HCl. The mixture was extracted thoroughly with ethyl acetate and the combined extracts were washed with brine, dried (MgSO4) and evaporated to give 2-t-butoxycarbonyl-4-ethoxybutyric acid (1.06 g) as a yellow oil: NMR Spectrum (CDCl3) 1.19 (3H, t), 1.49 (9H, s), 2.19 (2H, m), 3.50 (5H, m); Mass Spectrum m/Z 233 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([C@@H:12]3[CH2:14][C@H:13]3[C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:11][C:7]=2[C:6](F)=[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:4]=1[CH3:27])#[N:2].C(N(CC)CC)C.[CH3:35][N:36]([CH3:42])[C@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>CS(C)=O>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([C@@H:12]3[CH2:14][C@H:13]3[C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:11][C:7]=2[C:6]([N:39]2[CH2:40][CH2:41][C@H:37]([N:36]([CH3:42])[CH3:35])[CH2:38]2)=[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:4]=1[CH3:27])#[N:2]
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reactant: CN(C)[C@H]1CCNC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1C[C@H]1c1nc2c(C#N)c(C)c(-c3ccccc3)c(N3CC[C@H](N(C)C)C3)c2o1
Temperature: 95 °C
Reaction time: 4 h
Yield: 41.6 %

Procedure:
Ethyl (1R*,2R*)-2-[4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-2-yl]cyclopropanecarboxylate (I-216) (200 mg, 0.55 mmol) was dissolved in dimethyl sulfoxide (5 ml), then triethylamine (146 μl, 1.10 mmol) and (3S)-3-(dimethylamino)pyrrolidine (146 μl, 1.15 mmol) were added, followed by stirring at 95° C. for 4 hours. After cooled, this was concentrated under reduced pressure, diluted with chloroform, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was subjected to preparative TLC. The eluate with chloroform/methanol (5:1, v/v) gave the entitled compound (105 mg, 42%) as a red brown solid.
Reaction SMILES: [CH2:1]([OH:7])[C@@H:2]([OH:6])[CH2:3][CH2:4][OH:5].[CH3:8][CH2:9][C:10](=O)[CH2:11][CH3:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>CCN(CC)CC>[CH2:9]([C:10]1([CH2:11][CH3:12])[O:6][C@@H:2]([CH2:3][CH2:4][OH:5])[CH2:1][O:7]1)[CH3:8]
Reactant: CCC(=O)CC
Reactant: OCC[C@H](O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Product: CCC1(CC)OC[C@H](CCO)O1
Temperature: 53 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-1,2,4-butanetriol intermediate 67a (6.76 g, 63.68 mmol) in freshly distilled pentan-3-one (320 mL) was added p-toluenesulfonic acid (p-TSA) (6.06 g, 31.84 mmol). The reaction mixture was stirred at 53° C. for 16 hours, then Et3N (10 mL) was added and the reaction mixture stirred at ambient temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure. Gradient flash chromatography (CH2Cl2/MeOH, 100:0 to 97:3 to 95:5) afforded the protected alcohol intermediate 67b (9.84 g, 89%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[CH:4][C:3]=1[F:11].[C:12](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[CH:9]=[CH:10][C:5]2=[CH:4][C:3]=1[F:11]
Reactant: Fc1cc2cc[nH]c2nc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1ccc2cc(F)c(Cl)nc21
Temperature: 70 °C
Yield: 28.4 %

Procedure:
To a solution of 6-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine (4.15 g, 24.33 mmol) in DMF (50 mL), under a nitrogen atmosphere, is added potassium carbonate (6.73 g, 48.66 mmol), followed by methyl iodide (2.27 mL, 36.49 mmol), and reaction heated to 70° C. for 2 h. The reaction is cooled, poured onto brine (ca. 50 mL) and the product extracted with CHCl3 (ca. 2×30 mL). The combined organic extracts are dried over magnesium sulphate, filtered, and concentrated in vacuo to give a brown solid. This is purified by column chromatography on silica, eluting with 0 to 50% DCM in hexane, to give the title compound as a white solid (1.274 g, 6.90 mmol). MS (m/z): 185/187 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)=[CH:5][C:4]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([N:22]3[C:34](=[O:35])[C:33]4[S:32][C:31]5[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=5[C:25]=4[CH:24]=[N:23]3)[C:17]=2[CH:36]=[O:37])=[CH:3]1.[BH4-].[Na+]>CO>[OH:37][CH2:36][C:17]1[C:18]([N:22]2[C:34](=[O:35])[C:33]3[S:32][C:31]4[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=4[C:25]=3[CH:24]=[N:23]2)=[N:19][CH:20]=[CH:21][C:16]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: Cn1cc(-c2ccnc(-n3ncc4c5c(sc4c3=O)CCCC5)c2C=O)cc(Nc2cnccn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(-c2ccnc(-n3ncc4c5c(sc4c3=O)CCCC5)c2CO)cc(Nc2cnccn2)c1=O
Temperature: 30 °C
Reaction time: 2 h
Yield: 29.2 %

Procedure:
A mixture of 194b (200 mg, 0.4 mmol) and NaBH4 (48 mg, 1.2 mmol) in methanol (20 mL) was stirred at 30° C. for 2 h. The mixture was quenched with water (5 mL) and concentrated under reduced pressure. The residue was extracted with ethyl acetate (3×10 mL). The combined with ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 194 (60 mg, 30%) as a white solid. MS-ESI: [M+H]+ 514.2. 1H NMR (500 MHz, CDCl3) δ 8.78 (d, J=2.0 Hz, 1H), 8.69 (d, J=5.0 Hz, 1H), 8.31 (s, 1H), 8.29 (s, 1H), 8.17 (s, 1H), 8.13 (s, 1H), 8.04 (d, J=2.5 Hz, 1H), 7.83 (d, J=2.5 Hz, 1H), 7.56 (d, J=5 Hz, 1H), 4.44-4.37 (m, 3H), 3.76 (s, 3H), 3.01-2.99 (m, 2H), 2.88-2.86 (m, 2H), 2.01-1.96 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].O.CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:23](O)[CH2:24][OH:25].C1(C)C=CC=CC=1>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:7]2[O:25][CH2:24][CH2:23][O:8]2)[CH:9]=1
Reactant: OCCO
Reactant: O=Cc1cc(Br)ccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc(Br)cc1C1OCCO1

Procedure:
5-Bromo-2-fluorobenzaldehyde (14.6 mL, 0.123 mol, Avocado) is combined with 4-methylbenzenesulfonic acid hydrate (2.34 g, 12.0 mmol, Aldrich), ethylene glycol (13.7 mL, 0.25 mol, Mallinkrodt) and toluene (75 mL). The mixture is heated to reflux overnight. The resulting solution is diluted into EtOAc (100 mL) and washed 2× with saturated NaHCO3, 1× with water and 1× with brine (170 mL ea). The organic layer is dried over Na2SO4 and filtered. The solvent is removed by rotary evaporation and the product is purified on a Biotage Flash 75L (800 g silica) cartridge using 96:3:1 heptane:EtOAc:TEA as eluent.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].[C:13](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[F:8][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[C:3]([O:12][CH3:13])[C:2]=1[F:1]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1c([N+](=O)[O-])ccc(F)c1F
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To a solution of 2,3-difluoro-6-nitrophenol (15.01 g, 85.8 mmol) in anhydrous dimethylformamide (120 mL) was cautiously added potassium carbonate (16.6 g, 120 mmol) and methyl iodide (6.63 mL, 107 mmol). The resulting suspension was stirred overnight. The next morning the reaction was poured into water and extracted twice with diethyl ether. The organic layers were washed twice with 5% LiCl, dried over sodium sulfate. The solvents were removed under reduced pressure to afford 1,2-difluoro-3-(methyloxy)-4-nitrobenzene as a yellow oil (14.7 g, 91% yield). 1H NMR (400 MHz, CDCl3) δ ppm 4.13 (s, 3 H), 7.00 (td, J=9.07, 7.15 Hz, 1 H), 7.67 (ddd, J=9.35, 5.32, 2.20 Hz, 1 H).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1[Cl:3].[C:10](=O)(O)[O-:11]>CO>[Cl:3][C:2]1[N:4]=[C:5]([Cl:6])[N:7]=[C:8]([O:11][CH3:10])[N:1]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: O=C([O-])O
Solvent: CO
Product: COc1nc(Cl)nc(Cl)n1

Procedure:
Cyanuric chloride was reacted with methanol in the presence of bicarbonate at 30° C. as described in the literature to give the product: mp 89-91° C. (lit mp 87-89° C., J. R. Dudley, et al, J. Amer. Chem. Soc., 1951, 73, 2986-2990), after recrystallization from heptane. 1H-NMR (CDCl3): δ4.12 (OCH3).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.Cl.[NH2:11][C:12]1[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:15]([NH:17][CH:18]1[CH2:20][CH2:19]1)=[O:16]>>[Br:1][C:2]1[S:6][C:5]([C:7]([NH:11][C:12]2[CH:13]=[C:14]([C:15](=[O:16])[NH:17][CH:18]3[CH2:20][CH2:19]3)[CH:21]=[CH:22][C:23]=2[CH3:24])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Agent: Cl
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(Br)s1

Procedure:
Compound a was prepared by coupling 5-bromothiophene-2-carboxylic acid with 3-amino-N-cyclopropyl-4-methylbenzamide hydrochloride (prepared as described in WO04071440) using the method described in Example 2. HPLC Ret time=3.16 min. LCMS [M+H]+ 379.15.
Reaction SMILES: [NH2:1]N.C[N:4](C)[C:5]([CH3:31])=[CH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[CH:28]=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:11][CH:10]=1)=O>C(O)(=O)C>[CH3:31][C:5]1[NH:4][N:1]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][N:20]4[CH:28]=[CH:29][CH:30]=[C:19]4[CH2:18]3)=[O:16])=[CH:11][CH:10]=2)[CH:6]=1
Reactant: CC(=CC(=O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)N(C)C
Reactant: NN
Solvent: CC(=O)O
Product: Cc1cc(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)n[nH]1
Yield: 71.6 %

Procedure:
Anhydrous hydrazine (0.10 g) was added to a solution of 3-Dimethylamino-1-[4-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepine-10-carbonyl)-phenyl]-2-buten-1-one (0.50 g) in glacial acetic acid (25 ml). The reaction mixture was refluxed for 18 hours and then concentrated under vacuum. The solid was extracted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a steam bath with the gradual addition of hexane to give an opaque solution. After cooling the amorphous solid was recovered by filtration to yield the product (0.33 g), MS, m/z: 368 (M)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[CH2:9][C:10]#[N:11].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:11][CH2:10][CH2:9][N:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]1[CH2:2][OH:1]
Reactant: N#CCN1CCCCC1CO
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCN1CCCCC1CO
Yield: 26.6 %

Procedure:
The method follows that of S6 using 2-hydroxymethyl-piperidin-1-yl-acetonitrile (31.96 g, 0.208 mol), LiAlH4 (23.68 g, 0.624 mol) and dry THF (200 mL). The title compound (8.74 g, 27%) was afforded as straw-coloured oil by kugelrohr distillation (225° C., 0.13 mbar). δH (250 MHz; CDCl3); 1.2-1.75 (m, 6H, CH2CH2CH2, CH2CH2CH and CH2CH2CH), 2.2 (m, 1H, 1×NCH2CH2) 2.35 (m, 2H, H2NCH2CH2N), 2.58 (s (broad), 3H, OH and NH2), 2.75 (t, 2H, H2NCH2CH2N), 2.85 (3×d, 1H, 1×NCH2CH2), 2.92 (m, 1H, NCHCH2), 3.4 (2×d, 1H, J=4 Hz and 12 Hz, 1×CHCH2OH) and 3.76 (2×d, 1H, J=4 Hz and 12 Hz, 1×CHCH2OH; FAB MS, m/z(M+H)+ 159.
Reaction SMILES: [CH:1]1([C:6]([OH:8])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][NH:10][C@H:11]1[CH2:30][N:15]2[C:16]3[C:21]([C:22]([CH2:23][C:24]([O:26]CCC)=[O:25])=[C:14]2[CH2:13][CH2:12]1)=[CH:20][CH:19]=[CH:18][CH:17]=3>>[CH:1]1([C:6]([N:10]([CH3:9])[C@H:11]2[CH2:30][N:15]3[C:16]4[C:21]([C:22]([CH2:23][C:24]([OH:26])=[O:25])=[C:14]3[CH2:13][CH2:12]2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: O=C(O)C1CCCC1
Product: CN(C(=O)C1CCCC1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 2 (Method B) from cyclopentanecarboxylic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 355.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13](OCC)[O:14][CH2:15][CH3:16])[CH:6]=1)[CH3:2].[N:21]([Si](C)(C)C)=[N+:22]=[N-:23]>Cl[Sn](Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]([N:21]=[N+:22]=[N-:23])[O:14][CH2:15][CH3:16])[CH:6]=1)[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCOC(=O)c1cccc(OCC(OCC)OCC)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Product: CCOC(=O)c1cccc(OCC(N=[N+]=[N-])OCC)c1
Reaction time: 1 h

Procedure:
To a mixture of 3-(2,2-diethoxy-ethoxy)-benzoic acid ethyl ester (1.128 g, 4 mmol) and azidotrimethylsilane (0.584 ml, 4.4 mmol) was added SnCl4 (40 μl) at room temperature. After 1 hr, the precipitates were filtered off and the filtrate was evaporated under reduced pressure. The residue was dissolved in methanol, after 10 minutes, solvent was removed under reduced pressure. The residue was purified by a column chromatography (3×20 cm). The product was eluted with 10% petroleum ether (60-80° C.) in DCM. The title compound was obtained as a colourless oil (0.909 g, 81.5%).