Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8](OCC)=O)=[CH:5][C:6]=1[CH3:7].[CH2:13]=O.O.N>C(O)(=O)C.I.[PH2](O)=O>[CH3:8][C:4]1[NH:3][C:2]([CH3:1])=[C:6]([CH3:7])[C:5]=1[CH3:13]
Reactant: CCOC(=O)c1cc(C)c(C)[nH]1
Reactant: C=O
Agent: I
Agent: N
Agent: O=[PH2]O
Solvent: O
Solvent: CC(=O)O
Product: Cc1[nH]c(C)c(C)c1C
Yield: 53 %

Procedure:
A solution of 2,3-dimethyl-5-carbethoxy-pyrrole (0.82 g) in acetic acid (10 ml), hydriodic acid (10 ml), hypophosphorous acid (2 ml) and paraformaldehyde (0.6 g) was stirred and heated at 100° under nitrogen for 3 hr. then poured into water. The mixture was made alkaline with ammonia and extracted with ether. The ether was evaporated and the residue distilled (65°, 15 mm) to give the product (53%) m.p. 105°-107°.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([Cl:12])[CH:6]=1)C.[NH4+:14].[OH-]>>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([NH2:14])=[O:3])=[CH:6][C:7]=1[Cl:12]
Reactant: CCOC(=O)c1ccc(N)c(Cl)c1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)c1ccc(N)c(Cl)c1
Temperature: 50 °C
Yield: 62.3 %

Procedure:
A 18 ml vial was loaded with 4-Amino-3-chloro-benzoic acid ethyl ester (350 mg, 1.88 mmole) and 5 ml of 30% NH4OH. The vial was sealed and the mixture was heated at 50° C. for 3 days. The mixture was cooled down and concentrated to half. The suspension was filtered off, solid was washed with water and dried to give 200 mg product, 62.3% yield.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[O:38]1[C:42]2[CH:43]=[CH:44][C:45]([CH2:47][CH2:48][NH2:49])=[CH:46][C:41]=2[O:40][CH2:39]1>>[O:38]1[C:42]2[CH:43]=[CH:44][C:45]([CH2:47][CH2:48][NH:49][C:3]([C:5]3[N:14]4[C:8]([CH2:9][N:10]([C:19]([C:21]5[CH:26]=[CH:25][C:24]([C:27]6[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=6[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=5)=[O:20])[C:11]5[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=5[CH2:13]4)=[CH:7][CH:6]=3)=[O:4])=[CH:46][C:41]=2[O:40][CH2:39]1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCCc4ccc5c(c4)OCO5)n3Cc3ccccc32)ccc1-c1ccccc1C

Procedure:
The title compound was prepared in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and 2-benzo[1,3]dioxol-5-yl-ethylamine. Purification was performed using HPLC with a normal phase column. Elution with a two phase solvent system (A=hexane, B=dichloromethane/methanol, 4:1) gave the title compound in 75% yield, m.p. 178-179° C.; MS [(+)ESI, m/z]: 600 [M+H]+
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CCN(CC)CC.[CH3:20][NH:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1.C(Cl)Cl>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:21]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH3:20])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: CNC1CCCCC1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C1CCCCC1)S(=O)(=O)c1ccc(CBr)cc1
Yield: 24.7 %

Procedure:
The 4-(bromomethyl)benzene-1-sulfonyl chloride (1 g, 3.71 mmol), Et3N (0.776 mL, 5.56 mmol) and N-methylcyclohexylamine (0.42 g, 3.71 mmol) were reacted overnight in THF (6 mL) at ambient temperature. The mixture was diluted with DCM and washed with water. The organics were dried over MgSO4, filtered, concentrated and purified by chromatography on silica gel using an heptane/EtOAc gradient (100/0 to 50/50) to give the title compound (0.317 g, 24.6%): 1H NMR (CDCl3) δ 7.88-7.77 (d, 2H, J=8.4 Hz), 7.52 (d, 2H, J=8.4 Hz), 4.62 (s, 2H), 3.87-3.60 (m, 1H), 2.75 (s, 3H), 1.79-1.69 (m, 2H), 1.66-1.57 (m, 1H), 1.52-1.50 (m, 1H), 1.30 (m, 4H), 1.14-0.84 (m, 2H)
Reaction SMILES: [CH2:1]([C:4]1([CH3:36])[C:10](=[O:11])[N:9]([CH2:12][C:13]([N:15]([CH:22]([CH3:24])[CH3:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[C:8]2[CH:25]=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:5]1=[O:35])[CH:2]=C.I([O-])(=O)(=O)=[O:38].[Na+].CCOC(C)=O>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH:22]([N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](=[O:14])[CH2:12][N:9]1[C:10](=[O:11])[C:4]([CH3:36])([CH2:1][CH:2]=[O:38])[C:5](=[O:35])[N:6]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:7]2[CH:28]=[CH:27][CH:26]=[CH:25][C:8]1=2)([CH3:23])[CH3:24]
Reactant: C=CCC1(C)C(=O)N(CC(=O)N(c2ccccc2)C(C)C)c2ccccc2N(c2ccccc2)C1=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)N(C(=O)CN1C(=O)C(C)(CC=O)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Reaction time: 0.02 h
Yield: 69.4 %

Procedure:
To a stirring solution of 200 mg (0.42 mmol) of 2-(3-Allyl-3-methyl-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl acetamide, prepared as in Intermediate 6, in 10 mL of 1,4-dioxane and 3 mL of H2O is added 0.5 mL of a 4% solution of osmium tetraoxide in H2O. The resulting solution is stirred 1 min, then 220 mg (1.03 mmol, 2.5 equiv) of sodium periodate is added. The reaction mixture is stirred 3 h at RT then poured into 25 mL of EtOAc and extracted with H2O (1×25 mL), sat. NaHSO3 (1×25 mL), dried (MgSO4), and the solvents removed in vacuo. Purification of the crude material by silica gel flash column chromatography using hexane/EtOAc 1/1 as eluent afforded 141 mg of the title compound as a white foam: 1H NMR (CDCl3, 300 MHz, mixture of conformations) δ9.65 (s, 0.8H), 9.40 (s, 0.2H), 7.50-7.03 (m, 13H), 6.83 (d, 0.8H), 6.75 (d, 0.2H), 5.07 (m, 0.8H), 4.96 (m, 0.2H), 4.41 (d, 1H), 4.02 (d, 1H), 2.96 (dd, 2H), 1.62 (s, 0.6H), 1.17 (s, 2.4H), 1.09 (m, 6H); low resolution MS (FAB) m/e 619 (MH+), 574.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=2)[CH:14]=1.C([O:29][B:30](OCCCC)[O:31]CCCC)CCC.Cl>O1CCCC1.O>[CH3:24][O:23][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([B:30]([OH:31])[OH:29])[CH:14]=2)[CH:19]=1
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2cc(B(O)O)ccc2c1
Reaction time: 1.17 h
Yield: 58.5 %

Procedure:
A solution of n-butyl lithium in hexane (1.5M; 8.9 ml, 13.4 mmol) was added dropwise to a solution of 2-bromo-6-methoxynaphthalene (3.0 g, 12.7 mmol) in tetrahydrofuran (45 ml) under argon atmosphere at −60° C. and the mixture was stirred at the same temperature for 70 min. To the mixture was added tri-n-butylborate (5.2 ml, 19.0 mmol) and the mixture was stirred at the same temperature for 1 hr. and then at 5° C. for 1.5 hrs. To the reaction mixture was added dropwise 20% hydrochloric acid (13 ml) at 5° C., and water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine in turn and dried. The solvent was distilled off under reduced pressure, and the residue was triturated with ethyl acetate and diethyl ether, filtered and dried to give (2-methoxy)-6-naphthalene boronic acid (1.50 g, 59%) as a colorless solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20]C)=O)[CH:16]=3)[CH:11]=[CH:10]2)=[CH:5][CH:4]=1.O.[NH2:23][NH2:24]>C(O)C>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([NH:23][NH2:24])=[O:20])[CH:16]=3)[CH:11]=[CH:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc2ccn(-c3ccc(SC)cc3)c2c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CSc1ccc(-n2ccc3ccc(C(=O)NN)cc32)cc1

Procedure:
A mixture of methyl 1-[4-(methylthio)phenyl]-1H-indole-6-carboxylate (2.50 g, 8.41 mmol), hydrazine monohydrate (4.08 mL, 84.1 mmol) and ethanol (40 mL) was heated under reflux overnight. After cooling, the precipitate was collected by filtration and washed with ethanol to give crude 1-[4-(methylthio)phenyl]-1H-indole-6-carbohydrazide.
Reaction SMILES: [CH:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(O)(=O)[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]>CCCCCCCC>[CH2:4]([O:3][C:1](=[O:2])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=COCc1ccccc1
Reactant: O=C(O)CCCCC(=O)O
Solvent: CCCCCCCC
Product: O=C(O)CCCCC(=O)OCc1ccccc1
Temperature: 100 °C
Yield: 87 %

Procedure:
DOWEX® 50W-X2 (2 g), benzyl formate (10 mL, mol), and adipic acid (2 g, mol) were added to octane (10 mL). The mixture was refluxed for 4 hours at 100° C., and the crude product was purified via silica chromatography to yield a clear, colorless liquid (87% yield). 1H NMR (CDCl3) 1.59-1.78 (m, 4H, CH2CH2), 2.33-2.39 (m, 4H, CH2COOH), 5.09 (s, 2H, PhCH2), 7.25-7.30 (m, 5H, aromatic).
Reaction SMILES: [N:1]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([O:5]N1C(=O)CCC1=O)=O.[NH2:23][C@@H:24]([C:35]([OH:37])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1.[OH-].[K+].C(OCC)(=O)C>CN(C)C=O.O>[N:1]1([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([NH:23][C@@H:24]([C:35]([OH:37])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:5]
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)ON1C(=O)CCC1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A chilled mixture of BocProOSu (96.1 mmole.) and dimethylformamide (100 ml.) was added with cooling to 0° C. to a solution of HDTrpOH (0.1 mole) and potassium hydroxide (85%, 0.1 mole) in dimethylformamide (150 ml.) and water (25 ml.). The mixture was stirred for one hour at 0° C., allowed to warm to room temperature overnight, and stripped of volatiles. The residue was partitioned between ethyl acetate and aqueous citric acid (5%). Crystals which formed between the layers were collected by filtration and recrystallized from methanol-water. More product was obtained by stripping the ethyl acetate layer of ethyl acetate and recrystallizing the residue from methanol-water. The recrystallizates were combined, affording BocProD-TrpOH in 86% yield (33.1 g., m.r. 210°-213° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:5]=1)([O-])=O.NN>CO.C(OCC)(=O)C.[Ni].O>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][N:6]2[CH:7]=[CH:8][C:4]([NH2:1])=[N:5]2)[CH:11]=1
Reactant: O=[N+]([O-])c1ccn(Cc2cccnc2)n1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccn(Cc2cccnc2)n1
Reaction time: 1 h
Yield: 75.1 %

Procedure:
3-(3-Nitro-pyrazol-1-ylmethyl)-pyridine (113 mg, 0.55 mmol) was dissolved in a mixture of methanol and ethyl acetate (1 mL each). Hydrazine (156 μL, 4.97 mmol) was added followed by a slurry of Raney nickel in water (1.5 mL) causing vigorous gas evolution. After stirring 1 h, the reaction mixture was filtered and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 3% methanol/chloroform) to afford 1-pyridin-3-ylmethyl-1H-pyrazol-3-ylamine (72 mg, 75%) as a white solid: LC-MS (ESI) m/e calcd for C9H10N4 [M+] 174.09, found 175 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[F:11][C:12]1[CH:31]=[CH:30][C:15]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[O:19])=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:26]([C:23]2[CH:22]=[CH:21][C:20]([C:18]([NH:17][CH2:16][C:15]3[CH:30]=[CH:31][C:12]([F:11])=[CH:13][CH:14]=3)=[O:19])=[CH:25][CH:24]=2)(=[O:27])=[O:28])[N:3]=1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1n[nH]c2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2nc(Cl)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
Dissolve 3-chloro-1H-indazole (120 mg, 0.79 mmol) and 4-(4-fluoro-benzylcarbamoyl)-benzenesulfonyl chloride (114 mg, 0.35 mmol) in CH2Cl2 (2.0 mL) and treat with Et3N (50 L, 0.36 mmol). Stir the solution for 1 h at RT, then dilute with additional CH2Cl2 (20.0 mL) and wash with satd aq. NaHCO3 (15 mL). Dry, filter, and concentrate the organic phase and purify the crude material by flash chromatography (100% hexanes to 50% EtOAc/hexanes linear gradient) to give the title compound (129 mg, 83%) as a white foam. MS (ES+) 443.9 (M+1)+, (ES−) 442.0 (M−1)−. 1H NMR (400 MHz, CDCl3): δ 8.17 (d, 1H, J=8.3), 8.03 (d, 2H, J=8.2), 7.83 (d, 2H, J=8.9), 7.64 (m, 2H), 7.41 (t, 1H, J=7.4), 7.27 (m, 2H), 7.01 (t, 2H, J=8.9), 6.31 (br s, 1H), 4.57 (d, 2H, J=5.9).
Reaction SMILES: [CH2:1]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH3:28])=[CH:18][CH:17]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:29](O)=[O:30])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:34])=O.[CH3:36][N:37]([CH:39]=O)[CH3:38]>>[ClH:34].[ClH:34].[CH2:1]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH3:28])=[CH:18][CH:17]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:29]([NH:5][C:11]2[CH:12]=[CH:13][C:14]([CH2:39][N:37]([CH3:36])[CH:38]3[CH2:24][CH2:23][O:22][CH2:19][CH2:18]3)=[CH:15][CH:10]=2)=[O:30])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCC(C(=O)O)=Cc2cc(-c3ccc(OCCOCCC)cc3)ccc21
Reactant: O=S(Cl)Cl
Reactant: CN(C)C=O
Product: CCCCN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(-c3ccc(OCCOCCC)cc3)ccc21
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In DMF (6 ml) was dissolved 1-butyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.30 g). Under ice-cooling, to the mixture was added thionyl chloride (0.15 ml). The mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure. In THF (20 ml) was suspended the residue, and the suspension was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.17 g) and triethylamine (0.42 ml) in THF (5 ml), under ice-cooling. The mixture was stirred at room temperature overnight under nitrogen atmosphere. The solvent was evaporated under reduced solvent. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/methanol/triethylamine). The material was dissolved in ethyl acetate-ethanol, and 6N hydrochloric acid was added to the solution. The solvent was evaporated. Diethyl ether was added to the residue, and the precipitates were filtered to give 1-butyl-7-[4-(2-propoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide dihydrochloride (Compound 30) (0.36 g) as pale yellow amorphous.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[C:18](=O)([O-])[O-].[Na+].[Na+]>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12][CH3:18])=[O:11])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc([N+](=O)[O-])cn1
Yield: 89 %

Procedure:
5-Nitropyridine-2-carboxylic acid (100 g, 0.60 mol) was heated at reflux in methanol (1 L) and sulfuric acid (57 mL) for 5 hours. The reaction mixture was cooled, reduced to half volume in vacuo, and the residue neutralized with a solution of sodium carbonate. The resulting precipitate was filtered to give methyl 5-nitropyridine-2-carboxylate (yield 89%, 98 g).
Reaction SMILES: [CH:1]([C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7](=S)[C:6]=2[N:5]=1)([CH3:3])[CH3:2].COS(C(F)(F)F)(=O)=O.[CH3:28][O:29][CH2:30][CH2:31][C@H:32]1[CH2:37][NH:36][CH2:35][CH2:34][NH:33]1>ClCCl.N1C=CC=CC=1>[CH3:28][O:29][CH2:30][CH2:31][C@@H:32]1[NH:33][CH2:34][CH2:35][N:36]([C:7]2[C:6]3[N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[S:13][C:12]=3[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=2)[CH2:37]1
Reactant: CC(C)c1nc2c(s1)Nc1ccccc1NC2=S
Reactant: COCC[C@H]1CNCCN1
Agent: COS(=O)(=O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(C)C)nc32)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
Combine 2-isopropyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione (2.61 g, 9.48 mmoles) with trifluoromethanesulfonic acid methyl ester (1.61 mL, 14.2 mmoles) in dichloromethane (20 mL). Stir at room temperature for 2 h, then remove solvent in vacuo. Suspend residue in pyridine (20 mL) and add (S)-2-(2-methoxyethyl)piperazine (1.37 g, 9.48 mmoles). Heat at 115° C. for 8 h, then remove solvent in vacuo and apply residue to silica gel column. Elute column with dichloromethane followed by 5% 2N ammonia-methanol in dichloromethane to obtain the title compound (2.11 g, 58%) as a yellow oil: mass spectrum (APCI): m/z=386.2 (M+1).
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.[F:10][C:11]1[CH:12]=[C:13]([CH:36]=[CH:37][CH:38]=1)[CH2:14][N:15]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]3[C:30]4=[C:31]([CH2:34]O)[CH:32]=[CH:33][N:29]4[N:28]=[CH:27][N:26]=3)=[CH:21][CH:22]=2)[CH:17]=[N:16]1.C(N(CC)CC)C.[F:46][C:47]1([F:54])[CH2:53][NH:52][CH2:51][CH2:50][NH:49][CH2:48]1>C(Cl)Cl.ClCCCl>[F:46][C:47]1([F:54])[CH2:53][N:52]([CH2:34][C:31]2[CH:32]=[CH:33][N:29]3[C:30]=2[C:25]([NH:24][C:20]2[CH:19]=[C:18]4[C:23](=[CH:22][CH:21]=2)[N:15]([CH2:14][C:13]2[CH:36]=[CH:37][CH:38]=[C:11]([F:10])[CH:12]=2)[N:16]=[CH:17]4)=[N:26][CH:27]=[N:28]3)[CH2:51][CH2:50][NH:49][CH2:48]1
Reactant: OCc1ccn2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Reactant: FC1(F)CNCCNC1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: Fc1cccc(Cn2ncc3cc(Nc4ncnn5ccc(CN6CCNCC(F)(F)C6)c45)ccc32)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 9.5 %

Procedure:
A solution of methanesulfonic anhydride (114 mg, 3.2 equiv.) in DCM (0.6 mL) was added to a solution of {4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methanol (78 mg, 2 mmole) in dry DCM (1.4 mL) at 0° C. under nitrogen followed by triethylamine (0.140 mL, 5 equiv.). After stirring at 0° C. for 1 hr, 6,6-difluoro-[1,4]diazepane (82 mg, 3 equiv.) and 1,2 dichloroethane (2 mL) were added. The reaction mixture was transferred to a microwave reactor (Personal Chemistry's Smith Creator) and irradiated at 65° C. for 50 min. Removal of the solvent followed by preparative HPLC afforded the title compound as a solid (29 mg, 29%). MS: 507 (M+H+); HPLC Ret Time: 1.47 min (YMC Xterra ODS S7 3.0×50 mm column, 2 min gradient, 5 ml/min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:36])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:37]([O:39]CC)=[O:38].[OH-].[Na+].C1COCC1.Cl>C(OCC)(=O)C.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:36])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:24]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:37]([OH:39])=[O:38]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4cccc(Oc5ccccc5)c4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(NCCc1cccc(Oc2ccccc2)c1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Yield: 83.2 %

Procedure:
Ethyl 6-chloro-7-(4-(3-phenoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate (71.6 mg, 0.125 mmol) was reacted with 1.0 molar sodium hydroxide (501 μl, 0.501 mmol) in a 3:1 THF:Ethanol solution (0.05 M). After 2 hours the reaction was diluted with ethyl acetate, neutralized with 1.0 molar hydrochloric acid (526 μl, 0.526 mmol) and partitioned between saturated aqueous sodium chloride. The organic layer was dried with sodium sulfate, filtered, concentrated, and dried under high vacuum to provide the title compound (56.4 mg, 0.104 mmol, 82.8% yield) as a solid.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][CH:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][CH:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn(CC4CCCC4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(C)cc(-c3cn(CC4CCCC4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-cyclopentylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:21][C:22]1([CH3:29])[C:26]([CH3:28])([CH3:27])[O:25][BH:24][O:23]1.C(N(CC)CC)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O1CCOCC1>[CH3:21][C:22]1([CH3:29])[C:26]([CH3:28])([CH3:27])[O:25][B:24]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[O:23]1
Reactant: CC1(C)OBOC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Br)cc2)CC1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Temperature: 110 °C
Yield: 59.4 %

Procedure:
To a solution of tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate (13.5 g, 39.7 mmol) in dioxane (40 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.64 mL, 59.5 mmol) and triethylamine (16.6 mL, 119 mmol). The solution was purged with argon for 5 minutes. Dichlorobis(acetonitrile) palladium (0.309 g, 1.19 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.95 g, 4.76 mmol) were then added, and the reaction mixture was again purged with argon for 5 minutes. The reaction mixture was then sealed and heated at 110° C. for 90 minutes. The reaction mixture was cooled to ambient temperature and filtered through a glass fiber filter paper. The filtrate was concentrated under reduced pressure and the residue purified by silica gel column chromatography, eluting with 5-10% EtOAc in hexanes to afford tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate (9.13 g, 23.6 mmol, 59.4% yield) as a solid. MS (apci) m/z=288.3 (M+H-Boc).