Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[NH:23]1[CH:27]=[C:26](B(O)O)[CH:25]=[N:24]1.C([O-])([O-])=O.[K+].[K+].O>COCCOC.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>[NH:23]1[CH:27]=[C:26]([C:2]2[CH:3]=[C:4]([N:8]3[C:16]4[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=4[C:10]4[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]3=4)[CH:5]=[CH:6][CH:7]=2)[CH:25]=[N:24]1
Reactant: OB(O)c1cn[nH]c1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3cn[nH]c3)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 1H-pyrazole-4-boronic acid (62 mg, 0.56 mmol) and K2CO3 (116 mg, 0.84 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.014 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure and residue and dissolved in EtOAc (30 mL). The organic layer was washed with water (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-(3-(1H-pyrazol-4-yl)phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) d (ppm): 8.03 (s, 2H), 7.7 (d, 1H), 7.58 (m, 2H), 7.3 (s, 1H), 7.22 (d, 1H), 7.1 (d, 1H), 7.0 (d, 1H), 4.8 (d, 1H), 4.4 (d, 1H), 3.8 (m, 1H), 3.57 (m, 1H), 3.2 (m, 1H), 3.17 (s, 3H), 3.0 (m, 1H), 2.42 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][CH:13]([CH3:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=S)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1CCC(N=C=NC2CCCCC2)CC1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[N:12][CH:13]([CH3:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(NC(=S)Nc1cc(Cl)cc(Cl)c1)C(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(N=C=Nc1cc(Cl)cc(Cl)c1)C(C)(C)C

Procedure:
To a solution of 2.5 g of N-(3,5-dichlorophenyl)-N'-(1,2,2-trimethylpropyl)thiourea produced in Example A-6 in 50 ml of THF were added 2.2 g of DCC and 0.36 g of triethylamine. The mixture was refluxed for 4 hours and evaporated in vacuo. The residue was extracted with petroleum ether. The extract was evaporated in vacuo to give N-(3,5-dichlorophenyl)-N'-(1,2,2-trimethylpropyl)carbodiimide as an oil. To a solution of this oil in 20 ml of THF were added 1.0 g of cyanamide and 1 ml of diisopropylethylamine. The mixture was refluxed for 40 hours and evaporated in vacuo. The residue was recrystallized from benzene to give 1.2 g of the title compound as colorless needles melting at 154.0°-156.0° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1([OH:22])[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8]1)=[O:6].[CH3:23]I.O>CN(C=O)C>[CH3:3][O:4][C:5]([C:7]1([O:22][CH3:23])[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8]1)=[O:6]
Reactant: COC(=O)C1(O)CCN(C(=O)OCc2ccccc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(OC)CCN(C(=O)OCc2ccccc2)C1
Temperature: 17 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a suspension of NaH (52 g, 1.3 mol) in 2.2 L of anhydrous DMF at 8° C., was added a solution of 3-Hydroxy-pyrrolidine-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester 3a (278 g, 1.0 mol) in 700 DMF, keeping the reaction temperature below 11° C. After complete addition (˜20 min), ice bath was removed, stirred at 16-18° C. for 1 h, and then at ambient temperature for 1 h. Cooled back to 15° C., added MeI (81 mL, 1.3 mol) slowly. Reaction mixture was stirred at ambient temperature for 1 overnight. The reaction mixture was then poured in a cold water (4 L) and then extracted with Et2O (6 L) and EtOAc (2 L), washed the organic later with water (5 L), brine (700 mL), dried over magnesium sulfate, filtered and evaporated to give crude 3-Methoxy-pyrrolidine-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester 4a 289 g (99% crude yield, contains mineral oil) (stirring/separation with pentane wash gave 4a, 268.2 g (92%).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[C:6](Cl)(=O)[C:7]1[CH:12]=[CH:11][CH:10]=[N:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>N1C=CC=CC=1.O>[SH:4][C:3]1[N:5]=[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:1][N:2]=1
Reactant: NNC(N)=S
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: Sc1n[nH]c(-c2cccnc2)n1

Procedure:
To a solution of 19 g (0.200 mol) of thiosemicarbazide in 175 ml of dry pyridine, 29 g (0.200 mol) of nicotinoyl chloride was slowly added at 10° C. After reflux for 40 min. the reaction mixture was concentrated to half the original volume, 500 ml of water was added, and stored in the cold overnight. The precipitate formed was removed by filtration, and the filtrate was evaporated in vacuo. The resulting heavy, yellow oil was dissolved in 300 ml of water, and 64 g (0.600 mol) of sodium carbonate in 400 ml of water was added. After reflux for 4 h the solution was cooled and acidified with conc. hydrochloric acid to pH=4. The formed, colorless precipitate, 65, was isolated by filtration and dried in vacuo. Yield: 35 g (0.297 mol, 98%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:26](O)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[NH2:30][CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:26]([NH:30][CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25]3)=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C3(C(=O)O)CCCC3)cc2)cc1
Reactant: CC(C)(C)OC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C3(C(=O)NCCC(=O)OC(C)(C)C)CCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-1-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)cyclopentanecarboxylic acid (15 mg, 0.040 mmol), tert-butyl 3-aminopropanoate hydrochloride (7.94 mg, 0.044 mmol), HATU (16.62 mg, 0.044 mmol), and TEA (0.017 mL, 0.119 mmol) in DMF (0.4 mL) was stirred at room temperature overnight. The mixture was acidified with 1M HCl and purified by HPLC. LCMS m/z=505.5 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=O)[C:6]([NH2:12])=[CH:5][CH:4]=1.C(O)(=O)C.[O-:17][C:18]#[N:19].[K+].[OH-].[Na+]>O>[OH:17][C:18]1[N:19]=[C:8]([OH:10])[C:7]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2)[N:12]=1
Reactant: N#C[O-]
Reactant: COc1ccc(N)c(C(=O)O)c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2nc(O)nc(O)c2c1
Yield: 82 %

Procedure:
A mixture of 5-methoxy anthranilic acid (40 g, 0.24M), acetic acid (18.0 g, 0.3M) and 1 liter warm water (35° ) was stirred and allowed to cool. A solution of potassium cyanate (24.3 g, 0.3M) in water (100 ml) was added over 15 minutes and then stirred for a further 30 minutes. Sodium hydroxide (320 g, 8.0M) solid was added portionwise and the reaction was then heated at 90° for 30 minutes and allowed to cool overnight. The solid was filtered off and dissolved in hot water (500 ml) and then acidified with dilute sulphuric acid to precipitate the product. The solid was filtered off and washed free of acid with water and then dried at 100°/vacuum to yield the title compound (37.7 g) m.p. >290°.
Reaction SMILES: C(O)=[O:2].[CH:4]1([N:10]=[C:11]=[N:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>C(Cl)Cl>[CH:13]1([NH:12][C:11](=[O:2])[NH:10][CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=CO
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
In this example, 11.7 g (0.2534 mole) of formic acid was added to a stirred slurry containing 26.1 (0.1267 mole) of dicyclohexyl carbodiimide in 300 ml of methylene chloride at about -10° C. A precipitate of dicyclohexyl urea formed. The mixture was then stirred at 0° to 3° C. for 20 minutes and then a solution containing 24.6 g (0.0756 mole) of N-(2-[4-(4-trifluoromethylphenoxy)-phenoxy]propyl)-N-methylformamide and 0.1267 mole of 4-dimethylaminopyridine in 125 ml of methylene chloride was slowly added over a 2-hour period. The mixture was allowed to warm to room temperature and stirred at room temperature overnight (about 12 hours). Thin layer chromatographic analysis of a sample showed complete reaction. The mixture was then filtered and the filter cake washed with methylene chloride. The combined filtrate and washing was washed with 200 ml aqueous 5% by weight hydrochloric acid, then with 200 ml of water and then dried over magnesium sulfate and filtered. The filtrate was evaporated under vacuum affording a semi-oil product. The semi-oil product was treated with ethyl ether and then filtered. The filtrate was evaporated under vacuum affording an oil which was then chromatographed on 300 g of silica gel sequentially eluting with pet (i.e., petroleum ether); 80:20 volume pet:ethyl ether; 60:40 volume pet:ethyl ether; ethyl ether and 96% ethyl ether in methanol affording the title compound as an oil contaminated with water and methanol. The oil was then dissolved in methylene chloride and the resulting solution then washed with water, then with 100 ml of a saturated aqueous solution of sodium bicarbonate and then dried over magnesium sulfate and filtered. The filtrate was evaporated under vacuum affording 10.3 g of the title compound as a clear oil. Elemental analysis: Calculated: C-61.19%, H-5.13%, N-3.96%; Found: C-62.56%, H-5.31%, N-4.05%.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[N+:14]([O-])([OH:16])=[O:15]>>[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15]
Reactant: Fc1ccc(F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(F)ccc1F
Reaction time: 0.5 h

Procedure:
To a cooled solution (0°-5° C./-15° C. with CO2 /acetone/water) of conc. sulfuric acid (600 ml) and 90% nitric acid (330 ml) in a three-necked flask equipped with a mechanical stirrer and thermometer was added 1,4-difluorobenzene dropwise (300 g., 2.63 moles) over 2.5 hours. After an additional 30 min. stirring, the mixture was carefully poured into ice and extracted with ethyl ether (3×600 ml). The organic layers were washed with brine, water, 5% sodium bicarbonate solution, dried over (Na2SO4) and evaporated in vacuo. The orange liquid was distilled under vacuum to obtain 1,4-difluoro-2-nitrobenzene, b.p. 102°-105° C. at 30 torr.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[C:15]([C:19]1[N:23]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:22]2[CH:31]=[CH:32][C:33]([S:35]([N:38]3[CH:42]=[C:41]([C:43](O)=[O:44])[CH:40]=[N:39]3)(=[O:37])=[O:36])=[CH:34][C:21]=2[N:20]=1)([CH3:18])([CH3:17])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:15]([C:19]1[N:23]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:22]2[CH:31]=[CH:32][C:33]([S:35]([N:38]3[CH:42]=[C:41]([C:43]([NH:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)=[O:44])[CH:40]=[N:39]3)(=[O:37])=[O:36])=[CH:34][C:21]=2[N:20]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: NC1CCC1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
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: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)NC4CCC4)cn3)ccc2n1CC1CCOCC1
Yield: 46.6 %

Procedure:
Following the same procedure in Example 24, Step A, using cyclobutylamine (13 uL, 10 mg, 0.15 mmol), DIPEA (28 uL, 21 mg, 0.16 mmol), 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carboxylic acid (0.073 mmol) and HATU (44 mg, 0.12 mmol) in DMF (2.5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:2) on silica gel to give 17 mg (47%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.40-1.56 (m, 4 H), 1.58 (s, 9 H), 1.67-1.79 (m, 2 H), 1.96-2.09 (m, 2 H), 2.22-2.34 (m, 3 H), 3.25-3.34 (m, 2 H), 3.83-3.94 (m, 2 H), 4.34-4.39 (m, 1 H), 4.41 (d, J=7.62 Hz, 2 H), 7.90 (d, J=8.6 Hz, 1 H), 7.97 (dd, J=8.8, 1.8 Hz, 1 H), 8.04 (d, J=0.59 Hz, 1 H), 8.33 (d, J=1.37 Hz, 1 H), 8.77 (d, J=0.59 Hz, 1 H); MS (ESI) (M+H)+=499.8; Anal. Calcd for C25H33N5O4S+0.70 TFA+0.30 EtOAc+0.20H2O (613.09): C, 54.66; H, 6.00; N, 11.42. Found: C, 54.63; H, 5.95; N, 11.51.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH2:28])=[CH:22][CH:21]=1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:28][CH2:27][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=1)=[O:14]
Reactant: Cc1ccc(CCN)cc1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: Cc1ccc(CCNC(=O)c2ccncc2Nc2ccc(I)cc2F)cc1

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-[2-(4-methylphenyl)ethyl]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.54 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.62 mmol of 2-(4-methylphenyl)ethylamine. LC/MS [10.25 min; 476 (M+1)]
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:34])=[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:24][CH:23]=1)[C:10]([O:17][CH:18]([F:20])[F:19])=[N:11]2.[OH-].[Li+]>O1CCCC1.O>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:35])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([O:17][CH:18]([F:19])[F:20])[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:33])[C:29]([CH3:30])([CH3:31])[CH3:32])=[CH:24][CH:23]=1)=[C:8]2[CH3:34]
Reactant: COC(=O)COc1ccc(Cl)c2nc(OC(F)F)c(Cc3ccc(C(=O)C(C)(C)C)cc3)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(C(=O)C(C)(C)C)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
A solution of {8-chloro-2-difluoromethoxy-3-[4-(2,2-dimethylpropionyl)benzyl]-4-methylquinolin-5-yloxy}acetic acid methyl ester (0.18 g) in tetrahydrofuran (10 mL) and water (1.5 mL) was treated with 1.0 M aqueous lithium hydroxide solution (0.71 mL), and the resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, diluted with water and dichloromethane and then acidified by the addition of 0.1 M aqueous hydrochloric acid solution. The aqueous phase was extracted with dichloromethane and the combined organic phases dried over magnesium sulfate. The solvent was removed under reduced pressure to give title compound as a white solid (0.16 g).
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Br:17]Br>C(O)(=O)C>[C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([Br:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: COc1ccc2c(c1)CCN(C(C)=O)CC2
Solvent: CC(=O)O
Product: COc1cc2c(cc1Br)CCN(C(C)=O)CC2

Procedure:
A solution of 3-acetyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (2.3 g, 0.01 m) in acetic acid (20 ml) was treated with a solution of bromine (1.8 g, 0.011 m) in acetic acid (10 ml). The mixture was warmed to 70° for 1.5 hours, concentrated in vacuo and partitioned between water and ethyl acetate. The ethyl acetate phase was washed, dried with sodium sulfate and concentrated in vacuo to give 3-acetyl-8-bromo-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine. NMR (CDCl3) 6.7, 7.3; aryl protons.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:44])[CH2:4][N:5]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[C:6]1[CH:11]=[C:10]([O:12]CC2C=CC=CC=2)[CH:9]=[C:8]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:7]=1.[H][H]>[Pd].C1COCC1>[CH3:1][O:2][C:3](=[O:44])[CH2:4][N:5]([C:6]1[CH:7]=[C:8]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:9]=[C:10]([OH:12])[CH:11]=1)[CH2:39][C:40]([O:42][CH3:43])=[O:41]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCc2ccccc2)cc(N(CC(=O)OC)CC(=O)OC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(N(CC(=O)OC)CC(=O)OC)c1
Reaction time: 23 h
Yield: 96.5 %

Procedure:
A mixture of 15.55 g of N-(2-methoxy-2-oxoethyl)-N-[3-(octadecyloxy)-5-(phenylmethoxy) phenyl]glycine methyl ester and 3.0 g of 10% palladium on carbon in 500 mlof THF was stirred in a hydrogen atmosphere at room temperature until uptake ceased after 23 hours. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to a solid which was triturated with hexane and filtered to give 12.8 g (97% yield, 96°-98°) of N-[3-hydroxy-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester.
Reaction SMILES: C1N(P(N2CC2)(NC(C2C(I)=CC=CC=2)=O)=O)C1.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]=[CH2:33])=[CH:28][N:27]=2)[CH2:22][CH2:21]1.I[C:35]1[C:43]2[C:38](=[CH:39][C:40]([CH:44]=[O:45])=[CH:41][CH:42]=2)[N:37]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[N:36]=1>>[CH3:19][N:20]1[CH2:21][CH2:22][N:23]([C:26]2[N:27]=[CH:28][C:29](/[CH:32]=[CH:33]/[C:35]3[C:43]4[C:38](=[CH:39][C:40]([CH:44]=[O:45])=[CH:41][CH:42]=4)[N:37]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[N:36]=3)=[CH:30][CH:31]=2)[CH2:24][CH2:25]1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Reactant: C=Cc1ccc(N2CCN(C)CC2)nc1
Agent: O=C(NP(=O)(N1CC1)N1CC1)c1ccccc1I
Product: CN1CCN(c2ccc(/C=C/c3nn(COCC[Si](C)(C)C)c4cc(C=O)ccc34)cn2)CC1

Procedure:
The title compound was synthesized according to the method of Example A103, utilizing 1-methyl-4-(5-vinylpyridin-2-yl)piperazine (65 mg, 0.32 mmol) and 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (100 mg, 0.25 mmol). Purified by prepTLC (SiO2 10% MeOH/DCM) to provide the title compound to as a pale orange material (46 mg, 39%). 1H NMR (400 MHz, CD3OD) δ ppm 10.14 (s, 1H), 8.34 (d, J=2.26 Hz, 1.0H), 8.24-8.28 (m, 2H), 8.00 (dd, J=8.91, 2.38 Hz, 1H), 7.80 (d, J=8.78 Hz, 1H), 7.51 (d, J=16.56 Hz, 1H), 7.36 (d, J=16.56 Hz, 1H), 6.97 (d, J=9.29 Hz, 1H), 5.85 (s, 2H), 3.77-3.87 (m, 4H), 3.63 (t, J=7.91 Hz, 2H), 3.06-3.15 (m, 4H), 2.75 (s, 3H), 0.88 (t, J=8.03 Hz, 2H), −0.09 (s, 9H); MS ESI 478.3 [M+H]+, calcd for [C26H35N5O2Si+H]+ 478.7.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl:15][C:16]([Cl:21])([Cl:20])[C:17](Cl)=[O:18]>O1CCCC1>[Cl:15][C:16]([Cl:21])([Cl:20])[C:17]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:18]
Reactant: Nc1cccnc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnc1)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 87.3 %

Procedure:
To a solution of 3-aminopyridine (1.0 g, 11 mmol) and triethylamine (1.3 g, 13 mmol) in tetrahydrofuran (30 mL) was added at 0° C. trichloroacetyl chloride (1.4 mL, 13 mmol), and the mixture was stirred at 0° C. for 20 minutes. The reaction solution was concentrated, and ethyl acetate was added to the residue. The resulting mixture was washed with water and saturated brine and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated. The residue was washed with diisopropyl ether and collected by filtration to obtain the title compound (2.3 g, yield 89%) as colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:19][C:20]([CH3:23])=[N:21][N:22]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.O1CCCC1.[H][H]>[C].[Pd].CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:19][C:20]([CH3:23])=[N:21][N:22]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: COc1ccc(-c2coc3ccc(-c4nnc(C)o4)cc23)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C2COc3ccc(-c4nnc(C)o4)cc32)cc1
Yield: 74.4 %

Procedure:
A mixture of 2-[3-(4-methoxyphenyl)-1-benzofuran-5-yl]-5-methyl-1,3,4-oxadiazole (447 mg, 1.46 mmol), 10% palladium carbon (50% containing water, 450 mg), tetrahydrofuran (5 mL) and methanol (15 mL) was stirred at room temperature for 48 hr under 1 atm hydrogen atmosphere. Palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate), and crystallized from hexane/ethyl acetate to give the title compound (335 mg, yield 74%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18]([C:19]4[CH:20]=[N:21][C:22]([N:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:35]CN(CC)CC.C=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18]([C:19]4[CH:20]=[N:21][C:22]([N:29]5[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]5)=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:24]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCN(CC)CC
Reactant: COc1ccc(-c2nn3c(-c4cnc(N5CCNCC5)c(C(F)(F)F)c4)cnc3s2)cc1OC
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(-c2nn3c(-c4cnc(N5CCN(C)CC5)c(C(F)(F)F)c4)cnc3s2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
To a mixture of 2-(3,4-Dimethoxy-phenyl)-5-(6-piperazin-1-yl-5-trifluoromethyl-pyridin-3-yl)-imidazo[2,1-b][1,3,4]thiadiazole (105 mg, 0.199 mmol, 1 eq), Et3N (0.056 mL, 0.399 mmol, 2 eq), formaldehyde (0.180 mL, 2.39 mmol, 12 eq) and acetic acid (0.02 mL, 0.239 mmol, 1.2 eq) in MeOH (4 mL) was added Sodium cyanoborohydride (0.175 g, 2.79 mmol, 14 eq). The reaction mixture was stirred at rt for 2 h. Solvents were evaporated to dryness and the residue was dissolved in sat NaHCO3/EtOAc. Layers were separated and the aqueous layer was extracted once with EtOAc. The combined organic layers were dried, filtered and evaporated. The residue was purified on silica gel (isolute flash Si II, 10 g, 96:4 DCM/7N NH3 in MeOH) to give the desired product (50 mg, 50%). HPLC-MS: (5-100% B in 8 min, 0.8 mL/min, 50° C.): tR=3.47 min, [M+H]+ m/z 505.3; 1H NMR (300 MHz, CDCl3) δ 8.92 (s, 1H), 8.49 (d, J=1.9 Hz, 1H), 7.52 (s, 1H), 7.42 (d, J=1.7 Hz, 1H), 7.36 (dd, J=8.3, 2.0 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 3.94 (s, 3H), 3.88 (s, 3H), 3.41 (m, 4H), 2.57 (m, 4H), 2.34 (s, 3H).