Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[C:10](=[N:23][NH2:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:23][NH:24][C:2]2[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Reactant: COc1ccnc(Cl)c1
Product: COc1ccnc(NN=C(c2ccccc2)c2ccccc2)c1
Yield: 71.9 %

Procedure:
According to the process described in Example 2.2, starting with 0.5 g of 2-chloro-4-methoxypyridine and 0.75 g of benzophenone hydrazone, 0.76 g of 2-[2-(diphenylmethylidene)hydrazino]-4-methoxypyridine is obtained in the form of a yellow solid, which is used without further purification in the following step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.[C:11]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:11])[C:5]([F:9])=[C:4]([F:10])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(Br)cc(F)c1F
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(Br)cc(F)c1F
Temperature: 25 °C
Yield: 94.7 %

Procedure:
To a solution of 5-bromo-2,3-difluorophenol (19 g, 90 mmol) in acetone (180 mL), K2CO3 (18 g, 0.13 mol) and iodomethane (25.8 g, 0.18 mol) were added. The resulting mixture was refluxed for 4 h. Upon completion, the mixture was cooled to room temperature and filtered, and the filtrate was evaporated to give the crude product, which was further purified by column chromatography on silica gel (eluting with petroleum ether/ethyl acetate=80/1˜40/1) to give a light yellow liquid 5-bromo-1,2-difluoro-3-methoxybenzene (19 g). 1H NMR (CDCl3): δ 7.00-6.88 (m, 2H), 3.89 (s, 3H).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[C:11]2=[N+]=[N-]>ClCCl.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[C:11]12[CH2:1][CH:2]1[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=CCCCC
Reactant: [N-]=[N+]=C1C(=O)Nc2ccc(Br)cc21
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCCCC1CC12C(=O)Nc1ccc(Br)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
A solution containing 1-hexene (10 equiv.) and 1 mol % of rhodium (II) acetate in dry dichloromethane (10 mL) was degasified under an argon atmosphere. To this reaction mixture, a solution of 5-bromo-3-diazo-oxindole (1 equiv.) (J. Am. Chem. Soc. 1958, 80, 2257–2263) was added dropwise slowly over 1 h under an argon atmosphere at room temperature. The reaction mixture was stirred for 16 hours at room temperature, and concentrated to dryness in vacuo. The solid residue was chromatographed using hexane and ethyl acetate (v/v 1:1) as eluent. The chromatographed material gave the title compound in 70% yield. MS: m/z 294.3 [M+1]+. 1H NMR (CCl3D): δ 8.32 (br, 1H), 7.25 (d, 1H), 6.89 (d, 1H), 6.78 (d, 1H), 1.89 (m, 2H), 1.65 (m, 1H), 1.51 (m, 2H), 1.18–1.31 (m, 4H), 0.79 (t, 3H).
Reaction SMILES: [CH:1]([O:4][P:5]([CH2:11][O:12][CH2:13][N:14]1[C:22]([CH2:23][CH2:24][CH2:25][N:26]=[N+]=[N-])=[N:21][C:20]2[C:15]1=[N:16][C:17]([C:32]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[N:18][C:19]=2[NH:29][O:30][CH3:31])([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[CH:8]([O:7][P:5]([CH2:11][O:12][CH2:13][N:14]1[C:22]([CH2:23][CH2:24][CH2:25][NH2:26])=[N:21][C:20]2[C:15]1=[N:16][C:17]([C:32]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[N:18][C:19]=2[NH:29][O:30][CH3:31])([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])([CH3:9])[CH3:10]
Reactant: CONc1nc(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc2c1nc(CCCN=[N+]=[N-])n2COCP(=O)(OC(C)C)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CONc1nc(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc2c1nc(CCCN)n2COCP(=O)(OC(C)C)OC(C)C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 38 (805 mg, 1.15 mmol) in THF (8 mL) and water (1.6 mL) is treated with triphenylphosphine (640 mg, 2.44 mmol) and stirred at room temperature for 14 h. The reaction mixture is concentrated and purified on silica gel column using chloroform:CMA-80 (1:0 to 1:1) as eluent to give 660 mg (85%) as a white solid: 1H NMR (DMSO-d6): δ 8.09 (s, 1H), 7.72 (s, 1H), 7.17-7.00 (m, 13H), 6.67 (d, J=9.0 Hz, 2H), 4.70-4.59 (m, 1H), 4.28-4.16 (m, 2H), 3.95 (t, J=9.2 Hz, 1H), 3.68-3.45 (m, 3H), 3.54 (s, 3H), 2.29-2.05 (m, 2H), 1.93-1.60 (m, 4H), 0.96-0.91 (m, 6H), 0.84 (d, J=6.1 Hz, 6H). IR (neat, cm−1) 3414, 3020, 1605, 1511 and 1216. Anal. Calcd for C36H45N6O5P.1.5 H2O: C, 61.79; H, 6.91; N, 12.01. Found: C, 61.70; H, 6.63; N, 12.07.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.CN1CCCC1=O.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+]>O>[N:22]1([CH2:21][CH2:20][CH2:19][NH:18][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(NCCCN2CCCC2)cc1
Temperature: 60 °C
Yield: 93.4 %

Procedure:
2 g of 4-fluoronitrobenzene were added to a solution of 20 ml of N-methyl-pyrrolidinone, 2.18 g of N-(3-aminopropyl)pyrrolidine and 2.35 g of K2CO3. The reaction medium was heated at 60° C. for 12 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 3.3 g of N-(3-pyrrolidin-1-ylpropyl)-4-nitro-1-aminobenzene (13) were obtained.
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.S(C)C.[Br:25][CH2:26][C:27]([C:29]1[CH:38]=[CH:37][C:32]2[O:33][CH2:34][CH2:35][O:36][C:31]=2[CH:30]=1)=[O:28]>C1COCC1>[Br:25][CH2:26][CH:27]([C:29]1[CH:38]=[CH:37][C:32]2[O:33][CH2:34][CH2:35][O:36][C:31]=2[CH:30]=1)[OH:28]
Reactant: O=C(CBr)c1ccc2c(c1)OCCO2
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: CSC
Solvent: C1CCOC1
Product: OC(CBr)c1ccc2c(c1)OCCO2

Procedure:
(R)-2-Methyl-CBS-oxazaborolidine (1M in toluene, 1.95 ml, 1.95 mmol) was added to a flask containing 20 ml dry THF under Ar2(g) at 0° C. BH3.SMe2 (2M in THF, 6.0 ml, 12.0 mmol) was added over 5 min. 2-Bromo-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethanone (4.7 g) was dissolved in 30 ml dry THF, added to a dropping funnel and added to the above solution slowly (ca 4 h) at 0° C. The mixture was stirred over night. The reaction was quenched by addition of 0.4 ml MeOH. The mixture was concentrated under reduced pressure, diethyl ether (200 ml) was added and the solution was extracted with 0.5M HCl (pH=1). The aq-phase was extracted with 100 ml diethyl ether and the combined organic phases were washed with ca 2% NaHCO3 followed by brine. The organic phase was dried with MgSO4 and concentrated to yield the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.S(=O)(=O)(O)O.[C:11](O)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: c1cn[nH]c1
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Product: CC(C)(C)n1cccn1
Temperature: 195 °C
Yield: 72.8 %

Procedure:
As in Example 2, the column was charged with 30 g of glass rings of diameter 3 mm, 16.4 g (0.24 mol) of pyrazole and 1.02 g (0.01 mol) of 96% by weight sulfuric acid, heated to 195° C. and reacted over the course of 7 hours with 703 g (9.5 mol) of tert-butanol vaporized at 180° C. 21.7 g of N-tert-butylpyrazole were obtained, boiling point 103° C., with a content of 99.4% (GC), which corresponds to a yield of 72.5%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([NH2:21])=[O:20])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][C:15]([CH3:17])=[CH2:16])[C:6]=2[N:18]=1.[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[C:3]([C:19]([NH2:21])=[O:20])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:6]=2[N:18]=1
Reactant: [H][H]
Reactant: C=C(C)Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Agent: [Pd]
Solvent: CCO
Product: CC(C)Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.5 %

Procedure:
2-Amino-9-(2-methylprop-2-en-1-yl)-9H-pyrido[2,3-b]indole-3-carboxamide (xii-a, 143 mg) was dissolved in ethanol (40 mL) and placed under an argon atmosphere. 10% Palladium on carbon (26 mg) was added and the reaction placed under an atmosphere of hydrogen by repeated evacuation followed by back-filling using a balloon filled with hydrogen gas. The reaction stirred for 16 h at room temperature then the catalyst was removed by filtration through Celite® and the filtrate concentrated in vacuo. The residue was purified by silica gel chromatography (5% methanol in methylene chloride) to afford the title compound (44, 44 mg, 65%). NH4OAc standard conditions. DAD Retention time=7.45 min. M+H=283. 1H NMR (300 MHz, CDCl3): 8.22 (s, 1H), 7.83 (d, J=7.3 Hz, 1H), 7.30-7.36 (m, 3H), 7.21 (br s, 1H), 6.66 (br s, 1H), 5.67 (br s, 1H), 4.07 (d, J=7.3 Hz, 1H), 2.28-2.42 (m, 1H), 0.94 (d, J=6.7 Hz, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:23][N:24]([CH2:32][C:33]#[CH:34])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>C(N(CC)CC)C>[CH3:23][N:24]([CH2:32][C:33]#[C:34][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:9])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:12][CH:11]=2)=[CH:6][N:7]=1)[C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28]
Reactant: C#CCN(C)C(=O)OC(C)(C)C
Reactant: O=C(c1ccc(OC2CCCCO2)cc1)c1ccc(Cl)nc1
Solvent: CCN(CC)CC
Product: CN(CC#Cc1ccc(C(=O)c2ccc(OC3CCCCO3)cc2)cn1)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
A 25 mL Schlenk flask was charged with (6-chloropyridin-3-yl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone (318 mg, 1.0 mmol), tetrakis(triphenylphos-phine)Palladium(0) (116 mg, 0.1 mmol, 10 mol %), cuprous iodide (38 g, 0.2 mmol, 20 mol %), triethylamine (5 mL), and tert-butyl methyl(prop-2-ynyl)carbamate (169 mg, 1 mmol). The flask was flushed with nitrogen three times and the mixture was stirred at 80° C. for 2 h. The solvent was evaporated under vacuum and the residue was purified by column chromatography to afford the desired product as yellow solid (180 mg, 40% yield).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:31])[C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[F:30])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[F:30][C:24]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=1[C:22]([N:19]1[CH2:20][CH2:21][CH:16]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[C:14]=2[CH3:15])[CH2:17][CH2:18]1)=[O:31]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)c3cc(F)ccc3F)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(C(=O)c2cc(F)ccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
To a solution of {4-[1-(2,5-difluoro-benzoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (73 mg, 0.160 mmol) in THF (8.0 mL) was added a solution of lithium hydroxide monohydrate (76.6 mg, 1.8 mmol) in water (2 mL). The reaction mixture was stirred at room temperature overnight. After this time, the reaction mixture was concentrated. Water (˜20 mL) was added and the mixture was acidified with 1.0 N aqueous HCl (3.2 mL). The resulting white precipitate was collected by vacuum filtration, washed with hexanes, and then further dried under vacuum to give {4-[1-(2,5-difluoro-benzoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (57.5 mg, 81%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.46 (br. s, 1H), 7.80-8.20 (m, 1H), 7.90 (dd, J=9.00, 6.50 Hz, 1H), 7.69 (s, 1H), 7.31-7.52 (m, 4H), 4.62-4.77 (m, 1H), 3.68-4.08 (m, 4H), 3.48-3.60 (m, 1H), 2.95-3.21 (m, 1H), 2.43 (br. s., 3H), 2.11-2.34 (m, 2H), 1.57-1.82 (m, 2H). MS cald. for C25H23F3NO3 [(M+H)+]: 442, obsd. 442.2.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27].N(C(OCC)=O)=NC(OCC)=O.[OH:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][CH:48]=1)[CH2:44]O>C(Cl)Cl.O1CCCC1>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:44][C:43]1[CH:42]=[C:41]([OH:40])[CH:48]=[CH:47][CH:46]=1
Reactant: OCc1cccc(O)c1
Reactant: Oc1ccccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Oc1cccc(COc2ccccc2Cl)c1
Reaction time: 1 h
Yield: 50.9 %

Procedure:
At 0° C. to 616 mg (2.35 mmol) of triphenylphosphine and 400 μL (3.84 mmol) of 2-chlorophenol in 20 mL of methylene chloride was added 370 mL (2.35 mmol) of diethyl azodicarboxylate followed by dropwise addition of a solution of 233 mg (1.9 mmol) 3-hydroxybenzyl alcohol in 2 mL of tetrahydrofuran. The reaction mixture was stirred at 0° C. to ambient temperature for 1 h. The reaction mixture was quenched with water, extracted into diethyl ether, dried (MgSO4), and purified by flash chromatography (methylene chloride/hexane (2:1 to 4:1)) to provided 227 mg (44% yield) of the title compound as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ 7.39 (dd, 1 H, J=1.6, 7.8 Hz), 7.25 (t, 1 H), 7.15-7.21 (m, 1 H), 6.88 -7.01 (m, 4 H), 6.79 (dd, 1 H, J=2.5, 8.1 Hz), 5.12 (s, 2 H), and 4.97 (s, 1 H).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[C:19]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH:32]([F:34])[F:33])[CH:26]=3)(=[O:24])=[O:23])[CH:18]=[CH:17][C:16]=2[O:35][CH3:36])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:37]>ClCCl.C(OCC)C>[ClH:37].[N:11]1([C:15]2[CH:20]=[C:19]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH:32]([F:34])[F:33])[CH:26]=3)(=[O:24])=[O:23])[CH:18]=[CH:17][C:16]=2[O:35][CH3:36])[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: COc1ccc(NS(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(NS(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCCNCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.64 g of 4-[5-(3-difluoromethoxy-benzenesulfonylamino)-2-methoxy-phenyl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (1.213 mmol) were dissolved in 20 mL of dichloromethane and 1.82 mL of a 2N solution of hydrochloric acid in diethyl ether was added. After stirring at room temperature for 16 h, the solvents were evaporated, the residue redissolved in water, the aqueous phase washed with dichloromethane and then lyophilized to yield the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(N(CC)CC)C>CN(C)C=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:22]([CH2:23][C:24]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:12][CH:13]=1
Reactant: Nc1ccccn1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cn1c(-c2ccc(Br)cc2)nc2cccnc21)Nc1ccccn1
Temperature: 25 °C
Yield: 47 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (3.4 g, 0.027 mole) was added dropwise (slowly) to a stirred and chilled (10° C.) suspension of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (8.4 g, 0.025 mole) in anhydrous dimethylformamide (50 ml). The reaction mixture was heated at 55°-60° C. for 4 hours, cooled to room temperature, and added dropwise to a stirred and chilled (10° C.) solution of 2-aminopyridine (2.6 g, 0.028 mole) and triethylamine (5.4 g, 0.0053 mole) in anhydrous dimethyl formamide (100 ml). The reaction was stirred at room temperature overnight. Dimethylformamide (100 ml) was distilled off at 100 mm Hg. The residue was cooled, triturated in potassium bicarbonate solution (2×50 ml), and filtered. The filter cake was rinsed with water (2×50 ml) and recrystallized from ethanolisopropyl ether to give 4.8 g (47%) of white solid, mp. 191.5°-195° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10](=[O:12])[CH3:11])=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[Br-:13].[Br-].[Br-].C[N+](C)(C)C1C=CC=CC=1.C[N+](C1C=CC=CC=1)(C)C.C[N+](C1C=CC=CC=1)(C)C>O1CCCC1>[Br:13][CH2:11][C:10]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([O:8][CH3:9])=[CH:5][N:4]=1)=[O:12]
Reactant: COc1cnc(C(C)=O)c(Cl)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: COc1cnc(C(=O)CBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
To 0.90 g of 1-(3-chloro-5-methoxypyridin-2-yl)ethanone in 10 ml of tetrahydrofuran, 1.82 g of trimethylphenylammonium tribromide was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the precipitated solid was filtered off, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 0.57 g of the desired product as pale yellow crystals.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[N:19]=[C:18]([N:20]([CH3:22])[CH3:21])[CH:17]=[CH:16][CH:15]=1.[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C.[Cl-].[NH4+]>C1COCC1>[CH3:21][N:20]([CH3:22])[C:18]1[N:19]=[C:14]([F:13])[C:15]([B:23]([OH:28])[OH:24])=[CH:16][CH:17]=1
Reactant: CN(C)c1cccc(F)n1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CN(C)c1ccc(B(O)O)c(F)n1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
In a microwave tube was placed 2,6-difluoropyridine (0.500 mL, 5.47 mmol), dimethylamine, (2.0 M solution in THF, 4.11 mL, 8.21 mmol). The mixture was heated at 150° C. for 20 min. Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 536 mg of a crude yellow oil, which was purified by column chromatography (3/1 Hex/ethyl acetate) to give 500 mg of 6-fluoro-N,N-dimethylpyridin-2-amine as a light yellow oil. To a solution of diisopropylamine (0.15 mL, 1.1 mmol) in 2 mL of THF at 0° C. was added butyllithium (1.6 M in hexane, 0.69 mL, 1.1 mmol). The reaction stirred for 30 minutes and was then cooled to 60° C. at which time 6-fluoro-N,N-dimethylpyridin-2-amine (0.124 g, 0.88 mmol) was added in 1 mL of THF. The reaction stirred at −60° C. for 45 min. Then triisopropyl borate (0.25 mL, 1.1 mmol) was added and the reaction was allowed to stir for 1 h at 23° C. Ammonium chloride (sat.) was added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 136 mg of a brown oil, which was purified by column chromatography (3/1 hexanes/ethyl acetate to 1/1 EtOAc/hexanes) to give 46 mg of a white solid. ES+=185.1 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]([OH:21])=O)=[CH:11]2)[C:4]=1[CH3:22].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[CH2:48]([CH2:50][NH2:51])[OH:49]>C(Cl)Cl>[OH:49][CH2:48][CH2:50][NH:51][C:19]([C:12]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:18]2[N:10]([CH2:9][C:5]2[C:4]([CH3:22])=[C:3]([O:2][CH3:1])[N:8]=[CH:7][N:6]=2)[CH:11]=1)=[O:21]
Reactant: NCCO
Reactant: COc1ncnc(Cn2cc(C(=O)O)c3ncccc32)c1C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ncnc(Cn2cc(C(=O)NCCO)c3ncccc32)c1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45 %

Procedure:
See FIG. 18(a). 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (1 g, 3.35 mmol) was taken in DCM (20 mL) to get a suspension. Triethyl amine (1.394 mL, 10.06 mmol) was added followed by the addition of 1-Propanephosphonic acid cyclic anhydride (3.991 mL, 6.70 mmol). The reaction mass was stirred at RT for 5 minutes. Ethanol amine (6.02 mL, 10.06 mmol) was added and stirred at RT for 2 h. After completion of the reaction, diluted with DCM and then washed with water and brine solution. The organic layer was separated, dried, evaporated and the crude compound was purified by silica gel chromatography. Yield-45%. ES+MS m/z: 342 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.24 (s. 3 H ) 3.37-3.64 (m, 4 H ) 3.94 (s, 3 H ) 4.80 (t, J=4.99 Hz, 1 H ) 5.67 (s, 2 H ) 7.24 (dd, J=8.29, 4.52 Hz, 1 H ) 7.92 (d, J=8.10 Hz, 1 H ) 8.23 (s, 1 H ) 8.41 (s, 1 H ) 8.47 (d, J=4.52 Hz, 1 H ) 8.85 (t, J=5.37 Hz, 1 H ).
Reaction SMILES: ClC(O[CH:5](Cl)[CH3:6])=O.C(N1CC=C([N:21]([CH3:38])[C:22](=[O:37])[C:23]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)([OH:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)CC1)C1C=CC=CC=1>C(Cl)Cl>[NH:21]1[CH2:6][CH:5]=[C:24]([CH2:38][NH:21][C:22](=[O:37])[C:23]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)([OH:30])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:23][CH2:22]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: CN(C(=O)C(O)(c1ccccc1)C1CCCCC1)C1=CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Product: O=C(NCC1=CCNCC1)C(O)(c1ccccc1)C1CCCCC1

Procedure:
A solution of 1-chloroethyl chloroformate (0.53 ml) in methylene chloride (5 ml) was added dropwise to a solution of N-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-methyl-2-cyclohexyl-2-hydroxy-2-phenylacetamide (1.50 g) in methylene chloride (25 ml) below 7° C. After being refluxed for 1 hour, the reaction mixture was evaporated in vacuo. To the residue was added methanol (20 ml) and the mixture was refluxed for 1.5 hours. The reaction mixture was evaporated in vacuo, and to the residue was added 1N aqueous solution of sodium hydroxide. The mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of 2-propanol and ethanol to give N-(1,2,3,6-tetrahydropyridin-4-yl)methyl-2-cyclohexyl-2-hydroxy-2-phenylacetamide (0.19 g).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:10]=1[NH:16][CH2:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21].[C:23](Cl)(=O)[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][CH2:38][CH2:39][CH3:40]>ClCCl>[Cl:8][C:9]1[C:10]2[N:16]([CH2:17][CH2:18][CH2:19][N:20]([CH3:21])[CH3:22])[C:40]([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23])=[N:15][C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CN(C)CCCNc1c(N)cccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCc1nc2cccc(Cl)c2n1CCCN(C)C
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 55.3 %

Procedure:
Triethylamine (0.587 g) was added to a solution containing 3-chloro-N2-[3-(dimethylamino)propyl]-1,2-benzenediamine (1.100 g) in dichloromethane (22 ml), and then stearoyl chloride (1.610 g) was added thereto while being cooled with ice. After being stirred for 4.5 hours at room temperature, the reaction mixture was diluted with dichloromethane, washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (4.0 ml) was added to a solution containing the residue (3.451 g) in ethanol (24 ml). After being stirred for 4 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (2.95 g) was purified by silica gel column chromatography (silica gel 92 g, chloroform:methanol=1:0-100:1), thereby yielding the entitled compound (1.271 g) as pale yellow solid.