Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:19][CH2:18]2)=[O:16])=[C:9]([CH3:29])[CH:8]=1>C1COCC1.O>[CH3:26][C:25]([CH3:28])([CH3:27])[CH2:24][CH2:23][N:20]1[CH2:21][CH2:22][N:17]([C:15](=[O:16])[CH2:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:30])=[O:5])=[CH:8][C:9]=2[CH3:29])[CH2:18][CH2:19]1
Reactant: COC(=O)c1ccc(CCC(=O)N2CCN(CCC(C)(C)C)CC2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1CCC(=O)N1CCN(CCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
Lithium hydroxide monohydrate (2.4 g, 56.7 mmol) was added to a solution of 4-{3-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-3-oxo-propyl}-3-methyl-benzoic acid methyl ester from Example E44.1 (8.5 g, 22.7 mmol) in THF (200 ml) and water (100 ml). The mixture was stirred for 24 h at room temperature then solvents were removed in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 2% acetic acid:4% methanol:94% dichloromethane) to yield the title compound (8.1 g, 99%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](O)=[O:7].C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[N:20]1([N:25]2[C:33](=[O:34])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]2=[O:35])[CH:24]=[CH:23][CH:22]=[CH:21]1>C(Cl)Cl.O>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:21]1[N:20]([N:25]2[C:33](=[O:34])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]2=[O:35])[CH:24]=[CH:23][CH:22]=1)=[O:7]
Reactant: O=C1c2ccccc2C(=O)N1n1cccc1
Reactant: O=C(O)c1ccc[nH]1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccc[nH]1)c1cccn1N1C(=O)c2ccccc2C1=O
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
To a suspension of pyrrole-2-carboxylic acid (5.55 g) in 500 ml of DCM was added oxalyl chloride (8.7). The reaction mixture was heated under reflux for 1 hour, cooled to -10° C., and tin (IV) chloride (5.85 ml) was added. After stirring the mixture at -10° C. for 30 minutes, 2-(1H-pyrrol-1-yl)-1H-isoindole-1,3(2H)dione (10.6 g) was added in four portions over a period of 30 minutes, followed by stirring at -10° C. for additional 30 minutes. The reaction mixture was then poured into 500 ml of water and extracted with DCM. The combined extracts were washed with 1N sodium hydroxide solution, 1N sulfuric acid, and finally with water. The dried (magnesium sulfate) organic phase was filtered and evaporated in vacuo. The residue was triturated with DCM, affording the product as a powder (10.55 g), mp 204°-206° C.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:18])[C:10]2[CH:15]=[C:14]([OH:16])[CH:13]=[C:12]([OH:17])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][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][CH3:37].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[C:1]1([CH2:7][O:8][C:9](=[O:18])[C:10]2[CH:11]=[C:12]([O:17][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][CH2:23][CH2:22][CH2:21][CH3:20])[CH:13]=[C:14]([OH:16])[CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OCc1ccccc1)c1cc(O)cc(O)c1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(C(=O)OCc2ccccc2)c1
Yield: 36 %

Procedure:
A mixture of 30 g (0.123 mol) of 3,5-dihydroxybenzoic acid phenylmethyl ester, 40.9 g (0.123 mol) of 1-bromooctadecane, 17 g (0.123 mol) of anhydrous potassium carbonate in 500 ml of acetone and 10 ml of DMF was stirred at reflux for 25 hours. The reaction mixture was filtered and the filtrate was concentrated at reduced pressure to a solid. The residue was treated with water and the product was extracted with methylene chloride. The dried extract was concentrated at reduced pressure to a solid which was purified by HPLC using 1% ethyl acetate-methylene chloride to give 22 g (36% yield, mp 72°-75°) of 3-hydroxy-5-(octadecyloxy)benzoic acid phenylmethyl ester. The structure was confirmed by nmr and mass spectra.
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C@@H:7]([NH2:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.[CH3:13][N:14]1[C:23]2[C:18](=[CH:19][C:20](B3OC(C)(C)C(C)(C)O3)=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1=[O:33]>>[NH2:12][C@H:7]1[C:6]2[CH:5]=[N:4][CH:3]=[C:2]([C:20]3[CH:19]=[C:18]4[C:23](=[CH:22][CH:21]=3)[N:14]([CH3:13])[C:15](=[O:33])[CH2:16][CH2:17]4)[C:11]=2[CH2:10][CH2:9][CH2:8]1
Reactant: N[C@@H]1CCCc2c(Br)cncc21
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: CN1C(=O)CCc2cc(-c3cncc4c3CCC[C@H]4N)ccc21

Procedure:
In analogy to the procedures described for the preparation of intermediate A-2 [E] and for the preparation of intermediate B-1, Suzuki reaction of (+)-(R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (intermediate B-3b) with 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) gave (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one and after subsequent reaction with propionyl chloride the title compound as colorless solid. MS: 364.2 (M+H+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:9]=2[CH2:18][CH2:19][NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:5]=[CH:4][CH:3]=1.[CH3:35][NH:36][CH3:37]>CN1CCCC1=O>[CH3:35][N:36]([CH3:37])[C:2]1[N:7]=[C:6]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:9]=2[CH2:18][CH2:19][NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CCCCCc1ccc(S(=O)(=O)NCCc2c(-c3cccs3)n[nH]c2-c2cccc(Br)n2)cc1
Solvent: CN1CCCC1=O
Product: CCCCCc1ccc(S(=O)(=O)NCCc2c(-c3cccs3)n[nH]c2-c2cccc(N(C)C)n2)cc1
Temperature: 190 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
A mixture of N-{2-[5-(6-Bromo-pyridin-2-yl)-3-thiophen-2-yl-1H-pyrazol-4-yl]-ethyl}-4-pentyl-benzenesulfonamide (5 mg, 8.9 μmol) and dimethylamine (2.0M in MeOH, 8.0 ml) in 1-methyl-2-pyrrolidinone (500 μL) was stirred at 190° C. in a seal tube for 3 h. The reaction mixture was concentrated to 2 ml. The crude product was purified by Prep-HPLC. Removal of the solvent in vacuo provided the title compound (1.2 mg, 26% yield). MS m/e 524; HPLC retention time 3.34 min (Method A).
Reaction SMILES: C[O:2][C:3]1[N:12]=[CH:11][C:10]2[CH2:9][CH2:8][C:7]3[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:14][N:15]([CH3:16])[C:6]=3[C:5]=2[N:4]=1.[I-].[Na+].C[Si](Cl)(C)C.CO>C(#N)C>[OH:2][C:3]1[N:12]=[CH:11][C:10]2[CH2:9][CH2:8][C:7]3[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:14][N:15]([CH3:16])[C:6]=3[C:5]=2[N:4]=1
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(OC)nc1-2
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CCOC(=O)c1nn(C)c2c1CCc1cnc(O)nc1-2
Yield: 78 %

Procedure:
1.5 g (5.2 mmol) of ethyl 8-methoxy-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate were dissolved in 90 mL of acetonitrile and 1.6 g (10.6 mmol) of sodium iodide and 1.5 mL of trimethylsilylchloride were added. After a day under stirring and nitrogen atmosphere at room temperature the solvent was evaporated, the residue redissolved with a mixture dichloromethane/methanol 4/1 and washed with a saturated aqueous solution of Na2S2O3. The organic layer was dried over Na2SO4 and evaporated to dryness. The residue crystallized from methanol leading 1.1 g of the title compound (78% yield).
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C=O>[CH2:13]([O:5][C:4]1[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(O)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48.5 %

Procedure:
Orcinol monohydrate (7.10 g, 50 mmol) in N,N-dimethylformamide (20 mL) was added dropwise to a mixture of NaH (95%, 24 g, 100 mmol) in N,N-dimethylformamide (60 mL) and the mixture was stirred at room temperature for 20 min. Benzyl bromide (8.55 g, 50 mmol) in N,N-dimethylformamide (20 mL) was added dropwise to the mixture and stirred at room temperature for 2 hours. Water (100 mL) was added slowly to the reaction mixture. The reaction mixture was extracted with ethyl acetate (3×100 mL) and then the organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After the solvent was evaporated, the residue was purified by flash column chromatography (silica gel, 3:1 hexane:ethyl acetate) to give the title compound as a yellow oil (5.20 g, 48%). 1H-NMR (300 MHz, CDCl3) δ7.39 (m, 5H), 6.40 (s, 1H), 6.29 (t, J=5.3 Hz, 1H), ), 6.26 (s, 1H), 5.25 (s, 1H), 4.99 (s, 2H), 2.26 (s, 3H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=2[C:4]#[N:5])=[CH:14][C:13]=1[CH3:19]
Reactant: Cc1cc(O)ccc1N
Reactant: N#Cc1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(Oc2ccc(F)cc2C#N)ccc1N
Temperature: 25 °C
Yield: 99.1 %

Procedure:
In a 5 L flask that had been evacuated and back-filled with Argon, 2,5-difluorobenzonitrile (1092 mL, 3057 mmol) and 4-amino-3-methylphenol (376.5 g, 3057 mmol) were dissolved in dry DMSO (2.75 M) with rapid stirring at ambient temperature. The solution was evacuated/backfilled with Argon. Potassium carbonate (697.2 g, 5044 mmol) was added. The reaction was evacuated/backfilled with Argon and warmed to 81° C. for 14 hours. After cooling to ambient temperature, the reaction was poured slowly into 3 separate beakers, each containing 2.5 L of rapidly stirring ice water to prevent clumping. The residue in the round bottom flask was taken up in water repeatedly and poured into the beakers until a total volume of 3.5 L was realized in each of the three beakers. The suspension was stirred rapidly for 2 hours as it came to ambient temperature. The brown solids were collected by filtration, washed with water (15 L), air dried, dried with latex dam, and dried under high vacuum at 45° C. for 72 hours to provide 734 g (99%) of desired product as a tan solid. MS M+1 (243).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][C:10]([O:13][C:14]([N:16]([C:24]1[NH:25][CH:26]=[C:27]([CH:29]=[O:30])[N:28]=1)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:15])([CH3:12])[CH3:11]>CN(C=O)C.CCOC(C)=O>[CH3:12][C:10]([O:13][C:14]([N:16]([C:24]1[NH:28][C:27]([CH:29]=[O:30])=[C:26]([Br:8])[N:25]=1)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[O:15])([CH3:9])[CH3:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(C=O)c[nH]1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(Br)c(C=O)[nH]1
Temperature: 50 °C
Yield: 40.9 %

Procedure:
NBS (0.206 g, 1.156 mmol) was added to a solution of bis(1,1-dimethylethyl)(4-formyl-1H-imidazol-2-yl)imidodicarbonate (0.300 g, 0.964 mmol) in DMF (3 mL). The mixture was heated at 50° C. for 3 hrs. The reaction mixture was diluted with EtOAc and washed 2× with water. The organic layer was dried over sodium sulfate and concentrated. Chromatography (EtOAc:hexane) gave the desired product (0.154 g, 41%) as a white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 10.54 (br. s., 1H), 9.54 (s, 1H), 1.50 (s, 18H). ES MS: m/z 390.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][CH2:8][NH:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=2[N:11]=1>C(Cl)(Cl)Cl>[Cl:3][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=2[N:11]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCNc1nc2ccccc2n1-c1ccccc1
Solvent: ClC(Cl)Cl
Product: ClCCCNc1nc2ccccc2n1-c1ccccc1

Procedure:
Thionyl chloride (10 ml.) was added dropwise to a stirred solution of 2-(3-hydroxypropylamino)-1-phenylbenzimidazole (11.0 g.) in dry chloroform (100 ml.) and the solution heated under reflux for 2 hours. On dilution with ether the title compound crystallised as its hydrochloride (13.06 g., m.p. 176° to 179° C). Found: C, 59.65, H, 5.3, N, 12.95%. C16H16ClN3.HCl requires: C, 59.65, H, 5.3, N, 13.05%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]1[C:7](=[CH:8][C:9](=[O:24])[C:10]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:11]1)[S:6]2.[Br:25]Br.CCCCCC>C(O)(=O)C>[Br:25][C:8]1[C:9](=[O:24])[C:10]([N:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]2)=[CH:11][C:12]2[C:7]=1[S:6][C:5]1[C:14](=[CH:15][CH:16]=[C:3]([O:2][CH3:1])[CH:4]=1)[N:13]=2
Reactant: COc1ccc2nc3cc(N4CCN(C)CC4)c(=O)cc-3sc2c1
Reactant: BrBr
Solvent: CCCCCC
Solvent: CC(=O)O
Product: COc1ccc2nc3cc(N4CCN(C)CC4)c(=O)c(Br)c-3sc2c1
Reaction time: 0.08 h

Procedure:
To a suspension of 7-methoxy-2-(4-methylpiperazin-1-yl)-3H-phenothiazin-3-one (500 mg) in acetic acid (10 ml) was added a solution of bromine in acetic acid (0.5M) (6 ml) and stirred for 5 minutes. Hexane (100 ml) was added and the resulting precipitate was filtered. The solid was suspended in a mixture of aqueous K2CO3 (50 ml), EtOAc (100 ml) and methanol (20 ml) and stirred for 15 minutes. After filtration and decantation, the organic layer was washed with brine, dried and evaporated to dryness to afford the title compound (190 mg) m.p. 209°-210° (dec.).
Reaction SMILES: [F:1][C:2]1[C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][C:5]([C:17]2[N:21]3[N:22]=[CH:23][C:24]([C:26]([OH:29])([CH3:28])[CH3:27])=[N:25][C:20]3=[N:19][CH:18]=2)=[C:4]([O:30][CH3:31])[CH:3]=1.Br[C:33]1[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:34]=1[C:35]#[N:36]>>[F:41][C:40]1[CH:39]=[CH:38][CH:37]=[C:34]([C:35]#[N:36])[C:33]=1[C:7]1[CH:6]=[C:5]([C:17]2[N:21]3[N:22]=[CH:23][C:24]([C:26]([OH:29])([CH3:27])[CH3:28])=[N:25][C:20]3=[N:19][CH:18]=2)[C:4]([O:30][CH3:31])=[CH:3][C:2]=1[F:1]
Reactant: N#Cc1cccc(F)c1Br
Reactant: COc1cc(F)c(B2OC(C)(C)C(C)(C)O2)cc1-c1cnc2nc(C(C)(C)O)cnn12
Product: COc1cc(F)c(-c2c(F)cccc2C#N)cc1-c1cnc2nc(C(C)(C)O)cnn12
Yield: 40 %

Procedure:
2-{7-[4-Fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]imidazo[1,2-b][1,2,4]triazin-3-yl}propan-2-ol was coupled to 2-bromo-3-fluorobenzonitrile (from Example 2, step a) under the conditions described in Example 1, step e. The residue was purified by flash column chromatography (silica gel, 3% isopropyl alcohol in dichloromethane) to give the title compound in 40% yield: 1H NMR (400 MHz, CDCl3) δ 1.69 (6H, s), 3.53 (1H, s), 3.96 (3H, s), 6.96 (1H, d, J 10.3), 7.43–7.62 (3H, m), 8.11 (1H, d, J 7.9), 8.34 (1H, s), 8.71(1H, s); MS (ES+) m/z 422 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[N:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][OH:20])=[CH:13][C:12]=3[N:21]\2[C@H:22]2[CH2:27][CH2:26][C@@H:25]([C:28](=[O:33])[NH:29][CH:30]([CH3:32])[CH3:31])[CH2:24][CH2:23]2)=[O:7])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[N:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]=[O:20])=[CH:13][C:12]=3[N:21]\2[C@H:22]2[CH2:23][CH2:24][C@@H:25]([C:28](=[O:33])[NH:29][CH:30]([CH3:31])[CH3:32])[CH2:26][CH2:27]2)=[O:7])=[CH:34][CH:35]=1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ncc(OCCO)cc32)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ncc(OCC=O)cc32)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(E)-4-Fluoro-N-(6-(2-hydroxyethoxy)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-imidazo[4,5-e]pyridin-2(3H)-ylidene)benzamide (0.043 g, 0.089 mmol) was suspended in DCM (3.56 mL) under nitrogen, and the reaction flask was cooled to 0° C. To the flask was added Dess-Martin periodinane (0.057 g, 0.133 mmol), and the reaction was allowed to warm to RT and stirred for 1 hour. The reaction was quenched with aqueous NaHCO3 (8 mL) and sodium thiosulfate (85 mg). The product was extracted with 5% MeOH/DCM. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-oxoethoxy)-1H-imidazo[4,5-e]pyridin-2(3H)-ylidene)benzamide as a light pink solid. MS m/z=482.0 [M+H], calc 481.52 for C25H28FN5O4.
Reaction SMILES: O.Cl.[C:3]([NH2:11])(=[NH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+].N[C:18]1[NH:22][N:21]=[C:20]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=2)[C:19]=1[C:31]#[N:32].O>C(O)(=O)C>[NH2:32][C:31]1[N:11]=[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=[C:18]2[NH:22][N:21]=[C:20]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=3)[C:19]=12
Reactant: N=C(N)c1ccccc1
Reactant: N#Cc1c(Nc2ccc(Br)cc2)n[nH]c1N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(-c2ccccc2)nc2[nH]nc(Nc3ccc(Br)cc3)c12
Reaction time: 4 h

Procedure:
1.87 g (10.7 mmol) benzamidin hydrochloride hydrate and 0.89 g (10.7 mmol) sodium acetate are added to 1.0 g (3.6 mmol) 5-amino-4-cyano-3-(4-bromophenyl)aminopyrazol in 20 ml ethanoic acid by stirring. The reaction mixture is boiled for a period of 4 h, treated with 50 ml water, filtered and washed with 20 ml of cold methanol and 20 ml of cold ester. The raw product is purified by means of crystallization from ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].S(Cl)([Cl:16])=O>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([Cl:16])=[O:13])=[N:9][CH:10]=1)=[O:4]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Product: COC(=O)c1ccc(C(=O)Cl)nc1
Temperature: 25 °C

Procedure:
To 5-(Methoxycarbonyl)pyridine-2-carboxylic acid (Maybridge, 1.0 g, 5.52 mmol) was added thionyl chloride (Aldrich, 25 mL) and this reaction mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the intermediate 5-(methoxycarbonyl)pyridine-2-carboxylic acid chloride as a tan solid which was used without further purification.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)=[C:8]([CH:21]=1)[C:9]([O:11]CC1C=CC(C#N)=CC=1)=[O:10]>O.C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=2)=[C:8]([CH:21]=1)[C:9]([OH:11])=[O:10]
Reactant: N#Cc1ccc(COC(=O)c2cc(Br)ccc2OCc2ccc(C#N)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(COc2ccc(Br)cc2C(=O)O)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Lithium hydroxide (281 mg, 6.71 mmol) in water (20 ml) was added dropwise to a stirred solution of (4-cyanophenyl)methyl 5-bromo-2-{[(4-cyanophenyl)methyl]oxy}benzoate (may be prepared as described in Description 23; 300 mg, 0.67 mmol) in THF (20 ml) over 5 min. The reaction mixture was stirred at 20° C. for 16 h. The organic phase was evaporated and the aqueous phase (20 ml) was extracted with ethyl acetate (20 ml). The aqueous phase (20 ml) was adjusted to pH 2 with 2M hydrochloric acid (1 ml). The aqueous phase was then extracted with ethyl acetate (3×20 ml). The organic phase was then evaporated in vacuo to yield the title compound as a light yellow solid. 145 mg.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([OH:9])=O.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1.[C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:34])[NH:32][NH2:33]>ClCCl>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([NH:33][NH:32][C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:9]
Reactant: Cn1ccnc1C(=O)O
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cn1ccnc1C(=O)NNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-methyl-1H-imidazole-2-carboxylic acid (500 mg, 3.57 mmol, commercially available from e.g. Sigma-Aldrich), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide (554 mg, 3.57 mmol) and 1-H-1,2,3-benzotriazol-1-ol (54.6 mg, 0.357 mmol) in dichloromethane (20 ml) pre-stirred for 30 mins under argon at room temp was added solid t-butyl carbazate (722 mg, 5.35 mmol). The reaction mixture was stirred at RT for 18 h. The reaction mixture was partitioned between dichloromethane (˜50 ml) and saturated sodium bicarbonate solution (˜50 ml). The aqueous phase was extracted with dichloromethane (2×25 ml) and the combined organic extracts washed with saturated sodium bicarbonate solution (˜25 ml), dried over magnesium sulphate and evaporated in vacuo to give the crude product as a yellow oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[Cl:20])[CH:16]([OH:21])[N:15]([CH:22]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]1)[CH:14]2[OH:28].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[Cl:20])[CH:16]([OH:21])[N:15]([C@@H:22]1[CH2:26][CH2:25][C@H:24]([O:27][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:23]1)[CH:14]2[OH:28]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCC(N2C(O)c3cc(Cl)c(Cl)cc3C2O)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)O[C@H]1CC[C@@H](N2C(O)c3cc(Cl)c(Cl)cc3C2O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a flask was added DCM (40 mL), DIPEA (2.0 mL, 11.48 mmol), c is 5,6-dichloro-2-(3-hydroxy-cyclopentyl)-2,3-dihydro-1H-isoindole-1,3-diol 1.071 g, 3.57 mmol) and methanesulfonyl chloride (0.6 mL, 7.72 mmol) and the mixture stirred overnight at RT. The mixture was concentrated in vacuo, EtOAc (100 mL) and H2O (100 mL) added, filtered off insolubles, separated and extracted the aqueous layer with EtOAc (50 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to give cis methanesulfonic acid 3-(5,6-dichloro-1,3-dihydroxy-1,3-dihydro-isoindol-2-yl)-cyclopentyl ester as a tan solid (1.5 g, impure as >100% yield).
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:34][CH2:33][C:32]2[CH:35]=[CH:36][C:37]([NH2:39])=[CH:38][C:31]=2[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH2:34][CH2:33][C:32]2[CH:35]=[CH:36][C:37]([NH:39][C:2]3[N:20]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:38][C:31]=2[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: FC(F)(F)c1cccc(-c2cccn3nc(Cl)nc23)c1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Nc3nc4c(-c5cccc(C(F)(F)F)c5)cccn4n3)cc2CC1

Procedure:
7-[8-(3-Trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(3-trifluoromethyl-phenyl)-[1,2,4]-triazolo[1,5-a]pyridine (0.272 g, 914 mmol) and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.360 g, 1.37 mmol) in a manner analogous to Example 311a and 311b to give product (0.203 g, 44%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.62 (s, 1H), 8.83 (d, 1H), 8.65 (s, 1H), 8.40 (d, 1H), 7.95 (d, 1H), 7.82 (m, 2H), 7.50 (m, 2H), 7.15 (t, 1H), 7.05 (d, 1H), 3.45 (m, 4H), 2.75 (m, 4H), 1.41 (s, 9H). MS=524 (MH)+.