Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH:3]1[C:8]([OH:9])=[CH:7][CH:6]=[C:5]([Br:10])[CH:4]=1.[H][H].Br[CH2:14][C:15]1[C:16]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=1>O.CN(C)C=O.CCCCCC>[Br:10][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([O:23][CH3:24])=[O:22])=[CH:3][CH:4]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccccc1CBr
Reactant: Oc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1COc1ccc(Br)cc1
Reaction time: 0.75 h

Procedure:
Wash 15.12 gm (0.315 mole) of sodium hydroxide, 50% dispersion in oil, free of oil with hexane and suspend in 250 cc. of N,N-dimethylformamide. Add 54.5 gm. (0.315 mole) of p-bromophenol in portions as hydrogen is evolved. After gas evolution has subsided, add a solution of 68 gm. (0.3 mole) of methyl α-bromo-o-toluate in 50 cc. of N,N-dimethylformamide at a rapid dropwise rate. Stir the mixture for 45 minutes and pour into 3 liters of cold water. Separate the solids by filtration, wash with water and dry to obtain 90 gm. of crude methyl o-(p-bromophenoxymethyl)benzoate which is used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([CH2:12][O:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[C:17]([C:23](O)=[O:24])[NH:18]4)=[CH:10][O:11][C:7]=2[CH:6]=[C:5]([O:26][CH3:27])[CH:4]=1.[ClH:28].Cl.Cl.[C@H:31]1([CH2:41][N:42]2[CH2:47][CH2:46][CH:45]([NH2:48])[CH2:44][CH2:43]2)[C@@H:40]2[N:35]([CH2:36][CH2:37][CH2:38][CH2:39]2)[CH2:34][CH2:33][CH2:32]1>>[ClH:28].[ClH:28].[C@H:31]1([CH2:41][N:42]2[CH2:47][CH2:46][CH:45]([NH:48][C:23]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[C:14]([O:13][CH2:12][C:9]3[C:8]5[C:3]([O:2][CH3:1])=[CH:4][C:5]([O:26][CH3:27])=[CH:6][C:7]=5[O:11][CH:10]=3)[CH:22]=[CH:21][CH:20]=4)=[O:24])[CH2:44][CH2:43]2)[C@@H:40]2[N:35]([CH2:36][CH2:37][CH2:38][CH2:39]2)[CH2:34][CH2:33][CH2:32]1
Reactant: NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Reactant: COc1cc(OC)c2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2c1
Agent: Cl
Product: COc1cc(OC)c2c(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)coc2c1

Procedure:
This compound is synthesized from 4-(4,6-dimethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid 126 (preparation see below) and amine 61 analogously to the method described in example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[N+:23]([C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=O)([O-:25])=[O:24].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19](=[N:22][CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[N+:23]([O-:25])=[O:24])[CH2:20][CH:21]=1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2nccc(OC3=CCC(=NCc4ccccc4[N+](=O)[O-])C=C3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenyloxy)quinoline (500 mg, 1.6873 mmol) was dissolved in tetrahydrofuran (64 ml), and after adding 2-nitrobenzaldehyde (320 mg, 2.1091 mmol) and acetic acid (0.58 ml), sodium triacetoxyborohydride (720 mg, 3.3746 mmol) was further added and the mixture was stirred at room temperature for 11 hours and 30 minutes. Water and saturated saline were added, the mixture was extracted with ethyl acetate, washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crystals were washed with hexane-diethyl ether, filtered out, washed with hexane and dried by aspiration at room temperature to obtain the title compound (453 mg) as light yellow crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][N:25]([CH3:29])[C:26](=[O:28])[CH3:27])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:30])[CH3:9])=[CH:4][CH:3]=1.[CH3:31][C:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[CH:34][N:33]=1>>[CH3:29][N:25]([CH2:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:30])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:36]3[CH:35]=[CH:34][N:33]=[C:32]([CH3:31])[CH:37]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1)[C:26](=[O:28])[CH3:27]
Reactant: CC(=O)N(C)CCC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: Cc1cc(B(O)O)ccn1
Product: CC(=O)N(C)CCC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(-c3ccnc(C)c3)cc2)C(=O)O1

Procedure:
The title compound was prepared from N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)-N-methylacetamide and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 459 Step 1. LC-MS Method 2 tR=0.98, m/z=486.2; 1H NMR (CDCl3) 1.21-1.38 (m, 1H), 1.52 (d, 3H), 1.61-1.90 (m, 3H), 2.05 (d, 3H), 2.17 (m, 1H), 2.42 (m, 2H), 2.78 (s, 1H), 2.83 (s, 3H), 2.85 (s, 2H), 2.92 (m, 1H), 3.11-3.33 (m, 2H), 5.65 (m, 1H), 7.05 (d, 2H), 7.21 (m, 2H), 7.30 (m, 3H), 7.38 (d, 2H), 7.60 (s, 1H), 7.71 (d, 1H), 8.72 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:17](=[O:19])[CH3:18])=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[Br:20]Br.C(OCC)(=O)C>C(O)(=O)C>[Br:20][CH2:18][C:17]([C:9]1[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=2)=[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]2[N:10]=1)=[O:19]
Reactant: BrBr
Reactant: CC(=O)c1nn2ccccc2c1-c1ccnc(F)c1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(CBr)c1nn2ccccc2c1-c1ccnc(F)c1
Temperature: 80 °C
Yield: 63 %

Procedure:
To a solution of 1-[3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-2-yl]ethanone (580 mg, 2.27 mmol) in acetic acid (20 mL) was added bromine (0.12 mL, 2.27 mmol). After heating at 80° C. for 30 minutes, the solution was cooled to room temperature. Ethyl acetate was added to dilute the reaction mixture. The mixture was washed with water (×3), brine and dried over magnesium sulfate. Filtration and concentration, followed by recrystallization from ethyl acetate gave 2-bromo-1-[3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-2-yl]ethanone (478 mg, 64%) as a yellow solid. 1H NMR (CDCl3): δ 8.51 (d, 1H), 8.27 (d, 1H), 7.65 (d, 1H), 7.33 (m, 2H), 7.10 (s, 1H), 7.06 (t, 1H), 4.76 (s, 2H). MS m/334 (M+1).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10].Br[CH2:12][CH2:13][CH3:14].C(O)(C)C.C(=O)=O>C1(C)C=CC=CC=1>[CH2:12]([N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10])[CH2:13][CH3:14]
Reactant: O=C1CCCCCN1
Reactant: CCCBr
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CCCN1CCCCCC1=O
Temperature: 25 °C
Yield: 80.9 %

Procedure:
In a 1 liter 3-neck flask equipped with a dry ice-isopropanol condenser, an addition funnel and a mechanical stirrer was placed 10.2 g of 50% sodium hydride-mineral oil dispersion (5.1 g NaH, 0.2125 M) and 150 ml of petroleum ether. The suspension was momentarily stirred and then sodium hydride was allowed to settle. Most of the petroleum ether was pipetted out and 200 ml of dry toluene was added. To this was added dropwise a solution of 20 g (0.177 M) of azacycloheptan-2-one in 100 ml of dry toluene. The mixture was refluxed for 1 hour and then cooled to room temperature. A solution of 30.75 g (0.25 M) of 1-bromopropane in 100 ml of dry toluene was added dropwise under stirring. Upon completion of the addition, the mixture was warmed to 80°-100° and the temperature was maintained there for 4 hours. Then the isopropanol-dry ice condenser was replaced with a water condenser and the reaction mixture was heated to reflux for 15 hours. The reaction mixture was cooled, filtered and the filtrate was concentrated to a yellow oil. Distillation afforded 22.2 g (81%) of colorless product; b.p. 83°-86°/0.25 mm.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([OH:17])([CH3:16])[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[H-].[Na+].[CH3:22]I>C1COCC1>[F:19][C:2]([F:1])([F:18])[C:3]([O:17][CH3:22])([CH3:16])[CH2:4][N:5]1[C:6](=[O:15])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]1=[O:14]
Reactant: CI
Reactant: CC(O)(CN1C(=O)c2ccccc2C1=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)(CN1C(=O)c2ccccc2C1=O)C(F)(F)F
Temperature: 25 °C

Procedure:
To a stirring solution of 2-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)isoindoline-1,3-dione (250 mg, 0.915 mmol)) at 0° C. in THF (8 ml), NaH (80 mg, 2 mmol) was added. After 30 minutes methyl iodide (1.299, 9.15 mmol) was added. The reaction mixture was left stirring in a ice-bath and allowed to warm to 25° C. over 3.5 hours. The reaction was quenched with sat. NH4Cl and the mixture extracted with DCM. The organic extract was separated using a phase separator and purification by chromatography on silica, eluting in a 0% to 30% iso-hexane:EtOAc afforded the title product; 1H NMR (400 MHz, Methanol-d4) δ 7.91 (2H, m), 7.85 (2H, m), 3.97 (2H, m), 3.44 (3H, s), 1.42 (3H, s); LC-MS: Rt 1.17 min; MS m/z 288.10 [M+H]+; Method 2minLC_v003.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[F:7][C:8]([F:16])([CH2:14][OH:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[F:7][C:8]([F:16])([CH2:14][O:15][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(F)(F)CO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)C(F)(F)COC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dihydropyrane (2 ml, 22 mmol) was added to a solution of ethyl 2,2-difluoro-3-hydroxypropionate (3.1 g, 20 mmol) and pyridinium p-toluene sulfonate (0.25 g, 1 mmol) in anhydrous dichloromethane (50 ml). The mixture was stirred overnight at room temperature and the desired compound ethyl 2,2-difluoro-3-tetrahydropyranyloxypropionate was obtained by flash chromatography on silica gel (ethyl acetate:hexane; 15:85) (4 g, 80%).
Reaction SMILES: CN1C=CN=C1.[Cl:7][C:8]1[CH:9]=[C:10]([C:17]2[CH:21]=[CH:20][N:19]([CH2:22][C@@H:23]([NH:25][C:26]([C:28]3[N:29]=[C:30]([CH3:33])[NH:31][CH:32]=3)=[O:27])[CH3:24])[N:18]=2)[CH:11]=[C:12]([F:16])[C:13]=1[C:14]#[N:15].[CH:34]([C:36]([CH3:38])=[O:37])=[CH2:35].O>CS(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]([C:17]2[CH:21]=[CH:20][N:19]([CH2:22][C@@H:23]([NH:25][C:26]([C:28]3[N:29]=[C:30]([CH3:33])[N:31]([CH2:35][CH2:34][C:36](=[O:37])[CH3:38])[CH:32]=3)=[O:27])[CH3:24])[N:18]=2)[CH:11]=[C:12]([F:16])[C:13]=1[C:14]#[N:15]
Reactant: C=CC(C)=O
Reactant: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)c[nH]1
Agent: Cn1ccnc1
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)CCn1cc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)nc1C
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 42.3 %

Procedure:
1-Methylimidazole (1.030 μl, 0.013 mmol) and DMSO (3 ml) were added into a flask. (S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1H-imidazole-4-carboxamide (100 mg, 0.259 mmol) dissolved in 3 ml of DMSO was added. Lastly methyl vinyl ketone (0.065 ml, 0.776 mmol) was added and the resulting mixture was stirred in 70° C. for 2.5 h. The mixture was stirred at RT during the night and in the next morning the temperature was again raised to 70° C. for 3.5 h. During the last part of the reaction a total of 0.195 ml of methyl vinyl ketone and 16.48 μl of 1-methylimidazole were added and the mixture was stirred at 70° C. for three days. 10 ml of water was poured into the mixture and the resulting white solution was extracted with ethyl acetate. Combined ethyl acetate phases were dried, filtered and evaporated. The product was purified by flash-chromatography and recrystallization from ACN/water, respectively. Yield 42.3%. 1H-NMR (400 MHz; DMSO-d6): δ 1.05 (d, 3H), 2.09 (s, 3H), 2.35 (s, 3H), 2.97 (t, 2H), 4.04 (t, 2H), 4.23-4.45 (m, 3H), 7.01 (d, 1H), 7.48 (s, 1H), 7.85 (d, 1H), 7.93 (dd, 1H), 8.00 (s, 1H), 8.05 (d, 1H).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)[C@H:20]([CH2:30]OS(C)(=O)=O)[CH2:19][CH2:18][O:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[CH2:39]1[C:43]2([CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]([OH:49])[CH2:41][O:40]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[F:1][C:2]([F:36])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)[C@H:20]([CH2:30][N:46]3[CH2:45][CH2:44][C:43]4([CH2:39][O:40][CH2:41][CH:42]4[OH:49])[CH2:48][CH2:47]3)[CH2:19][CH2:18][O:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: OC1COCC12CCNCC2
Reactant: C[C@@H](O[C@H]1OCC[C@@H](COS(C)(=O)=O)[C@@H]1c1ccc(F)c(F)c1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C[C@@H](O[C@H]1OCC[C@@H](CN2CCC3(CC2)COCC3O)[C@@H]1c1ccc(F)c(F)c1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
A mixture of methanesulfonic acid [(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)-phenyl)ethoxy]-3-(3,4-difluorophenyl)-tetrahydropyran-4-yl]methyl ester (Description 16; 0.275 g, 0.49 mmol), 2-oxa-8-aza-spiro[4.5]decan-4-ol hydrochloride (Description 8; 0.1 g, 0.37 mmol), potassium carbonate (237 g, 1.7 mmol) and acetonitrile (3 ml) was stirred at 55° C. overnight and then at 65° C. for 18 hours. The mixture was treated with water and extracted into dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by preparative TLC (dichloromethane:methanol) to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[C:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+].B(F)(F)F.[CH3:33]COCC.C(O)(=O)CC>C1COCC1>[CH3:33][O:25][C:24](=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:12]1[C:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]=2[N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:11]=1
Reactant: O=C(O)CCCCCc1nn(-c2ccc([N+](=O)[O-])cc2)c2c1CCCC2
Reactant: CCOCC
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCC(=O)O
Solvent: C1CCOC1
Product: COC(=O)CCCCCc1nn(-c2ccc([N+](=O)[O-])cc2)c2c1CCCC2
Temperature: 70 °C
Yield: 40.4 %

Procedure:
A solution of 6-[4,5,6,7-tetrahydro-1-(4-nitrophenyl)-1H-inda-zol-3-yl]hexanoic acid (1.11 g, 3 mmol) in THF (10 ml) was treated with sodium borohydride (0.175 g) and boron trifluoride etherate (4.7 mmol) in THF (11 ml) during 0.5 hour. The solution was reacted for 18 hours at ambient temperature, treated with propionic acid (2 ml), and heated at 70° C. for 2 hours. The solution was cooled, dilution with water and the precipitate was extracted into ethyl acetate. Drying and evaporation of solvent gave crude title compound (1.69 g) as a viscous residue. Polar impurities were removed by filtration through silica gel (100 g) to yield pure title compound (0.45 g), m.p. 60°-61° C., after methanol crystallization.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[N:11]=[C:5]2[NH:4][C:3]1=[O:29].Br[CH2:31][CH:32]([CH3:34])[CH3:33].[CH2:35]1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[N:11]=[C:5]2[N:4]([CH2:31][C:32]([CH3:34])([CH3:35])[CH3:33])[C:3]1=[O:29]
Reactant: C1CCC2=NCCCN2CC1
Reactant: Cn1c(=O)[nH]c2nn(Cc3cccc4ccccc34)c(-c3ccncc3)c2c1=O
Reactant: CC(C)CBr
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(-c3ccncc3)n(Cc3cccc4ccccc34)nc2n(CC(C)(C)C)c1=O

Procedure:
This compound was synthesized by the reaction of 5-methyl-2-(1-naphthylmethyl)-3-pyridin-4-yl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione and 1-bromo-2-methylpropane using DBU as abase in DMF at 100° C. Mass: 454.36 (M+H).
Reaction SMILES: S(Cl)(Cl)=O.Cl.[CH3:6][C:7]1[NH:8][C:9]2[CH2:15][CH:14]([C:16]([OH:18])=O)[CH2:13][CH2:12][C:10]=2[N:11]=1.[CH3:19][O:20][C:21]1[C:22]([NH2:27])=[CH:23][CH:24]=[CH:25][CH:26]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:16]([CH:14]1[CH2:13][CH2:12][C:10]2[N:11]=[C:7]([CH3:6])[NH:8][C:9]=2[CH2:15]1)=[O:18]
Reactant: Cc1nc2c([nH]1)CC(C(=O)O)CC2
Reactant: COc1ccccc1N
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1NC(=O)C1CCc2nc(C)[nH]c2C1
Temperature: 90 °C
Reaction time: 16 h
Yield: 36.1 %

Procedure:
Thionyl chloride, 5 ml, was added to 0.50 g (0.97 mmols) of 2-methyl-4,5,6,7-tetrahydrobenzimidazole-5carboxylic acid hydrochloride (including 58 w/w % of NaCl) obtained in Reference Example 2 and the mixture was heated at 90° C. for 3 hours. After thionyl chloride was distilled off under reduced pressure, 10 ml of methylene chloride was added to the residue and at 0° to 5° C., 0.20 ml (1.78 mmol) of o-anisidine and 0.40 ml (2.89 mmols) of triethylamine were added to the mixture followed by stirring at room temperature for 16 hours. After 50 ml of methylene chloride was supplemented, the mixture was washed with 1 N sodium hydroxide solution and then dried over anhydrous magnesium sulfate, the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with methylene chloride-methanol-ammonia water (10 : 1 : 0.1). The solvent was distilled off and the resulting colorless crystals were recyrstallized from ethyl acetate to give 0.10 g (37.0%) of N-(2-methyoxyphenyl)-2-methyl -4,5,6,7-tetrahydrobenzimidazole-5-carboxamide monhydrate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+]([O-])=O)[C:3]=1[CH:12]=[CH:13][N:14]1CCCC1.O.NN>O1CCCC1.CO.[Ni].O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]2[C:3]=1[CH:12]=[CH:13][NH:14]2
Reactant: O=[N+]([O-])c1cc(F)cc(Br)c1C=CN1CCCC1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Fc1cc(Br)c2cc[nH]c2c1
Reaction time: 24 h
Yield: 43 %

Procedure:
To a solution of crude 1-[2-(2-bromo-4-fluoro-6-nitro-phenyl)-vinyl]-pyrrolidine (2.74 g) in tetrahydrofuran (25 ml) and methanol (25 ml) was added Raney nickel, 50% slurry in water, active catalyst (5.0 ml) followed by careful addition of hydrazine monohydrate (0.63 ml). After stirring for 24 hours the reaction mixture was filtered through celite and the filtrate reduced in vacuo. The residue was purified by flash chromatography to give 4-bromo-6-fluoro-1H-indole (0.80 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[N+:19]([C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:22]([O-:24])=[O:23])[C:13]=1[NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])([O-:21])=[O:20]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A mixture of tert-butyl (2-aminoethyl)carbamate (5.00 g, 31.2 mmol), 2-chloro-1,3-dinitrobenzene (5.27 g, 26.0 mmol) and triethylamine (7.25 mL, 52.0 mmol) in tetrahydrofuran (260 mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a yellow solid (8.44 g, 25.9 mmol, 99.6%).
Reaction SMILES: Br[C:2]1[C:3]([O:14][CH2:15][O:16][CH3:17])=[C:4]([CH:7]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1)[CH:5]=[O:6].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][N:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[C:10]([C:8]1[CH:9]=[C:2]([C:23]2[CH:22]=[N:21][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:25][CH:24]=2)[C:3]([O:14][CH2:15][O:16][CH3:17])=[C:4]([CH:7]=1)[CH:5]=[O:6])([CH3:13])([CH3:12])[CH3:11]
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Reactant: COCOc1c(Br)cc(C(C)(C)C)cc1C=O
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: [Na+]
Solvent: COCCOC
Product: COCOc1c(C=O)cc(C(C)(C)C)cc1-c1ccc(C(F)(F)F)nc1
Temperature: 80 °C
Yield: 75.7 %

Procedure:
To a degassed (argon) solution of 3-bromo-5-(tert-butyl)-2-(methoxymethoxy)benzaldehyde (4.0 g, 13.3 mmol) and 2-(trifluoromethyl)pyridine-5-boronic acid [purchased from Frontier Scientific] (2.79 g, 14.6 mmol) in 2M aqueous sodium carbonate solution (26.7 mL, 53.2 mmol) and dimethoxy ethane (80 mL) was added tetrakis(triphenylphosphine)palladium(0) (770 mg, 0.665 mmol), the mixture was degassed for five minutes and then heated at 80° C. for 16 hours. The cooled reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried (Na2SO4), filtered and concentrated under reduced pressure to give an orange syrup. The product was purified using flash chromatography on silica eluting with a solvent gradient of 0 to 100% ethyl acetate in hexanes to give the 5-(tert-butyl)-2-(methoxymethoxy)-3-(6-(trifluoromethyl)pyridin-3-yl)benzaldehyde (3.7 g, 76% yield) as a grey-green solid.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH:11]2[N:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:8]1[CH2:9][CH2:10]2)(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+].O>CN(C=O)C>[N:21]([CH2:6][CH:7]1[CH2:12][CH:11]2[N:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:8]1[CH2:9][CH2:10]2)=[N+:22]=[N-:23]
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(COS(C)(=O)=O)C2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C2CCC1C(CN=[N+]=[N-])C2
Temperature: 100 °C
Yield: 92.8 %

Procedure:
To the title compound of step A (3.4 g, 11.1 mmol) in DMF (15 mL) was added sodium azide (2.1 g, 33.4 mmol). The mixture was heated at 100° C. overnight, cooled to rt, poured into H2O and extracted with DCM. The combined organics were washed with brine and dried (Na2SO4). Purification via silica gel chromatography (10% EtOAc in petroleum ethers) gave the title compound (2.6 g).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[C:17]([N:6]2[C:7]3[C:3](=[CH:2][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)[CH:16]=[CH:15][CH:14]=1
Reactant: Brc1cccc2[nH]ccc12
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cccc(-n2ccc3ccccc32)c1
Temperature: 75 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
To a mixture of 4-bromoindole (3.00 g, 15.3 mmol), and 3-trifluoromethylphenylboronic acid (2.91 g, 15.3 mmol) in THF (52 mL)) were added Palladium catalyst Pd(PPh3)4 (530 mg, 0.46 mmol) and the freshly prepared sodium hydroxide solution (1.84 g, 45.9 mmol in 21 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 75° C. oil bath for 16 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 3.55 g (89%) of the product 4-(3-trifluoromethyl-phenyl)-1H-indole.