Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[H-].[Na+].[CH3:12]OS(OC)(=O)=O.O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:12]
Reactant: Cc1cccc(Br)c1O
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C)cccc1Br
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a solution of 2-bromo-6-methylphenol (34.6 g, 0.18 mol) in THF (300 mL) was added NaH (9.6 g, 0.24 mol, 60%) in several portions. After the mixture was stirred for 1 h, Me2SO4 (28.0 g, 0.22 mol) was added dropwise. Then the mixture was stirred over night. Water (50 mL) was added, and the solvent was removed under reduced pressure. Then the residue was dissolved in Et2O (250 mL) and the organic layer was washed with NaOH (5%, 100 mL), brine (100 mL), and dried with Na2SO4. After removing the solvent, 35.3 g of the crude product was obtained (yield: 95%). 1H NMR (400 MHz, CDCl3) δ 2.33 (s, 3H), 3.81 (s, 3H), 6.88 (t, J=8.0 Hz, 1H), 7.10 (d, J=8.0 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=1.O>CO.[OH-].[K+]>[O:12]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH3:11])[C:3]([OH:19])=[O:2])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(OC)c(Oc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)O)cc1Oc1ccccc1
Reaction time: 2 h
Yield: 92.5 %

Procedure:
3-Phenoxy-4-methoxybenzoic acid methyl ester (0.8 g, 3.1 mmol) was stirred in a mixture of methanol (8 mL) and 4N potassium hydroxide (10 mL) and heated to reflux. After 2 hours, the mixture was stirred into water (60 mL) and extracted with ether (25 mL). The aqueous solution was stirred and acidified with 4N HCl, and the resulting precipitate was filtered off, rinsed with water, and dried to afford the product (0.7 g); m.p. 186-187° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[C:17]([NH:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=3)=[O:21])[N:16]=[C:15]([NH:29][C:30]([CH:32]([N:34]([CH3:42])[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])=[O:31])[CH:14]=2)[C:5]2[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:6]=2[N:7]=1.[CH3:43][O-:44].[Na+].CO>O>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]([NH:19][C:17]2[N:16]=[C:15]([NH:29][C:30]([CH:32]([N:34]([CH3:42])[C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:39])[CH3:40])[CH3:33])=[O:31])[CH:14]=[C:13]([C:4]3[C:5]4[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:6]=4[N:7]=[C:2]([O:44][CH3:43])[N:3]=3)[CH:18]=2)=[O:21])=[N:23][CH:24]=1
Reactant: C[O-]
Reactant: Cc1nn(C)c2c(-c3cc(NC(=O)c4ccc(Cl)cn4)nc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)c3)nc(Cl)nc12
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(-c2cc(NC(=O)c3ccc(Cl)cn3)nc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)c2)c2c(n1)c(C)nn2C
Temperature: 50 °C
Reaction time: 1.17 h

Procedure:
A mixture of tert-butyl N-{1-[(4-{5-chloro-1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl}-6-(5-chloropyridine-2-amido)pyridin-2-yl)carbamoyl]ethyl}-N-methylcarbamate K63a (54 mg, 88 μmol), sodium methoxide (24 mg, 439 μmol) and methanol (400 μl) is stirred at 50° C. for 70 minutes. At RT water (10 ml) is added and the mixture extracted with DCM. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 30 mg (56%). HPLC-MS: M+H=610; tR=1.12 min (METHOD—2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH2:17][CH3:18])[C:15](=[O:19])[N:14]([CH3:20])[C:13](=S)[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CI.[CH3:24][C:25]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[C:26]=1[NH2:27]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH2:17][CH3:18])[C:15](=[O:19])[N:14]([CH3:20])[C:13](=[N:27][C:26]3[C:28]([CH3:33])=[CH:29][C:30]([CH3:32])=[CH:31][C:25]=3[CH3:24])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCn1c(-c2ccc(OC)c(OC)c2)cc(=S)n(C)c1=O
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: C1CCOC1
Solvent: CI
Product: CCn1c(-c2ccc(OC)c(OC)c2)cc(=Nc2c(C)cc(C)cc2C)n(C)c1=O
Yield: 37 %

Procedure:
To a solution of 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1-ethyl-3-methyl-4-thioxo-2(1H)-pyrimidinone (0.59 g) in tetrahydrofuran (50 ml) was added methyl iodide (10 ml) and the mixture was refluxed for 90 minutes. The precipitate was added to 2,4,6-trimethylaniline (2 g) and the mixture was heated at 110°-120° C. for 3 hours. The reaction mixture was washed with a mixture of hexane and diisopropyl ether to remove excess 2,4,6-trimethylaniline. The resulting precipitate was collected by filtration and then dissolved in chloroform. The solution was washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate and evaporated under reduced pressure to give crude product, which was purified by silica gel column chromatography to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1-ethyl-3-methyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (0.29 g); mp 57°-61° C. Thus obtained compound was recrystallized from a mixture of ethanol and water (3:1) to give the desired compound as crystals. mp 116°-118° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.Cl[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:17]>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=[O:17])=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1Cl
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: CCOCC
Product: O=C1CCCCC1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.8 %

Procedure:
A solution of 4-chlorophenylmagnesium bromide (200 mL of 1 M in ether, 200 mmol) was cooled in an ice-bath and a solution of 2-chlorocyclohexanone (26.5 g, 200 mmol) in 200 mL of ether was slowly added. The mixture was stirred at room temperature for 4 hours and was then concentrated under reduced pressure. Benzene (300 mL) was added and the mixture was heated under reflux for 12 h. Dilute aqueous HCl was added and the organic layer was separated, washed with brine, dried (sodium sulfate) and evaporated. Bulb-to-bulb distillation (2 mm) afforded 30.8 g of liquid product that subsequently crystallized.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[C:7]([C:9]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1)([CH:19]([CH3:21])[CH3:20])[CH2:10][CH2:11][CH2:12][N:13]([CH2:15][CH:16]([CH3:18])[OH:17])[CH3:14])#[N:8]>C1(C)C=CC=CC=1>[C:4]([O:17][CH:16]([CH3:18])[CH2:15][N:13]([CH2:12][CH2:11][CH2:10][C:9]([C:7]#[N:8])([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1)[CH:19]([CH3:20])[CH3:21])[CH3:14])(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: C=C1CC(=O)O1
Reactant: COc1ccc(C(C#N)(CCCN(C)CC(C)O)C(C)C)cc1OC
Solvent: Cc1ccccc1
Product: COc1ccc(C(C#N)(CCCN(C)CC(C)OC(=O)CC(C)=O)C(C)C)cc1OC
Temperature: 80 °C

Procedure:
2.7 ml of diketene was added, over 10 minutes, to a solution of 11.36 g of the compound prepared in Example 2 in 10 ml of toluene at 80° C. When the exothermic reaction was over, the reaction mixture was heated for 2 hours at 80° C. and, after cooling, it was evaporated to dryness in vacuo. The oily residue was then purified by silica gel column chromatography using ehtyl acetate containing decreasing amounts of petroleum ether as eluent. The unitary TLC fractions (chloroform:methanol 95:5 by volume) were evaporated to dryness in vacuo to give 11.61 g of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:18])[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][O:32]C(=O)C)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[OH-].[K+].C(O)C.C(O)(=O)C>O>[NH2:1][C:2]1[C:7]([C:8]([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])=[O:18])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][OH:32])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCOC(C)=O)CC2)nc1N
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCO)CC2)nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
A suspension of acetic acid 3-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-sulfonyl]-propyl ester (25 mg, 0.049 mmol, Example 274) in a solution of potassium hydroxide (50 mg, 0.9 mmol), water (1 mL) and ethanol (6 mL) was stirred at 25° C. for 1 hour. The solution was cooled, acidified with acetic acid and reduced in volume to 2 mL. This was diluted with water and the product extracted into methylene chloride. After washing with water, the organic layer was separated and dried (Na2SO4). The residue was purified by silica gel chromatography (ethyl acetate) and crystallized from methylene chloride/hexane to give [4-amino-2-[1-(3-hydroxy-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone as a white solid (12 mg, 50% yield). HRMS, observed: 468.1716; Calcd for (M+H)+: 468.1712
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[C:6]1[CH:7]=[C:8]([CH:16]=[C:17](Br)[CH:18]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>C(N(CC)CC)C.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>[OH:4][CH2:1][C:2]#[C:3][C:6]1[CH:7]=[C:8]([CH:16]=[C:17]([C:3]#[C:2][CH2:1][OH:4])[CH:18]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: C#CCO
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1cc(C#CCO)cc(C#CCO)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.9 %

Procedure:
Pd(Ph3P)4 (1.08 g), CuBrSMe2 (0.41 g) and propargyl alcohol (2.95 g, 50.2 mmol) are added successively to a solution of tert-butyl 3,5-dibromobenzoate (A6, 7.7 g, 22.9 mmol) in triethylamine (130 ml), and the mixture is stirred at RT for 10 min and then under reflux at 80° C. for 3.5 h. After cooling, the reaction mixture is filtered off with suction through kieselguhr, and the filter cake is washed with ethyl acetate (50 ml). The organic phase is concentrated under reduced pressure. Further purification is carried out by chromatography [toluene/acetone (8:2)] on a silica gel column. This gives the title compound (5.7 g) as a colorless solid. TLC, silica gel (glass plates), [toluene/acetone (7.5:2.5)], Rf=0.15.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=2)[NH:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])=[CH:5][CH:4]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([NH:10][CH2:11][CH:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[C:20]2[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(NCC(C)c2ccccc2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(NCC(C)c2ccccc2)c2cccc(N)c2)cc1
Yield: 86.4 %

Procedure:
In a similar manner to that described in Example (1b), a solution of N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]-N-(2-phenylpropyl)amine (3.17 g) [prepared as described in step (a) above] in methanol (60 ml), nickel chloride hexahydrate (3.7 g) and sodium borohydride (1.18 g) were reacted, to afford the title compound (2.52 g) as a clear purple oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:29])[N:14]([N:23]=[CH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:30]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:29])[N:14]([NH:23][CH2:24][CH2:25][CH:26]([CH3:27])[CH3:28])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: CC(C)CC=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CCNn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 250A (0.041 g, 0.097 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.008 mL, 0.194 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.074 mL, 0.148 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water (5.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92 (s, 3 H) 0.94 (s, 3 H) 1.45 (q, J=7.11 Hz, 2 H) 1.73 (m, 1 H) 2.79 (m, 2 H) 5.87 (t, J=6.80 Hz, 1 H) 7.07 (t, J=7.35 Hz, 1 H) 7.28 (t, J=8.46 Hz, 2 H) 7.55 (m, 3 H) 7.66 (d, J=7.72 Hz, 1 H) 8.08 (dd, J=7.91, 1.29 Hz, 1 H) 16.28 (s, 1 H). MS (ESI−) m/z 425 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2.[Br:16][CH2:17][CH2:18][CH2:19]Br.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:16][CH2:17][CH2:18][CH2:19][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2
Reactant: COC(=O)Cn1ccc2cc(O)ccc21
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1ccc2cc(OCCCBr)ccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 45.3 %

Procedure:
To a solution of methyl (5-hydroxy-1H-indol-1-yl)acetate (1.0 g, 4.87 mmol) (Example 9) in 35 mL DMF, was added 1,3-dibromopropane (5.90 g, 29.24 mmol) and Cs2CO3 (3.18 g, 9.75 mmol). The mixture was stirred at rt for 6 h, and then the solvent was evaporated under reduced pressure. The residue was suspended in EtOAc, filtered, and the filter cake was washed with EtOAc. The combined organic layers were dried, concentrated, and purified by column chromatography (0-10% EtOAc in hexane) to give 720 mg (45%) of the product containing minor impurities. This material was used in later steps with no further purification. 1H NMR (400 MHz, CDCl3) δ 7.18-7.10 (m, 2H), 7.05 (d, 1H), 6.94-6.85 (m, 1H), 6.50 (d, 1H), 4.80 (s, 2H), 4.18 (t, 2H), 3.75 (s, 3H), 3.65 (t, 2H), 2.40-2.30 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.Cl[CH2:13][P:14](=[O:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17].CC(C)([O-])C.[K+]>CS(C)=O>[CH2:16]([O:15][P:14]([CH2:13][C:5]1[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[N:4]=1)(=[O:21])[O:18][CH2:19][CH3:20])[CH3:17]
Reactant: CCOP(=O)(CCl)OCC
Reactant: COc1ncccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(OC)n1)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.5 %

Procedure:
A solution of 2-methoxy-3-nitropyridine (6.92 g, 44.9 mmol) and diethyl chloromethylphosphonate (7.00 mL, 44.9 mmol) in 40 mL DMSO was added drop wise to a stirred mixture of potassium tert-butoxide (15.1 g, 134.6 mmol) and 40 mL DMSO. The mixture was stirred at room temperature for 30 minutes, after which, it was poured into a 1N HCl/ice mixture and extracted with methylene chloride. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (DCM:EtOAc 1:1). The slower eluting regioisomer was collected and confirmed to be the desired product (750 mg, 5.5% yield). MS (ES+): m/z 305.16 (100) [MH−]; HPLC: tR=1.16 min (UPLC, Analytical).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].N>CO.O1CCCC1.[Ni]>[CH2:1]([S:3]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(C#N)cc1
Agent: [Ni]
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: CCS(=O)(=O)c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
[Step 3] To a mixture of 4-ethanesulfonylbenzonitrile (500 mg) in methanol (6 ml) and tetrahydrofuran (2 ml) was added 28% aqueous ammonia (1 ml) and then Raney nickel (500 mg) was added. Under a hydrogen pressure (0.5 Mpa), the mixture was stirred at room temperature for 2 hrs., and undesired substances were removed by filtration. The filtrate was concentrated under reduced pressure to give 4-ethanesulfonylbenzylamine (408 mg, 82%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([CH3:17])=[CH:11]2.[OH-].[Na+].[CH3:20][C:21](N(C)C)=[O:22]>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([CH3:17])=[C:11]2[C:21](=[O:22])[CH3:20]
Reactant: CC(=O)N(C)C
Reactant: COc1ccc2[nH]c(C)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc2[nH]c(C)c(C(C)=O)c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
Dimethylacetamide (17.5 ml, 188.4 mmol) is added dropwise with stirring to phosphorous oxychloride (12.9 ml, 138.2 mmol) at 0° C. Stirring is maintained for 45 minutes, at which time the bath is removed and 5-methoxy-2-methylindole (20.25 g, 125.6 mmol) in 15 ml of dimethylacetamide is added dropwise over a period of 75 minutes. The resulting mixture is warmed to 40°-45° C. for 4 hours. The reaction mixture is cooled to 0° C., and 100 g of ice water is added followed by dropwise addition of a solution of sodium hydroxide (50 g) in water (75 ml). The first 1/3 of this sodium hydroxide solution is added slowly and the remainder is added quickly. The exothermic reaction is quickly warmed to boiling for 15 minutes, cooled to room temperature and refrigerated overnight. The resulting crystals are collected by filtration and rinsed four times with water. Recrystallization from ethanol/water gives 17.2 g (67.2%) of pure 1-(5-methoxy-2-methyl-lH-indol-3-yl)ethanone; mp 229.0°-230.5° C.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][C:35](OCC)=[O:36])=[CH:27][CH:26]=1)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)(C)(C)C.C1COCC1>[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][C:35]([NH:3][C:2]([NH2:4])=[NH:1])=[O:36])=[CH:27][CH:26]=1)[C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])=[O:14])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)CCCOc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1
Reactant: N=C(N)N
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC(=N)N)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.8 %

Procedure:
A solution of 3.64 g (61.69 mmol) of guanidine in 150 ml of tert-butanol was added to a solution of 20 g (41.23 mmol) of (1.1) in THF and the mixture was stirred at room temperature for 18 h. A further 4.5 g of guanidine in 150 ml of tert-butanol were then added, and the reaction solution was stirred at room temperature for 7 h, concentrated to about a half and stirred at room temperature for a further 18 h. The solvent was removed in vacuo and the residue was first filtered through basic Al2O3 using CH2Cl2/MeOH/H2O (95/5/0.5) and then chromatographed on silica gel by means of MPLC using CH2Cl2/MeOH/acetic acid (90/10/0.5). 8.6 g (42%) of (1.2) were obtained.
Reaction SMILES: [N:1]([C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1)=[N+]=[N-]>[OH-].[Pd+2].[OH-].C(O)C>[CH:7]1[C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: [N-]=[N+]=Nc1cccc2c1oc1ccccc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Nc1cccc2c1oc1ccccc12

Procedure:
Palladium hydroxide (20%, 0.75 g, 1.068 mmol) was added to a Parr hydrogenation bottle, and the bottle was purged with nitrogen. Next, 4-azidodibenzo[b,d]furan (7.39 g, 35.3 mmol) and 150 mL ethanol were added, and the reaction mixture was hydrogenated on Parr hydrogenator overnight. The reaction mixture was filtered through a pad of Celite®, and the Celite® was washed with dichloromethane. The filtrate was evaporated, and the residue was purified by column chromatography eluting with 50% dichloromethane/hexanes (5.58 g, 86%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14](Cl)(=O)[C:15](Cl)=O>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([C:15]2[CH:14]=[CH:6][CH:5]=[CH:4][CH:9]=2)=[O:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 4-nitrophenylacetic acid (200 g) in benzene (1.5 L) was added oxalyl chloride (200 mL). The mixture was warmed to 50°-60° C. for 2 hrs, after which time benzene and excess oxalyl chloride were distilled off under vacuum at 50° C. until a final volume of 500 mL was achieved. The residue was diluted with benzene (1 L) and cooled to 0° C. To this was added anhydrous aluminum chloride (160 g) portion-wise over 15 minutes. Thereafter, the mixture was stirred overnight at room temperature. The reaction mixture was poured over a mixture of ice (3 L) and concentrated HCl (1 L). The resulting slurry was filtered through celite and the precipitate washed with ethyl acetate. The combined filtrates were washed with water, saturated sodium bicarbonate and with brine, dried over sodium sulfate and evaporated to give 227 grams of 2-(4-nitrophenyl)-1-phenylethanone.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.C(N(CC)CC)C.[O:20](S(C(F)(F)F)(=O)=O)[S:21]([C:24]([F:27])([F:26])[F:25])(=O)=[O:22]>ClCCl>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:12][S:21]([C:24]([F:27])([F:26])[F:25])(=[O:22])=[O:20])=[CH:10][CH:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1ccc(-n2cncn2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Oc1ccc(-n2cncn2)cc1)C(F)(F)F
Reaction time: 5 h

Procedure:
1.0 g of 4-[1,2,4]triazol-1-yl-phenol was dissolved in 10 ml of dichloromethane, and 1.72 ml of triethylamine was added thereto. 1.56 ml of Tf2O was added to the mixture and stirred for 5 hr. The reaction was terminated by using water, and the resulting mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under a reduced pressure to obtain the title compound.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:18]=[C:17]2[C:13]([CH2:14][CH2:15][C:16]2=[O:19])=[CH:12][CH:11]=1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][CH:14]1[C:13]2[C:17](=[CH:18][C:10]([F:9])=[CH:11][CH:12]=2)[C:16](=[O:19])[CH2:15]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCc2ccc(F)cc21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1CC(Br)c2ccc(F)cc21
Temperature: 25 °C
Yield: 65.8 %

Procedure:
A mixture of N-bromosuccinimide (2.76 g, 15.51 mmoles, Aldrich), benzoyl peroxide (0.01 g, 0.04 mmoles, Aldrich) and 6fluoro-1-indanone (2.29 g, 15.25 mmoles) in carbon tetrachloride (20 mL) was refluxed under nitrogen for two hours. The mixture was cooled to ambient temperature, filtered, and the solids were washed with dichloromethane. The washings and filtrate were combined, washed successively with 1.0N sodium hydroxide (2×30 mL), water (2×30 mL) and brine (30 mL), and evaporated in vacuo. The residue was chromatographed on silica gel eluting first with hexane, gradually increasing the polarity to hexane: ethyl acetate (95:5). The fractions containing the major spot were combined and evaporated in vacuo to give a 2.30 g (66%) of 3-bromo-6-fluoro-1-indanone as a yellow oil which was used without further purification.