Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=3)[CH:25]=[C:26]([CH2:28][OH:29])[CH:27]=2)[C:10]=1[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH3:2].[H-].[Na+].I[CH2:51][CH3:52]>>[CH2:1]([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=3)[CH:25]=[C:26]([CH2:28][O:29][CH2:51][CH3:52])[CH:27]=2)[C:10]=1[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(CO)cc(-c3ccc(S(C)(=O)=O)cc3)c2)c1CCC(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOCc1cc(OCCCCCCc2cccc(OCCCC(=O)OCC)c2CCC(=O)OCC)cc(-c2ccc(S(C)(=O)=O)cc2)c1
Yield: 42.7 %

Procedure:
A similar procedure as described in Example 24, step 1 was used, starting from 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-hydroxymethyl-4′-methanesulfonyl-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid ethyl ester (250 mg, 0.37 mmol), sodium hydride (29.9 mg, 0.75 mmol), and iodoethane (116.7 mg, 0.75 mmol) to obtain 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-ethoxymethyl-4′-methanesulfonyl-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid ethyl ester (110 mg, 42%) as a light brown oil: ES(+)-HRMS m/e calcd for C39H52O9S (M+Na)+ 719.3224, found 719.3227.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[CH2:21][C:22]([O:24][CH3:25])=[O:23].O>CN(C=O)C>[C:7]([C:15]1[N:16]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:17]=[CH:18][CH:19]=1)(=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)CBr
Reactant: O=C(c1ccccc1)c1ccc[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1cccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
Potassium tert-butoxide (7.22, 0.064 mol) was dissolved in DMF (40 ml) and 2-benzoylpyrrole (10 g, 0.058 mol) in DMF (10 ml) was added dropwise with stirring at room temperature. This was left for 16 hours then cooled to 0° C. when methyl bromoacetate (5.4 ml, 0.058 mol) in DMF (5 ml) was added dropwise. The reaction mixture was stirred for 16 hours then poured into water (150 ml) and extracted with diethyl ether (2×100 ml). The extracts were washed with brine (2×75 ml) dried and evaporated to give methyl (2-benzoylpyrrol-1-yl)acetate (12.6 g, 89%) as a brown oil which crystallised on standing.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:20]=[CH:21][CH:22]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][CH3:19])[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].C(N(C(C)C)C(C)C)C.Cl[C:33]1[N:38]=[C:37]([S:39][C:40]#[N:41])[C:36]([N+:42]([O-:44])=[O:43])=[CH:35][N:34]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([N:18]([CH3:19])[C:33]3[N:38]=[C:37]([S:39][C:40]#[N:41])[C:36]([N+:42]([O-:44])=[O:43])=[CH:35][N:34]=3)[CH:15]=[CH:16][CH:17]=2)=[O:10])[CH:20]=[CH:21][CH:22]=1)([CH3:5])[CH3:4])#[N:2]
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: CNc1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc([N+](=O)[O-])c(SC#N)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the above-mentioned crude product of 3-(1-cyano-1-methylethyl)-N-[3-(methylamino)phenyl]benzamide in tetrahydrofuran (15 mL) were added N-ethyl-N-isopropylpropane-2-amine (345 μL, 1.98 mmol) and 2-chloro-5-nitropyrimidin-4-yl thiocyanate (314 mg, 1.50 mmol), and the mixture was stirred at room temperature for 1.5 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (30 mL), and the mixture was extracted with ethyl acetate (30 mL, 10 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=85/15→70/30), and the fractions containing the object product were concentrated under reduced pressure to give 2-{[3-({[3-(1-cyano-1-methylethyl)phenyl]carbonyl}amino)phenyl](methyl)amino}-5-nitropyrimidin-4-yl thiocyanate as a yellow oil. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: OC1C=C(N2C3C=CN=CC=3N=C2)SC=1C(OC)=O.[OH:20][C:21]1[CH:25]=[C:24]([N:26]2[C:30]3[CH:31]=[N:32][CH:33]=[CH:34][C:29]=3[N:28]=[CH:27]2)[S:23][C:22]=1[C:35]([O:37][CH3:38])=[O:36].C([O-])([O-])=O.[K+].[K+].Br[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[C:53]([F:56])([F:55])[F:54]>CN(C)C=O>[N:28]1[C:29]2[CH:34]=[CH:33][N:32]=[CH:31][C:30]=2[N:26]([C:24]2[S:23][C:22]([C:35]([O:37][CH3:38])=[O:36])=[C:21]([O:20][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[C:53]([F:54])([F:55])[F:56])[CH:25]=2)[CH:27]=1
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1O
Reactant: FC(F)(F)c1ccccc1CBr
Agent: COC(=O)c1sc(-n2cnc3cnccc32)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example B3, 7.92 g of an isomeric mixture of methyl 3-hydroxy-5-(1H-imidazo[4,5-c]pyridin-1-yl)thiophene-2-carboxylate and methyl 3-hydroxy-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate (example C1) and 4.77 g of K2CO3 and 8.23 g of 1-(bromomethyl)-2-(trifluoromethyl)benzene in 60 ml N,N-dimethylformamide yield compound B1a and compound B1b.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[S:20][C:21]([CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:22][N:23]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:42].[OH-].[Na+]>C(O)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:14]3[NH:42][C:17]([C:19]4[S:20][C:21]([CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:22][N:23]=4)=[CH:16][CH:15]=3)[CH2:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: COCCOCc1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)s1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COCCOCc1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Temperature: 100 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
A mixture of 5-[4-(cyclopropylsulfonyl)phenyl]-1-[5-[(2-methoxyethoxy)methyl]-1,3-thiazol-2-yl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (0.52 g), ammonium acetate (0.55 g) and acetic acid (6 mL) was stirred at 100° C. for 2 hr. The reaction mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (0.47 g, yield 94%) was obtained as a yellow resin from a fraction eluted with tetrahydrofuran-hexane (1:4, volume ratio). MS: 531 (MH+).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.Cl.[CH3:32][NH2:33].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:32][NH:33][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[CH:20][CH:21]=1
Reactant: CN
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 47.2 %

Procedure:
(S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (87 mg, 0.214 mmol) and methanamine hydrochloride (21.62 mg, 0.320 mmol) were suspended in DMF (1 ml) and treated with DIPEA (0.186 ml, 1.068 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (162 mg, 0.427 mmol). The reaction mixture was stirred at room temperature for 23 h and purified using HPLC (25-95% acetonitrile in water, NH4HCO3 buffered) to afford (S)—N-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (42.4 mg, 0.101 mmol, 47.2% yield) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 1.83-2.01 (m, 3 H) 2.11-2.25 (m, 1 H) 2.39-2.48 (m, 4 H) 2.73 (d, J=4.55 Hz, 3 H) 3.13-3.27 (m, 4 H) 3.34-3.44 (m, 3 H) 3.52-3.64 (m, 1 H) 3.96-4.02 (m, 1 H) 6.92 (d, J=9.09 Hz, 2 H) 6.98 (d, J=2.02 Hz, 1H) 7.62 (d, J=1.77 Hz, 1 H) 7.69 (d, J=9.09 Hz, 2 H) 8.13 (q, J=4.29 Hz, 1 H) 10.44 (s, 1 H); [M+H] calc'd for C23H28N6O2, 421; found, 421.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[Cl:10][C:11]1[C:17](Cl)=[CH:16][C:14]([NH2:15])=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=1.[OH-].[K+]>O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C:17]1[C:11]([Cl:10])=[CH:12][C:13]([N+:19]([O-:21])=[O:20])=[C:14]([CH:16]=1)[NH2:15]
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: Oc1cccc(Cl)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(Oc2cccc(Cl)c2Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 8 h

Procedure:
A mixture of 171 g of 2,3-dichlorophenol and 186 g of 4,5-dichloro-2-nitroaniline is heated to 150° C. 101 g of a 50% potassium hydroxide solution are added dropwise to the dark-red liquid over a period of 1 hour. The water of reaction formed is distilled off with a small amount of phenol. The reaction mixture is stirred overnight at 150° C. and then, at that temperature, 450 ml of dimethylformamide are added. The solution is allowed to cool and is all poured onto a mixture of 3 1 of water and 150 ml of concentrated sodium hydroxide solution. The greenish suspension is stirred at room temperature for 1 hour, and the crystals that form are filtered off and washed neutral with water and then dried. The still moist yellowish crystals are used in crude form in the next reaction step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH2:18][CH3:19])[C:6](=O)[CH2:7][CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+].Cl>C(O)(=O)C.CO>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH2:18][CH3:19])[CH:6]([NH2:27])[CH2:7][CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(CC)C(=O)CCOCc1ccccc1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C(CC)C(N)CCOCc1ccccc1
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 134.3 %

Procedure:
The compound 5-benzyloxy-3-oxo-2-ethyl-pentanoic acid ethyl ester (146.8 g), methanol (1580 ml) and ammonium acetate (406.2 g) are charged in a 6-l five-necked flask equipped with a mechanical stirrer, a condenser, a thermometer, an Argon inlet tube, and a dropping funnel, and the mixture is stirred until a complete solution is obtained. Then sodium cyanoborohydride (16.6 g) is added thereto and, after 5 minutes, glacial acetic acid (330 ml). Stirring is continued for 40 hours at room temperature, then the temperature is lowered to -5° C. and a strong Argon stream is passed through the reaction mixture. 37% HCl (540 ml) is added drop by drop over a period of 20 minutes to lower the pH to about 2.5 and the bubbling Argon stream is continued while the temperature is allowed to rise to room temperature. Ammonium chloride which separates is filtered under vacuum and washed with methanol. The filtrate plus the methanol wash are concentrated to dryness under reduced pressure by heating to 40° -45° C. The residue is taken up with 5% HCl (400 ml) and toluene (900 ml) and the toluene layer is separated and extracted with 5% HCl (three 300 ml portions). The acidic extracts are combined, cooled to about -5° C. and brought to pH 8 by the addition of 50% NaOH (550 ml). The mixture is extracted with methylene chloride (four 300-ml portions) which is then dried over Na2SO4 and concentrated to dryness under reduced pressure yielding 3-amino-5-benzyloxy-2-ethyl-pentanoic acid ethyl ester (99.1 g) which may be used as such in the next step.
Reaction SMILES: [CH:1]([N:4]([CH:18]([CH3:20])[CH3:19])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].[C:21]1([NH:27][C:28](=[O:31])[NH:29][NH2:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)C>C(O)(=O)C.O>[C:21]1([NH:27][C:28](=[O:31])[NH:29]/[N:30]=[C:10]2/[C:8](=[O:9])[N:7]([CH2:6][CH2:5][N:4]([CH:18]([CH3:20])[CH3:19])[CH:1]([CH3:3])[CH3:2])[C:17]3[C:12]/2=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)N(CCN1C(=O)C(=O)c2ccccc21)C(C)C
Reactant: NNC(=O)Nc1ccccc1
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)N(CCN1C(=O)/C(=N/NC(=O)Nc2ccccc2)c2ccccc21)C(C)C
Temperature: 70 °C
Reaction time: 3 h
Yield: 60.9 %

Procedure:
To a solution of 1.37 g of 1-(2-diisopropylaminoethyl)isatin and 0.86 g of 4-phenylsemicarbazide in ml of a mixture of ethanol and water (2:1) was added 3 drops of acetic acid, and the mixture was stirred for 3 hours at 70° C. The yellow precipitates were collected by filtration, and recrystallized from ethanol to obtain 1.24 g of (E)-1-(2-diisopropylaminoethyl)isatin 3-(4-phenylsemicarbazone) having a melting point of 157°-159° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[F:12])=[N+:2]=[N-:3].[C:13]([O:17][CH3:18])(=[O:16])[C:14]#[CH:15]>>[F:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[CH2:4][N:1]1[CH:15]=[C:14]([C:13]([O:17][CH3:18])=[O:16])[N:3]=[N:2]1
Reactant: C#CC(=O)OC
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Product: COC(=O)c1cn(Cc2c(F)cccc2F)nn1

Procedure:
The process may involve reacting 2-(azidomethyl)-1,3-difluorobenzene of formula III with methyl propiolate, to obtain methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate of formula IV, and converting the methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate of formula IV to rufinamide.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Cl:18][S:19](O)(=[O:21])=[O:20].C(=O)(O)[O-].[Na+]>>[N:7]1([C:4]2[CH:5]=[CH:6][C:1]([C:12]3[CH:13]=[CH:14][C:15]([S:19]([Cl:18])(=[O:21])=[O:20])=[CH:16][CH:17]=3)=[CH:2][CH:3]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc(-c2ccc(N3CCCC3)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=S(=O)(Cl)c1ccc(-c2ccc(N3CCCC3)cc2)cc1
Temperature: 60 °C

Procedure:
6 g (0.023 mol) of the product from stage 1 was introduced into 11 ml of chlorosulfonic acid in portions with cooling and under protecting gas and the mixture was heated at 60° C. for 3.5 h. The solution was added to ice, the suspension was brought to pH 8 by addition of solid sodium bicarbonate, and the precipitated product was filtered off with suction and dried under reduced pressure.
Reaction SMILES: O=S(Cl)Cl.[C:5]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]=2[C:21]([OH:23])=[O:22])([CH3:8])([CH3:7])[CH3:6].[CH3:24]O>>[C:5]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]=2[C:21]([O:23][CH3:24])=[O:22])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)c1cc2cc([N+](=O)[O-])cc(C(=O)O)c2[nH]1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])cc2cc(C(C)(C)C)[nH]c12
Temperature: 80 °C
Reaction time: 12 h
Yield: 70 %

Procedure:
SOCl2 (3.6 g, 30 mol) was added dropwise to a solution of 2-tert-butyl-5-nitro-1H-indole-7-carboxylic acid (4.0 g, 15 mol) and methanol (30 mL) at 0° C. The mixture was stirred at 80° C. for 12 h. The solvent was evaporated under vacuum and the residue was purified by column chromatography on silica gel (5% EtOAc in petroleum ether) to afford methyl 2-tert-butyl-5-nitro-1H-indole-7-carboxylate (2.95 g, 70%). 1H NMR (CDCl3, 300 MHz) δ 9.99 (brs, 1H), 8.70 (d, J=2.1 Hz, 1H), 8.65 (d, J=2.1 Hz, 1H), 6.50 (d, J=2.4 Hz, 1H), 4.04 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].Cl>C(OCC)(=O)C.CN(C)C=O>[CH2:1]([NH:9][C:10]1[CH:22]=[C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NCc1ccccc1
Temperature: 80 °C
Reaction time: 9 h
Yield: 62.4 %

Procedure:
To N,N-dimethylformamide 0.5 mL solution of benzyl bromide 41 mg were added tert-butyl 2-amino-4-phenylbenzoate 54 mg and potassium carbonate 55 mg at room temperature, and it was stirred at 80° C. for 9 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 1.0 mol/L hydrochloric acid were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=100:1] to give tert-butyl 2-benzylamino-4-phenylbenzoate 45 mg of a white solid.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:19]=[CH:18][C:10]2[CH:11]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[O:13][C:9]=2[CH:8]=1.C(OCC)(=O)C>ClCCl>[OH:6][C:7]1[CH:19]=[CH:18][C:10]2[CH:11]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[O:13][C:9]=2[CH:8]=1
Reactant: COC(=O)c1cc2ccc(OC)cc2o1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cc2ccc(O)cc2o1
Temperature: 25 °C
Reaction time: 24 h
Yield: 10.1 %

Procedure:
Boron tribromide (24.9 g) was added dropwise to a solution of methyl 6-methoxybenzofuran-2-carboxylate (18.6 g) in dichloromethane (200 ml) at 0° C., followed by stirring at room temperature for 1 day. The reaction mixture was poured over ice water; ethyl acetate (300 ml) was added. After the organic layer was washed with water and dried (MgSO4), the solvent was distilled off; 10% hydrochloric acid-methanol (60 ml) was added to the residue, followed by heating at 70° to 80° C. for 5 hours. The reaction mixture was concentrated under reduced pressure; the resulting crystals of methyl 6-hydroxybenzofuran-2-carboxylate (10.75 g) were collected by filtration using diethyl ether-isopropyl ether (2:1, v/v). The filtrate was concentrated; the residue was subjected to silica gel column chromatography. From the fraction eluted with diethyl ether-hexane (1:2, v/v), methyl 6-hydroxybenzofuran-2-carboxylate (1.75 g) was obtained (total yield 73%), which was then recrystallized from diethyl ether-isopropyl ether to yield colorless prisms having a melting point of 176° to 177° C.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH3:8][C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]2[C:25]3[NH:24][C:23]4[CH2:26][CH2:27][NH:28][CH2:29][C:22]=4[C:21]=3[CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1>C(O)(=O)C>[C:5]([N:28]1[CH2:27][CH2:26][C:23]2[NH:24][C:25]3[C:17](/[CH:16]=[CH:15]/[C:12]4[CH:13]=[N:14][C:9]([CH3:8])=[CH:10][CH:11]=4)=[CH:18][CH:19]=[CH:20][C:21]=3[C:22]=2[CH2:29]1)(=[O:7])[CH3:6]
Reactant: Cc1ccc(/C=C/c2cccc3c4c([nH]c23)CCNC4)cn1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N1CCc2[nH]c3c(/C=C/c4ccc(C)nc4)cccc3c2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Acetic anhydride (1 mL; Fischer) was added dropwise to a solution of the product of Example 6C (45 mg, 0.16 mmol) in acetic acid (1 mL). The reaction mixture was stirred at room temperature for 10 minutes and then concentrated under vacuum. The resulting residue was purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 20-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (400 MHz, methanol-d4) (1:1 mixture of amide rotamers observed) δ ppm 2.23 and 2.24 (two s, 3H; amide rotamers), 2.54 (s, 3H), 2.90 and 2.99 (two t, J=5.8 Hz, 2H; amide rotamers), 3.91 and 3.99 (two t, J=5.8 Hz, 2H; amide rotamers), 4.74-4.77 (m, 2H), 7.05 and 7.06 (two t, J=7.6 Hz, 2H; amide rotamers), 7.24 (d, J=16.5 Hz, 1H), 7.31 (d, J=8.2 Hz, 1H), 7.36 and 7.39 (two dd, J=7.8, 0.8 Hz, 1H; amide rotamers), 7.42 and 7.43 (two d, J=7.3 Hz, 1H), 7.67 (d, J=16.5 Hz, 1H), 8.00 and 8.02 (two t, J=1.8 Hz, 1H), 8.61 (d, J=2.1 Hz, 1H); MS (APCI) m/z 332 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:15][CH2:14][C@H:13]([NH:16][C:17](=O)OC(C)(C)C)[CH2:12]3)=[N:7][C:6]=12.IC.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:15][CH2:14][C@H:13]([NH:16][CH3:17])[CH2:12]3)=[N:7][C:6]=12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccn3ncc(Br)c3n2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN[C@H]1CCN(c2ccn3ncc(Br)c3n2)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 97.7 %

Procedure:
(5)-tert-butyl (1-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-3-yl)carbamate (3.6 g, 9.4 mmol) taken up in 15 mL DMF and cooled to 0° C. in an ice bath. Iodomethane (1.026 mL, 16.5 mmol) added and stirred 5 minutes. Then sodium hydride 60% in oil (754 mg, 18.8 mmol) was slowly added. Reaction stirred 5 minutes at 0° C. then removed from ice bath and stirred 30 minutes at room temperature. Reaction was quenched with ice then extracted with ethyl acetate 2×. Ethyl acetate fractions combined dried over magnesium sulfate filtered reduce in vacuo. This was then taken up in 26 mL DCM and 4 mL TFA added. Stirred 1 hour until complete by LC/MS. Reaction washed with 1N NaOH, DCM layer removed dried over magnesium sulfate filtered, reduced in vacuo to get 2.72 g crude product carried on as is to part C. LRMS (ESI) m/z 296/298 [(M+H)]+, calc'd for C11H14BrN5: 296.17.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[OH:18])=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[O:18][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Cl
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(F)cc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)Oc1cc(F)ccc1C(=O)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-chlorophenyl)-1-(4-fluoro-2-hydroxy-phenyl)-ethanone (16.0 g, 60.6 mmol) in CH2Cl2 (300 ml) is added triethylamine (7.4 g, 72.7 mmol). A solution of isobutyryl chloride (7.1 g, 66.6 mmol) in CH2Cl2 (100 ml) is added slowly over 30 min. The reaction mixture is stirred at room temperature for 2 h. The organic phase is washed with 0.5 M HCl, water and brine and dried (MgSO4). The solvent is removed in vacuo, and the product is purified by flash chromatography on silica gel using iso-hexane:ethyl acetate (20:1 to 10:1) as the eluent to give the title compound.