Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][CH2:16][C:17]1[N:25]=[C:24]2[C:20]([N:21]=[CH:22][N:23]2[C@H:26]2[C@H:30]([OH:31])[C@H:29]([OH:32])[C@@H:28]([CH2:33][O:34]C)[O:27]2)=[C:19]([NH:36][CH2:37][CH:38]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:18]=1.[CH3:51][N:52]1[CH2:57][CH2:56][C:55](=O)[CH2:54][CH2:53]1.C(O)(=O)C>O1CCCC1>[C:39]1([CH:38]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:37][NH:36][C:19]2[N:18]=[C:17]([CH2:16][NH:15][CH:55]3[CH2:56][CH2:57][N:52]([CH3:51])[CH2:53][CH2:54]3)[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[C@H:26]2[C@H:30]([OH:31])[C@H:29]([OH:32])[C@@H:28]([CH2:33][OH:34])[O:27]2)[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN1CCC(NCc2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sodium triacetoxyborohydride (162 mg, 0.76 mmol) was added to a stirred solution of (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (250 mg, 0.51 mmol) (example 1), 1-methyl-4-piperidinone (52 mg, 0.46 mmol) and acetic acid (30 mg, 0.5 mmol) in tetrahydrofuran (20 ml). The reaction mixture was stirred for 24 hr at room temperature. The solvent was then removed under reduced pressure and the residue partitioned between dichloromethane (30 ml) and saturated aqueous sodium hydrogen carbonate solution (10 ml). The aqueous layer was discarded and the organic layer washed with water (10 ml), separated and the solvent removed under reduced pressure to give a residue which was purified by column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol:ammonia (90:10:0.5) increasing in polarity to (85:15:0.75) to give the title compound contaminated with example 1. The mixture was treated with diethyl ether (10 ml) and the solid filtered off. This solid was treated with diethyl ether (10 ml) and then filtered. The diethyl ether filtrates were combined and the solvent removed under reduced pressure to give the title compound (60 mg) as a solid. MS: 589 (MH+).
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[F:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>O1CCCC1>[F:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][CH:1]=[O:3]
Reactant: O=CO
Reactant: Nc1ccccc1F
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: O=CNc1ccccc1F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Under argon gas, at 0° C., formic acid (6.1 ml) was dropped to acetic anhydride (15.5 ml), which was stirred at 50° C. for 2 hours. The reaction solution was left up to room temperature, and diluted with tetrahydrofuran (10 ml). At room temperature, tetrahydrofuran (20 ml) solution containing 2-fluoroaniline (5.56 g) added to the above solution, which was stirred at room temperature for 1 hour. The reaction solution was concentrated to give a title compound having the following physical properties. The obtained title compound was used for the following reaction without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:25]=[CH:24][C:13]3[C@:14]4([CH3:23])[C@@H:19]([CH2:20][CH2:21][C:12]=3[CH:11]=2)[NH:18][C:17](=[O:22])[CH:16]=[CH:15]4)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:26](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:26][N:18]1[C@H:19]2[C@@:14]([CH3:23])([C:13]3[CH:24]=[CH:25][C:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)=[CH:11][C:12]=3[CH2:21][CH2:20]2)[CH:15]=[CH:16][C:17]1=[O:22]
Reactant: CC(C)(C)O
Reactant: C[C@]12C=CC(=O)N[C@@H]1CCc1cc(-c3cccc([N+](=O)[O-])c3)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1C(=O)C=C[C@]2(C)c3ccc(-c4cccc([N+](=O)[O-])c4)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(3-nitrophenyl)-10b-methyl-3,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one (12 mg, 0.034 mmol), 0.10 mL of t-butanol, and potassium t-butoxide (12 mg, 0.10 mmol). Methyl iodide (0.006 mL, 0.10 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 9 mg (75%) of the title compound as a white solid, upon trituration from diethyl ether/hexanes. mp 175°-177°. FDMS: m/e=348.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:18])[N:4](C)[C:5]2[C:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:19]C1C=C2C(=CC=1)NC(=O)C2=O>>[F:19][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:18])[C:2]([OH:1])=[C:11]2[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1c(O)c(=O)n(C)c2ccccc12
Reactant: O=C1Nc2ccc(F)cc2C1=O
Product: CCOC(=O)c1c(O)c(=O)[nH]c2ccc(F)cc12

Procedure:
Intermediate 21 was prepared as a white powder following the procedure described for Intermediate 16 by replacing indoline-2,3-dione with 5-fluoroindoline-2,3-dione. LC-MS (ESI) m/z 251.9 (M+H), RT=1.74 min (Method B).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1F)#[N:2].[NH:14]1[CH:18]=[CH:17][CH:16]=[N:15]1.[H-].[Na+]>CN(C)C=O.O>[C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N:14]1[CH:18]=[CH:17][CH:16]=[N:15]1)#[N:2]
Reactant: c1cn[nH]c1
Reactant: COC(=O)c1ccc(C#N)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(C#N)c(-n2cccn2)c1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
Methyl 4-cyano-3-fluorobenzoate (0.30 g) and 1H-pyrazole (0.14 g) were dissolved in N,N-dimethylformamide (10 ml). To the reaction solution, sodium hydride (0.10 g) was added under ice cooling while stirring the mixture, and the mixture was stirred for 30 min. After increasing the temperature to room temperature, the solution was further stirred for 2 hours. The reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, washed with water, and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a crude product, which was then purified by column chromatography to give methyl 4-cyano-3-(1H-pyrazol-1-yl)benzoate (0.28 g, yield 73%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1>CN(C)C=O.CCN(CN(CC)CC)CC.C(Cl)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:12][N:11]([CH2:5][CH3:4])[CH2:10][CH3:9])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1F)=NC2
Agent: CCN(CC)CN(CC)CC
Solvent: CC(=O)Cl
Solvent: CN(C)C=O
Product: CCN(CC)CCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1F)=NC2

Procedure:
In the manner given in Example 1, a solution of 8-bromo-1-methyl-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dimethylformamide, N,N,N',N'-tetraethyldiaminomethane and acetyl chloride (in 0.5 molar excess compared to the N,N,N',N'-tetraethyldiaminomethane) are reacted together to give 8-bromo-1-[2-(diethylamino)ethyl]-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=[C:9]2I.[C:24]1([S:30]([O-:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Na+]>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=[C:9]2[S:30]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:32])=[O:31]
Reactant: O=S([O-])c1ccccc1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(C3OCCO3)ccc21
Agent: [Na+]
Product: C[Si](C)(C)CCOCn1nc(S(=O)(=O)c2ccccc2)c2cc(C3OCCO3)ccc21

Procedure:
The title compound was prepared following the procedure described for Example 9A using 150 mg (0.336 mmol) 5-(1,3-dioxolan-2-yl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole (Example 6A) and 164 mg (1.01 mmol) sodium benzenesulfinate. After cooling, the reaction mixture was filtered, and the filtrate was purified by preparative RP-HPLC (acetonitrile/water+0.05% TFA gradient) to give 55 mg of a product mixture containing the title compound. This mixture was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[NH2:6][OH:7].[CH2:8](O)C>>[OH:7][NH:6][C@H:2]([C:3]([OH:5])=[O:4])[CH3:8].[NH2:1][CH2:2][C:3]([OH:5])=[O:4]
Reactant: NO
Reactant: CCO
Agent: NCC(=O)O
Product: C[C@H](NO)C(=O)O

Procedure:
3 g of N-(R, 2-bromo propanoyl)-glycine obtained by condensation of 2-bromo propionic acid (prepared according to E. Fischer et al., Annalen, 357, 1 (1907) with the glycine are dissolved in 100 ml of anhydrous ethanol and stirred for 48 hours with anhydrous hydroxylamine according to Example 5.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23](=[NH:26])[NH:24][OH:25])=[CH:13][CH:12]=2)[C:8]2[C:27]([C:31]([O:33][CH3:34])=[O:32])=[CH:28][CH:29]=[CH:30][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:42](OC(=O)C)(=[O:44])[CH3:43]>ClCCl>[C:42]([O:25][NH:24][C:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:9]2[C:8]3[C:27]([C:31]([O:33][CH3:34])=[O:32])=[CH:28][CH:29]=[CH:30][C:7]=3[N:6]=[C:5]2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:12][CH:13]=1)=[NH:26])(=[O:44])[CH3:43]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C(=N)NO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C(=N)NOC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 2-butyl-1-[[2'-(hydroxycarbamimidoyl)biphenyl-4-yl]methyl]bezimidazole-7-carboxylate (1.83 g) in dichloromethane (20 ml) was added triethylamine (0.46 g) and acetic anhydride (0.46 g), and the reaction mixture was stirred at room temperature for 2 hours. After evaporation of the solvent, the residue was partitioned between ethylacetate and water and the organic layer was washed with an aqueous solution of NaHCO3 and water. The solution was dried and concentrated to dryness to give a pale yellow solid (1.99 g, quant.)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][CH:16]=[C:10]2[C:11]([NH:13][C:14](=[O:15])[C:9]=12)=[O:12].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(OCC)C>[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH:21]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][CH:16]=[C:10]2[C:11]([NH:13][C:14](=[O:15])[C:9]=12)=[O:12]
Reactant: O=C1NC(=O)c2c(CCCCCCBr)cccc21
Reactant: CN1CCNCC1
Solvent: CCOCC
Product: CN1CCNCC1CCCCCCc1cccc2c1C(=O)NC2=O

Procedure:
6-Bromohexylphthalimide (460 mg; 2.0 mmoles) and N-methylpiperazine (0.44 ml; 4.0 mmoles) were dissolved in anhydrous ethyl ether (5 ml). Reaction times and process as per Example 1.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:15])=[CH:9][CH:8]=1)(OC)=[O:2].[NH3:26]>CO>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:15])=[CH:9][CH:8]=1)(=[O:2])[NH2:26]
Reactant: COC(=O)COc1ccc(CC(C)NCC(O)c2ccccc2)cc1
Reactant: N
Solvent: CO
Product: CC(Cc1ccc(OCC(N)=O)cc1)NCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-phenylethanamine (0.5 g) in methanol (10 ml) was treated with a solution of 0.880 ammonia (40 ml), the resulting mixture boiled for 11/2 hours then stirred at ambient temperature for 18 hours. The resulting white precipitate was filtered off to yield the title compound (0.17 g) m.p. 158°-162°, as an 82:18 mixture of diastereoisomers.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:12]=[C:13]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16]2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].CO.[Li+].[OH-].Cl>C1COCC1>[N:15]1([C:13]2[CH:14]=[C:9]([CH:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:34])=[O:2])[CH:10]=[C:11]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:26][CH:25]=3)[CH:12]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: COC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(N2CCc3ccccc32)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(N2CCc3ccccc32)c1
Yield: 8 %

Procedure:
A solution of 2-[5-(2,3-dihydro-indol-1-yl)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid methyl ester, MeOH (1 mL), THF (1 mL) and 10% aq. LiOH solution (0.5 mL) was stirred at 40° C. overnight. The solution was then acidified with aq. 2M HCl and extracted with DCM (3×1 mL). The organic layers were filtered through PTFE filter and concentrated to yield an oil. The residue was purified using reverse phase preparative HPLC (H2O: MeCN) to give the title product in 8% yield as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH3:2].[H-].[Na+].Br[CH2:19][CH2:20]Br.O>CN(C)C=O>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([C:5]2([C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH2:20][CH2:19]2)=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of ethyl(4-nitrophenyl)acetate (5.0 g) in N,N-dimethylformamide (100 mL) was added sodium hydride (60% in mineral oil, 1.9 g) in an ice bath, and the mixture was stirred at room temperature for 20 min. To the reaction mixture was added 1,2-dibromoethane (4.1 mL) in an ice bath, and the mixture was stirred at the same temperature for 30 min, and the at room temperature for 1 hr. The reaction mixture was colled to 0° C., water was added thereto, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.0 g).
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[CH2:25][C@@H:24]2[C@:11]([CH3:29])([CH2:12][C@H:13]([OH:28])[C@H:14]3[C@H:23]2[CH2:22][CH2:21][C:20]2[C@:15]3([CH3:27])[CH2:16][CH2:17][C:18](=[O:26])[CH:19]=2)[C@@:6]1([OH:30])[C:7](=[O:10])[CH2:8]O)[CH:2]=[CH2:3].[Cl-:31].[Li+]>CN(C)C=O.O>[CH2:1]([O:4][C@@H:5]1[CH2:25][C@@H:24]2[C@:11]([CH3:29])([CH2:12][C@H:13]([OH:28])[C@H:14]3[C@H:23]2[CH2:22][CH2:21][C:20]2[C@:15]3([CH3:27])[CH2:16][CH2:17][C:18](=[O:26])[CH:19]=2)[C@@:6]1([OH:30])[C:7](=[O:10])[CH2:8][Cl:31])[CH:2]=[CH2:3]
Reactant: C=CCO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO
Reactant: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CCl

Procedure:
A solution of 16α-allyloxy-11β,17,21-trihydroxypregn-4-ene-3,20-dione, 21-methanesulfonate (4.6 mmoles) in 60 ml of dimethylformamide is refluxed for 1 hour under nitrogen with 5 g of lithium chloride. The solution is cooled, diluted with water and filtered. The solid is dissolved in chloroform, washed with 5% hydrochloric acid, water, dried, and evaporated in vacuo to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:19]3=[C:20]4[C:14](=[C:15]5[N:24]([CH3:25])[CH:23]=[CH:22][C:21]([C:26](O)=[O:27])=[C:16]5[CH:17]=[CH:18]3)[C:13](=[O:29])[NH:12][C:11]4=[CH:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[F:39][C:40]1[CH:41]=[CH:42][C:43]([O:48][CH3:49])=[C:44]([CH2:46][NH2:47])[CH:45]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C(=O)C>[F:39][C:40]1[CH:41]=[CH:42][C:43]([O:48][CH3:49])=[C:44]([CH:45]=1)[CH2:46][NH:47][C:26]([C:21]1[CH:22]=[CH:23][N:24]([CH3:25])[C:15]2[C:16]=1[CH:17]=[CH:18][C:19]1[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9][CH:10]=[C:11]3[NH:12][C:13](=[O:29])[C:14]=2[C:20]=13)=[O:27]
Reactant: CN1C=CC(C(=O)O)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Reactant: COc1ccc(F)cc1CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1CNC(=O)C1=c2ccc3c4c([nH]c(=O)c-4c2N(C)C=C1)=CCN3c1ccc(F)cc1
Yield: 8 %

Procedure:
A stock solution of Example 56d and N,N-diisopropylethylamine (0.15 M and 0.42 M in N,N-dimethylacetamide, respectively, 254 μL) and (5-fluoro-2-methoxyphenyl)-methanamine (0.4 M in N,N-dimethylacetamide, 115 μL), and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.22 M in N,N-dimethylacetamide, 254 μL) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C., and passed through the reactor at 180 μL min−1 (10 minute residence time). Upon exiting the reactor, the reaction mixture was loaded directly into an injection loop and purified by reverse phase HPLC(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) to give 0.0016 g (8%) of the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ 8.39 (d, J=2.14 Hz, 1H), 7.88 (s, 1H), 7.79 (dd, J=8.24, 2.14 Hz, 1H), 7.37 (d, J=8.24 Hz, 1H), 7.05 (m, 4H), 6.87 (m, 2H), 6.56 (m, 2H), 4.49 (s, 2H), 4.07 (s, 3H), 4.61 (m, 2H), 3.85 (s, 3H). MS (APCI+) m/z 527.2 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(OC)(C)C>[F:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:2]2[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[CH:12][CH:11]=1
Reactant: Oc1ccc(F)cc1
Reactant: Oc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COC(C)(C)C
Solvent: O
Product: Oc1ccc(Oc2ccc(F)cc2)nc1
Temperature: 170 °C

Procedure:
A mixture of 6-bromo-pyridin-3-ol (8.0 g), 4-fluorophenol (15.5 g) and cesium carbonate (30 g) was heated to 170° C. for 6 hours. After the mixture reached room temperature, it was distributed between water and MTBE. The organic phase was dried (Na2SO4) and concentrated. The residue was purified by chromatography (SiO2; EA/heptane 1:1.5) to provide the subtitle compound. MS ESI+: m/z=206 [M+H]+.
Reaction SMILES: [OH-:1].[Na+].[CH:3]([C:6]1[C:7]([O:38][CH2:39][O:40][CH3:41])=[CH:8][C:9]([O:34][CH2:35][O:36][CH3:37])=[C:10]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:19][CH:18]=3)[C:15](S(C)(=O)=O)=[N:14][N:13]=2)[CH:11]=1)([CH3:5])[CH3:4]>CS(C)=O>[CH:3]([C:6]1[C:7]([O:38][CH2:39][O:40][CH3:41])=[CH:8][C:9]([O:34][CH2:35][O:36][CH3:37])=[C:10]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:19][CH:18]=3)[C:15](=[O:1])[NH:14][N:13]=2)[CH:11]=1)([CH3:5])[CH3:4]
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1-c1nnc(S(C)(=O)=O)n1-c1ccc(CN2CCOCC2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COCOc1cc(OCOC)c(C(C)C)cc1-c1n[nH]c(=O)n1-c1ccc(CN2CCOCC2)cc1
Temperature: 90 °C
Yield: 53 %

Procedure:
At room temperature aqueous sodium hydroxide (1.0 M aqueous solution, 7 mL) was added to a dimethylsulfoxide solution (7 mL) of the crude product (1.01 g), which was obtained in the previous step, containing 3-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-4-(4-molpholin-4-ylmethylphenyl)-5-methanesulfonyl-4H-[1,2,4]triazole (F45-05). The reaction mixture was heated at 90° C. for 5.5 hours while stirring, cooled to room temperature, extracted with ethyl acetate, and the extract was washed twice with water and then saturated sodium chloride solution. The extract was dried over anhydrous sodium sulfate, and then sodium sulfate was removed by filtration. The solvent was distilled off under reduced pressure to obtain a pale yellow foam. Reprecipitation purification was carried out (chloroform, diethyl ether), and the solids were washed with diethyl ether and dried under reduced pressure to obtain 5-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-4-(4-morpholin-4-ylmethylphenyl)-2,4-dihydro-[1,2,4]triazole-3-one (F45-06, pale yellow solid, 469 mg, 53%).
Reaction SMILES: [CH3:1][S:2](O)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[S:14]([NH2:17])(=[O:16])=[O:15].N1C=CC=CC=1.CS(Cl)(=O)=O>C(#N)C>[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:9][C:8]=1[S:14]([NH2:17])(=[O:15])=[O:16]
Reactant: Nc1ccc(N)c(S(N)(=O)=O)c1
Reactant: CS(=O)(=O)O
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Temperature: 23 °C
Reaction time: 20 h
Yield: 86.3 %

Procedure:
2,5-Diamino-benzenesulfonamide methanesulfonate (1.80 kg, 6.35 mol) was suspended in acetonitrile (24 L). Pyridine (1.55 L, 19.1 mol) was added, followed by the careful slow addition of methanesulfonyl chloride (517 mL, 6.68 mol). After stirring at 23° C. for 20 h, the mixture was partially concentrated in vacuo at 55° C. Water (18 L) was added to the concentrate, and the resulting suspension was stirred at 23° C. for 2 h. The solid was filtered and was then washed with water (4 L) and air dried on the filter. The solid was suspended in absolute ethanol (9 L), stirred at 23° C. for 9 h, and was then filtered. The solid was washed with absolute ethanol (2×2 L), and was then further dried in vacuo at 50° C. to afford the desired product, 2-amino-5-methanesulfonylamino-benzenesulfonamide (1.45 kg, 5.48 mol, 86%), as a purple solid.
Reaction SMILES: [C:1]1([CH:7](Br)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[N+:33]([O-:35])=[O:34])[CH2:18][CH2:17]1.OC1CCN(CCCOC2C=CC=CC=2[N+]([O-])=O)CC1>>[C:1]1([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[N+:33]([O-:35])=[O:34])[CH2:20][CH2:21]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1OCCCN1CCC(O)CC1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: O=[N+]([O-])c1ccc(F)cc1OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1

Procedure:
The procedure of Example 1 (a) was repeated except for using diphenylmethyl bromide and 4-hydroxy-1-[3-(5-fluoro-2-nitrophenoxy)propyl]piperidine instead of diphenylmethyl bromide and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-diphenylmethoxy1-[3-(5-fluoro-2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH2:4].[C:13](Cl)(Cl)=[S:14]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[N:4]=[C:13]=[S:14]
Reactant: S=C(Cl)Cl
Reactant: Cc1ccc([N+](=O)[O-])c(N)c1C
Solvent: Cc1ccccc1
Product: Cc1ccc([N+](=O)[O-])c(N=C=S)c1C
Yield: 95 %

Procedure:
To a solution of 2,3-dimethyl-6-nitroaniline (3.0 g, 1.0 equiv.) in toluene (150 mL) was added thiophosgene (2.5 mL, 1.8 equiv.) and the reaction mixture was heated at the reflux temp. overnight. The resulting mixture was concentrated under reduced pressure and the residue was purified by column chromatography (10% CH2Cl2/hex) to afford 2,3-dimethyl-6-nitrophenyl isothiocyanate as a light yellow solid (3.63 g, 95%): 1H NMR (CDCl3) δ2.39 (s, 3H), 2.40 (s, 3H), 7.17 (d, J=8.4 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H).