Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+].[Br:13][C:14]([F:18])=[C:15]([F:17])[F:16]>CN(C)C=O>[Br:13][CH:14]([F:18])[C:15]([F:17])([F:16])[O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: FC(F)=C(F)Br
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OC(F)(F)C(F)Br)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
278 g of 4-nitrophenol and 56 g of potassium hydroxide were dissolved in 800 ml of dimethylformamide, 179 g of bromotrifluoroethylene were fed in, a little at a time, at 40° C., and stirring was then continued for 2 hours at 60° C. The solvent was removed under reduced pressure in a rotary evaporator, the residue was poured into ice-water and extracted with 3×500 ml of methylene chloride, the extract was washed with dilute sodium hydroxide solution and water and dried over Na2SO4, and the solvent was removed. When the residue was distilled, 279.5 g of pure product passed over at 114° C./1.3 mbar.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12]Br)[CH:5]=1.[CH3:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]#[N:26])[CH:23]=2)[NH:18][C:17]=1[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][N:18]2[C:19]3[C:24](=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[C:16]([CH3:15])=[C:17]2[C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(OCCBr)c1
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(C#N)cc12
Product: COC(=O)c1cccc(OCCn2c(-c3cccnc3)c(C)c3cc(C#N)ccc32)c1

Procedure:
3-(2-Bromo-ethoxy)-benzoic acid methyl ester and 5-cyano-3-methyl-2-pyridin-3-yl-indol-1-yl (Example 6) are processed according to the method described in Example 59 to give 3-[2-(5-cyano-3-methyl-2-pyridin-3-yl-indol-1-yl)-ethoxy]-benzoic acid methyl ester. 1H NMR (400 MHz, MeOD) δ ppm 2.26 (s, 3H), 3.90 (s, 3H), 4.22 (t, J=4.9 Hz, 2H), 4.60 (t, J=5.1 Hz, 2H), 6.91 (dd, J=7.8, 2.3 Hz, 1H), 7.21-7.24 (m, 1H), 7.28 (t, J=8.0 Hz, 1H), 7.52-7.59 (m, 2H), 7.65 (dd, J=7.8, 5.1 Hz, 1H), 7.76 (d, J=8.6 Hz, 1H), 7.98-8.09 (m, 2H), 8.56-8.77 (m, 2H). HRMS (ESI) m/z 412.1664 [(M+H)+ Calcd for C25H22N3O3: 412.1661].
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.C[Sn](C)(C)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[BH4-].[Na+]>>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2ccncc2c1
Reactant: C[Sn](C)(C)c1ccccn1
Agent: [BH4-]
Agent: [Na+]
Product: c1ccc(-c2ccc3c(c2)CNCC3)nc1

Procedure:
In close analogy to the procedure described above, 7-Bromo-isoquinoline is reacted with 2-trimethylstannyl-pyridine and sodium borohydride to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[N:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[N:24][CH:23]=1.C1COCC1.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:26]4[CH:27]=[N:22][CH:23]=[N:24][CH:25]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(I)ccc1Oc1ncc(Br)cc12
Reactant: OB(O)c1cncnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1ncc(Br)cc12
Temperature: 110 °C

Procedure:
A sealable tube was charged with (S)-3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (2.000 g, 4.37 mmol), pd(ph3p)4 (0.504 g, 0.437 mmol), pyrimidin-5-ylboronic acid (0.568 g, 4.58 mmol) and THF (21.83 mL, 4.37 mmol). The mixture was flushed with Ar then a solution of potassium carbonate (1.5 M) (5.82 mL, 8.73 mmol) was added. The reaction was heated at 110° C. for 2 hours before being diluted with water 50 mL and poured into a separatory funnel containing ethyl acetate 50 mL. The layers were separated and the aqueous layer was extracted with ethyl acetate 3×100 mL. The aqeuous layer was then extracted with DCM (3×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a brown oil that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (80 g), 0-10% methanol in methylenechloride with 0.1% ammonium hydroxide) to provide (S)-3-bromo-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a light yellow foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:25])[C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][CH2:18][CH2:19]OS(C)(=O)=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][NH:27][CH3:28]>CC(N(C)C)=O>[C:1]([O:5][C:6](=[O:7])[N:8]([C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][CH2:18][CH2:19][N:27]([CH3:28])[CH3:26])=[CH:11][CH:10]=1)[CH3:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(C#CCCCOS(C)(=O)=O)cc1
Reactant: CNC
Solvent: CC(=O)N(C)C
Product: CN(C)CCCC#Cc1ccc(N(C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
A solution of 1.84 g (5 mmol) of Methanesulfonic acid 5-[4-(tert-butoxycarbonyl-methyl-amino)-phenyl]-pent-4-ynyl ester in 20 ml DMA was treated with 8.93 ml (50 mmol) of (33% in ethanol, 5.6 M) dimethylamine and stirred at RT for 18 h. The reaction was treated again with 4.46 ml (2 mmol) (25 mmol) of (33% in ethanol, 5.6 M) dimethylamine and stirred at RT for further 6 h. The solution was concentrated and the residual oil was extracted with aqueous sat. NaHCO3/Et2O (3×). The organic phases were washed with aqueous 10% NaCl solution, dried (Na2SO4) and evaporated to yield 1.50 g (95%) of [4-(5-Dimethylamino-pent-1-ynyl)-phenyl]-methyl-carbamic acid tert-butyl ester, MS: 317 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][CH3:13])=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([CH:8]=1)[NH2:7].O.O.[Sn](Cl)Cl>C(OCC)(=O)C>[NH2:9][C:5]1[CH:4]=[C:3]([CH2:12][CH3:13])[C:2]([Cl:1])=[CH:8][C:6]=1[NH2:7]
Reactant: CCc1cc([N+](=O)[O-])c(N)cc1Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1cc(N)c(N)cc1Cl
Yield: 100 %

Procedure:
A mixture of 5-chloro-4-ethyl-2-nitroaniline (supplied by the Sigma-Aldrich Library of Rare Chemicals, 2.62 g, 13.1 mmol), tin (II) chloride dihydrate (14.7 g, 65.3 mmol) and ethyl acetate (130 ml) was heated under reflux for 22h. The mixture was cooled and partitioned between 1M aqueous sodium hydroxide (500 ml) and ethyl acetate (500 ml). The aqueous layer was extracted with ethyl acetate (250 ml), and the combined organic solutions were washed with saturated aqueous sodium chloride (100 ml), dried (MgSO4) and concentrated under reduced pressure to give 1,2-diamino4-chloro-5-ethylbenzene (2.70 g, >100%) as a white solid which was used directly without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:28](=[O:34])[C:29]([O:31]CC)=[O:30])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:25])[F:26])[CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:28](=[O:34])[C:29]([OH:31])=[O:30])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3cccc(OC(F)(F)F)c3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3cccc(OC(F)(F)F)c3)cc12
Yield: 56.5 %

Procedure:
1-Benzyl-5-[3-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid was prepared from ethyl {1-benzyl-5-[3-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetate (1.1 g, 2.4 mmol), and potassium hydroxide (0.44 g, 7.8 mmol) in THF (25 mL) and water (25 mL), according to the procedure described in Step 4 of Example 5. Crystallization from methylene chloride/hexane yielded the title compound as a light yellow solid (0.596 g, 54%), mp: 141-142° C. Mass spectrum (+ESI, [M+H]+) M/z 440; 1HNMR (500 MHz, DMSO-d6): δ13.8-14.2 (br s, 1H), 8.75 (s, 1H), 8.45 (s, 1H), 7.7 (m, 2H), 7.6 (t, 3H, J=4.4 Hz), 7.25-7.35 (m, 6H), and 5.65 ppm (s, 2H). Elemental Analysis for C24H16F3NO4: Calculated: C, 65.61; H, 3.67; N, 3.19. Found: C, 65.41; H, 3.39; N, 3.09.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:13][CH:14](C)[C:15](F)(F)F)=[N:5][CH:6]=[C:7]([CH:12]=1)[C:8]([O:10]C)=[O:9])#[N:2].[OH-].[Na+]>CCO>[C:1]([C:3]1[C:4]([O:13][CH2:14][CH3:15])=[N:5][CH:6]=[C:7]([CH:12]=1)[C:8]([OH:10])=[O:9])#[N:2]
Reactant: COC(=O)c1cnc(OC(C)C(F)(F)F)c(C#N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1ncc(C(=O)O)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
To a solution of 498 mg (1.82 mmol) of methyl 5-cyano-6-(2,2,2-trifluoro-1-methylethoxy)nicotinate (from CARBOXYLIC ACID 20, Step C) in 10 mL of EtOH was added 1.8 mL of 5.0 N NaOH. After stirring at rt overnight, the mixture was acidified using Dowex H cation exchange resin until pH=3. The resin was filtered off and the filtrate was concentrated to give 160 mg of the title compound: 1H NMR (500 MHz, CD3OD) δ 1.37 (t, J=7.1, 3H), 4.50 (d, J=7.1, 2H), 8.43 (d, J=2.1, 1H), 8.85 (d, J=2.3, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[N:7][N:6]=1)[CH3:4].[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.C(OC(C)C)(C)C>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[CH2:3]([C:5]1[S:9][C:8](=[N:10][C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])[N:7]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([Br:17])=[CH:19][CH:20]=2)[N:6]=1)[CH3:4]
Reactant: BrCc1ccc(Br)cc1
Reactant: CCc1nnc(NC(=O)C(F)(F)F)s1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCc1nn(Cc2ccc(Br)cc2)c(=NC(=O)C(F)(F)F)s1
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
To a suspension of sodium hydride (4.4 g) in N,N-dimethylformamide (100 ml) was added 5-ethyl-2-trifluoroacetylamino-1,3,4-thiadiazole (24 g) in three portions on ice. After stirring at the same temperature for 30 minutes, to the resulting mixture was added 4-bromobenzyl bromide (25 g), followed by stirring at room temperature for one hour. To the reaction mixture, ethyl acetate (500 ml) was added. The resulting mixture was washed successively with 10% aqueous citric acid solution and water and was dried over anhydrous magnesium sulfate, followed by removal through distillation. The residue so obtained was dispersed in a 2:3 mixed solvent of diisopropyl ether and n-hexane, collected by filtration and then dried, whereby 24.8 g of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:13]C(=O)OC(C)(C)C)[CH2:10][C:11]#[N:12])[CH:5]=[CH:6][C:7]=1[F:8].Cl>O1CCOCC1>[ClH:1].[NH2:13][C@@H:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:10][C:11]#[N:12]
Reactant: CC(C)(C)OC(=O)N[C@H](CC#N)c1ccc(F)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Product: N#CC[C@@H](N)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 145.4 %

Procedure:
To a solution of 226 (0.350 g, 1.17 mmol) in dioxane (5 mL) was added 4N HCl in dioxane (2.93 mL, 11.7 mmol) and stirred for 1 h at RT then concentrated to dryness which afforded 0.2 g (72.6%) of (R)-3-amino-3-(3-chloro-4-fluorophenyl)propanenitrile hydrochloride (228), which was used without further purification.
Reaction SMILES: Cl[C:2]([C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11][C:12](=[O:14])[CH3:13])=[C:6]([CH3:15])[CH:5]=1)=[O:3].[NH2:16][C:17]1[C:22]([C:23](O)=[O:24])=[CH:21][N:20]=[CH:19][CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:10][C:8]1[CH:9]=[C:4]([C:2]2[O:3][C:23](=[O:24])[C:22]3[CH:21]=[N:20][CH:19]=[CH:18][C:17]=3[N:16]=2)[CH:5]=[C:6]([CH3:15])[C:7]=1[O:11][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)Oc1c(C)cc(C(=O)Cl)cc1C
Reactant: Nc1ccncc1C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)cc(-c2nc3ccncc3c(=O)o2)cc1C
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a solution of acetic acid 4-chlorocarbonyl-2,6-dimethylphenyl ester (2.32 g, 10.0 mmol) in anhydrous CH2Cl2 (30 mL) were added 4-amino-nicotinic acid (4) (1.10 g, 8.00 mmol) and pyridine (2.37 g, 30.0 mmol). The reaction mixture was stirred at room temperature under nitrogen for 40 hours. Solvent was evaporated. The residue was diluted with methanol (20 mL). The solid separated was filtered, washed with methanol (2×10 mL) and dried under vacuum to give acetic acid 2,6-dimethyl-4-(4-oxo-4H-pyrido[4,3-d][1,3]oxazin-2-yl)-phenyl ester (6) as yellow solid. Yield: 1.99 g (64%).
Reaction SMILES: [N+:1]([C:4]1[CH:74]=[CH:73][C:7]([CH2:8][CH:9]2[CH2:24][N:23]([CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])[CH2:22][CH2:21][N:20]([CH2:33][C:34]([O:36]C(C)(C)C)=[O:35])[CH2:19][CH2:18][N:17]([CH2:41][C:42]([O:44]C(C)(C)C)=[O:43])[CH2:16][CH2:15][N:14]([CH2:49][C:50]([O:52]C(C)(C)C)=[O:51])[CH2:13][CH2:12][N:11]([CH2:57][C:58]([O:60]C(C)(C)C)=[O:59])[N:10]2[CH2:65][C:66]([O:68]C(C)(C)C)=[O:67])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl>>[N+:1]([C:4]1[CH:74]=[CH:73][C:7]([CH2:8][CH:9]2[CH2:24][N:23]([CH2:25][C:26]([OH:28])=[O:27])[CH2:22][CH2:21][N:20]([CH2:33][C:34]([OH:36])=[O:35])[CH2:19][CH2:18][N:17]([CH2:41][C:42]([OH:44])=[O:43])[CH2:16][CH2:15][N:14]([CH2:49][C:50]([OH:52])=[O:51])[CH2:13][CH2:12][N:11]([CH2:57][C:58]([OH:60])=[O:59])[N:10]2[CH2:65][C:66]([OH:68])=[O:67])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)CN1CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC(Cc2ccc([N+](=O)[O-])cc2)N(CC(=O)OC(C)(C)C)N(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Agent: Cl
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CC(Cc2ccc([N+](=O)[O-])cc2)N(CC(=O)O)N(CC(=O)O)CCN(CC(=O)O)CC1
Yield: 93.4 %

Procedure:
To a 10 ml round-bottomed flask hexa-tert-butyl 2-(4-nitrobenzyl)-1,4,7,10,13,16-hexaazacyclohexadecane-1,4,7,10,13,16-hexaacetate (166 mg, 0.15 mmol) was combined with conc. HCl (5 ml) and heated at reflux for 6 hr. The HCl (aq) was removed by rotary evaporation and the residue was taken up in water (1–2 ml) and was lyophilized to give hexa-acid as a pale yellow solid (100 mg, 70%).
Reaction SMILES: CS(OC1C=CC(/C=[CH:13]/[C:14]([OH:16])=[O:15])=CC=1)(=O)=O.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][C:19]=1[C:26]#[N:27].C(C1C=CC(OS(C)(=O)=O)=CC=1)=O>>[C:26]([C:19]1[CH:20]=[C:21](/[CH:22]=[CH:13]/[C:14]([OH:16])=[O:15])[CH:24]=[CH:25][C:18]=1[F:17])#[N:27]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: CS(=O)(=O)Oc1ccc(/C=C/C(=O)O)cc1
Agent: CS(=O)(=O)Oc1ccc(C=O)cc1
Product: N#Cc1cc(/C=C/C(=O)O)ccc1F

Procedure:
5.52 g of (E)-3-(3-cyano-4-fluorophenyl)acrylic acid was synthesized as described for (E)-3-(4-(methanesulfonyloxy)phenyl)acrylic acid, using 4-fluoro-3-cyanobenzaldehyde (commercially available at Aldrich) instead of methanesulfonic acid 4-formylphenyl ester.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])[S:8]1(=[O:25])=[O:24].[CH:26]1([NH2:30])[CH2:29][CH2:28][CH2:27]1>CO>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:30][CH:26]2[CH2:29][CH2:28][CH2:27]2)[S:8]1(=[O:25])=[O:24]
Reactant: O=S1(=O)N(CCOCCBr)c2ccccc2N1c1c(F)cccc1F
Reactant: NC1CCC1
Solvent: CO
Product: O=S1(=O)N(CCOCCNC2CCC2)c2ccccc2N1c1c(F)cccc1F

Procedure:
In an analogous manner to general procedure V, 1-[2-(2-bromoethoxy)ethyl]-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.1 g, 0.23 mmol) was treated with cyclobutylamine (0.8 mL, 9.2 mmol) in methanol to give N-(2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethoxy}ethyl)cyclobutanamine which was treated with 1N hydrochloric acid in ether to give its hydrochloride salt as a white solid (0.59 g, 56%). HRMS: calcd for C20H23F2N3O3S+H+, 424.15009; found (ESI, [M+H]+Obs'd), 424.1497.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:18])[CH2:12]C(OCC)=O>O.FC(F)(F)C(O)=O.O>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:18])[CH3:12]
Reactant: CCOC(=O)CC(=O)c1cccc([N+](=O)[O-])c1C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)c1cccc([N+](=O)[O-])c1C
Temperature: 25 °C
Yield: 67.5 %

Procedure:
A solution of ethyl 2-methyl-3-nitro-β-oxobenzenepropanoate (10.0 g, 39.7 mmol) in 100 mL of 30% water/trifluoroacetic acid is heated at reflux for 5 hours. The reaction mixture is cooled to room temperature, diluted with water (100 mL), and extracted with ether. The organic layer is washed with water, saturated aqueous sodium bicarbonate, and brine. Evaporation of the organic layer, followed by recrystallization of the residue gives 1-(2-methyl-3-nitrophenyl)ethanone (4.8 g, 67%), mp=49-51° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.Cl.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37]([S:41](Cl)(=[O:43])=[O:42])[CH:36]=1>O1CCCC1.O>[F:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][N:5]([S:41]([C:37]2[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=2)(=[O:43])=[O:42])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1c[nH]c(-c2ccccc2)c1F
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: C1COCCOCCOCCOCCO1
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cn(S(=O)(=O)c2cccnc2)c(-c2ccccc2)c1F
Reaction time: 0.25 h
Yield: 72.9 %

Procedure:
By a similar reaction as in Reference Example 36 and using methyl 4-fluoro-5-phenyl-1H-pyrrole-3-carboxylate (172 mg), the title compound was obtained as a colorless solid (yield 206 mg, 73%). More specifically, to a solution of methyl 4-fluoro-5-phenyl-1H-pyrrole-3-carboxylate (172 mg) in tetrahydrofuran (10 mL) was added sodium hydride (60% in oil, 94 mg), and the mixture was stirred for 15 min. 15-Crown-5 (0.48 mL) was added, and the mixture was further stirred for 15 min. Pyridine-3-sulfonyl chloride hydrochloride (219 mg) was added and the mixture was stirred for 30 min. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→1:1) to give the title compound as a colorless solid (yield 206 mg, 73%).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](Cl)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH3:15][CH:16]([NH2:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>>[Br:1][C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7]([NH:21][CH:16]([CH3:15])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1
Reactant: O=S1(=O)N=C(Cl)Nc2ccc(Br)cc21
Reactant: CC(N)C(C)(C)C
Product: CC(NC1=NS(=O)(=O)c2cc(Br)ccc2N1)C(C)(C)C

Procedure:
Starting from 7-bromo-3-chloro-4H-1,2,4-benzothiadiazine 1,1-dioxide (300 mg; 1.01 mmol) and 1,2,2-trimethylpropylamine (359 mg; 4.04 mmol) with the use of same procedure as in example 21 200 mg (54.9%) of the title compound was prepared; m.p. >220° C.; 1H-NMR (DMSO-d6) ppm; 10.35 (s, 1H, NH), 7.78 (d, 1H, H-8), 7.6 (dd, 1H, H-6), 7.12 (br d, 1H, H-5), 6.95 (br, 1H, NH), 3.72 (q, 1H, CH), 1.10 (d, 3H, CH3), 0.92 (s, 9H, 3×CH3); MS:EI/70eV: 361 (M+1), 304, 277, 236, 170, 116, 90, 44.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C:3]([NH:5][C:6]1[NH:7][C:8](=O)[C:9]2[CH:14]=[CH:13][NH:12][C:10]=2[N:11]=1)=[O:4].O=P(Cl)(Cl)[Cl:20].CN(C)C1C=CC=CC=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[Cl:20][C:8]1[C:9]2[CH:14]=[CH:13][NH:12][C:10]=2[N:11]=[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:17])([CH3:16])[CH3:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)C(=O)Nc1nc2[nH]ccc2c(=O)[nH]1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: CC(C)(C)C(=O)Nc1nc(Cl)c2cc[nH]c2n1
Yield: 69.9 %

Procedure:
A mixture of 2,2-dimethyl-N-(4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-propionamide (210 g, 0.90 mol), POCl3 (828 g, 5.40 mol, 503 mL, 6.0 eq), benzyltriethylammonium chloride (411 g, 1.80 mol), N,N-dimethylaniline (220 g, 231 mL, 1.80 mol), and acetonitrile (2.0 L) was heated to reflux for 40-60 min, monitoring with HPLC. The solvent was evaporated on a rotary evaporator, and the residue was carefully (caution: exothermic and corrosive) and slowly added to ice water (16 L). The pH was adjusted to 7 with solid NaOH, and the resulting precipitate was collected by filtration. Drying afforded the title compound (159 g, 70% yield 70%, HPLC purity 100%). tR: 5.37 min. 1H-NMR (DMSO-d6) δ 12.35 (br. s, 1H), 10.06 (br. S, 1H), 7.54 (q, 1H), 6.52 (q, 1H), 1.25 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:23]=[CH:24][CH:25]=2)[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[O:11])=[CH:4][CH:3]=1.[S-:28][C:29]#[N:30].[K+].BrBr>C(O)(=O)C>[NH2:30][C:29]1[S:28][C:27]2[CH:26]=[C:5]([O:6][C:7]3[CH:8]=[C:9]([CH:23]=[CH:24][CH:25]=3)[C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=3)=[O:11])[CH:4]=[CH:3][C:2]=2[N:1]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(Oc2cccc(C(=O)Nc3ccc(C(F)(F)F)cc3)c2)cc1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(Oc3cccc(C(=O)Nc4ccc(C(F)(F)F)cc4)c3)cc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
To a solution (50 mL) of 3-(4-aminophenoxy)-N-[4-(trifluoromethyl)phenyl]benzamide (3.72 g, 10.0 mmol) in acetic acid was added potassium thiocyanate (3.89 g, 40.0 mmol), and the mixture was stirred at room temperature for 30 min. To the obtained transparent solution was added dropwise bromine (2.40 g, 15.0 mmol) under ice-cooling, and the reaction mixture was stirred at room temperature for 18 hr. The precipitated yellow powder was filtered off through celite, and the filtrate was concentrated under reduced pressure. To the residue was added 0.1N aqueous sodium hydroxide solution and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=1:1), and triturated with diethyl ether to give the title compound (2.93 g, 68%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:22][CH2:21][C:18]3([O:20][CH2:19]3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>CO.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:16][CH2:17][C:18]([CH2:19][NH:26][CH:23]3[CH2:25][CH2:24]3)([OH:20])[CH2:21][CH2:22]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc(N3CCC4(CC3)CO4)cc2)cc1
Reactant: NC1CC1
Solvent: CO
Solvent: CCOC(C)=O
Product: OC1(CNC2CC2)CCN(c2ccc(OCc3ccccc3)cc2)CC1
Yield: 85.8 %

Procedure:
6-[4-(benzyloxy)phenyl]-1-oxa-6-azaspiro[2,5]octane (500 mg, 1.69 mmol) and cyclopropylamine (195 mg, 3.38 mmol) were mixed in methanol, and heated overnight under reflux. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline in that order, and the organic layer was dried with sodium sulfate. The solvent was evaporated off under reduced pressure to obtain a crude product. The resulting crude product was purified through silica gel column chromatography (eluate: methanol/chloroform=1/99 to 6/94) to obtain the entitled compound (511 mg, 85%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:4][N:3]=1.[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH:14]([S:11]([C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[N:3][CH:4]=1)(=[O:13])=[O:12])([CH3:16])[CH3:15]
Reactant: NCC1CCOCC1
Reactant: CC(C)S(=O)(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Product: CC(C)S(=O)(=O)c1cnc(NCC2CCOCC2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from 2-chloro-5-(isopropylsulfonyl)-3-nitropyridine (Step D of Example 22) and 4-aminomethyltetrahydropyran (Apollo Scientific Ltd.).