Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][CH:5]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH:6]1.[OH-].[Na+].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:24][CH2:25]Br)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>C(Cl)Cl.C(N(CC)CC)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:24][CH2:25][N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:5]2[CH2:4][CH2:3][OH:2])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(CCBr)cc1OC
Reactant: OCCC1CCCCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCN2CCCCCC2CCO)cc1OC

Procedure:
2.9 g (0.016 mol) of 2-(2-hydroxyethyl)-hexahydro-azepinehydrochloride are liberated with concentrated sodium hydroxide solution, taken up in methylene chloride and, after drying, evaporated down over magnesium sulphate. The residue is refluxed for 2 hours with 3.9 g (0.016 mol) of 2-(3,4-dimethoxy-phenyl)ethylbromide in 10 ml of triethylamine. After cooling, the reaction mixture is combined with 2 molar sodium hydroxide solution/methylene chloride. The alkaline phase is separated off and extracted twice with methylene chloride and the combined organic phases are dried over magnesium sulphate. The solvent is distilled off in vacuo and the residue is purified by column chromatography over aluminium oxide N (activity II, eluant: methylene chloride). Yield: 3.7 g (75.2% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([CH2:16][C:17]([OH:19])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.C([N:22](CC)CC)C.ClC(OCC(C)C)=O.N.Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([CH2:16][C:17](=[O:19])[NH2:22])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: CCN(CC)CC
Reactant: O=C(O)CC1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)CC1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reaction time: 0.17 h
Yield: 14 %

Procedure:
To a solution of 8-bromo-5-carboxymethyl-5,6-dihydro-1H-pyrrolo[1,2,3-de]quinoxaline-2,3-dione (100 mg, 0.308 mmol)in DMF (2 mL)in the presence of triethylamine (64 μL, 0.461 mmol) was added isobutyl chloroformate (44 μL, 0.338 mmol) at -20° C. After being stirred for 10 min, aqueous 28% ammonia (94 μL, 1.538 mmol) was added at -20° C. The stirring was continued for 30 min at room temperature and 0.1N hydrochloric acid (20 mL) was added. The precipitates formed were collected by filtration, washed with water, and again suspended in aqueous sodium bicarbonate. The suspension was adjusted to pH 7.0 by addition of 1N hydrochloric acid and extracted with 2:1 ethyl acetate/THF. The organic layer was washed with brine, dried over magnesium chloride, and concentrated. The residual solids were rinsed with dichloromethane to give 14 mg of the title compound (14%): mp>300° C.; 1H NMR (270 MHz, DMSO-d6) δ12.10 (bs, 1H), 7.66 (s, 1H), 7.29 (s, 1H), 7.17 (s, 2H), 5.04~5.10 (m, 1H), 2.80 (dm, 1H, J=18 Hz), 2.58 (dm, 1H, J=14 Hz), 2.41 (m, 1H, J=14 Hz), 1.85~2.00 (m, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[C:19]2[C:25]#[C:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>N1C=CC=CC=1.O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[C:19]2[C:25]#[C:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)(=[O:13])=[O:12])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: Nc1ccc2[nH]nc(C#Cc3ccccc3)c2c1
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(C#Cc3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 17 %

Procedure:
2-Methylsulfonyl-N-(3-phenylethynyl-1H-indazol-5-yl)benzenesulfonamide can be obtained in the following way: 0.23 g of 2-methylsulfonylbenzenesulfonyl chloride is added to a solution, at a temperature in the region of 0° C. and under argon, of 0.2 g of 5-amino-3-phenylethynyl-1H-indazole in 3.5 ml of pyridine. The reaction mixture is then stirred for 1.5 hours at 0° C. and then 2 hours at a temperature in the region of 20° C., and is then diluted with 10 ml of water. After settling out, the aqueous phase is washed with 3 times 15 ml of ethyl acetate. The organic extracts are pooled, washed with 3 times 5 ml of water, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 20° C. The residue thus obtained is purified by chromatography under argon pressure (50 kPa), on a cartridge of 25 g of silica (particle size 20-40 μm), eluting with pure dichloromethane then successively with dichloromethane/methanol (99.5/0.5; 99/1 by volume) mixtures. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 20° C. The residue is recrystallized from 5 ml of isopropanol in the presence of 3S black. The crystals are filtered through sintered glass, washed with diisopropyl ether, partially dried, and then dried under reduced pressure (3 kPa) at a temperature in the region of 50° C. for 2 hours. 66 mg of 2-methylsulfonyl-N-(3-phenylethynyl-1H-indazol-5-yl)benzenesulfonamide are obtained in the form of an off-white powder melting at 198° C. (analysis C22H17N3O4S2 % calculated C, 58.52; H, 3.79; N, 9.31; O, 14.17; S, 14.20. % found C, 58.37; H, 3.88; N, 9.11; S, 13.73).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH:11]1([Mg]Br)[CH2:13][CH2:12]1>O1CCCC1>[CH:11]1([C:8]([C:4]2[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=2)([OH:10])[CH3:9])[CH2:13][CH2:12]1
Reactant: CC(=O)c1cccc(O)c1
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: CC(O)(c1cccc(O)c1)C1CC1

Procedure:
By using 3′-hydroxyacetophenone (200 mg) and a 0.5 M solution of cyclopropylmagnesium bromide in tetrahydrofuran (8.8 ml) as starting materials, the title compound (176.6 mg) was obtained in the same manner as that of Reference Example 69.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[Cl:24][C:25]1[C:26]([CH2:32][O:33][C:34]2[CH:39]=[CH:38][NH:37][C:36](=[O:40])[CH:35]=2)=[N:27][CH:28]=[C:29]([Cl:31])[CH:30]=1>>[Cl:24][C:25]1[C:26]([CH2:32][O:33][C:34]2[CH:39]=[CH:38][N:37]([C:2]3[CH:3]=[CH:4][C:5]4[C:6]5[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=5[N:8]([CH3:11])[C:9]=4[CH:10]=3)[C:36](=[O:40])[CH:35]=2)=[N:27][CH:28]=[C:29]([Cl:31])[CH:30]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CCC2
Reactant: O=c1cc(OCc2ncc(Cl)cc2Cl)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ncc(Cl)cc5Cl)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Yield: 66.5 %

Procedure:
tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (150 mg, 0.396 mmol) and 4-((3,5-dichloropyridin-2-yl)methoxy)pyridin-2(1H)-one (107 mg, 0.396 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (150 mg, 66%) as a green oil: ESI MS m/z 569 [M+H]+.
Reaction SMILES: [C:1]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCl>[N:8]1([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10]([NH:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:12]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Yield: 189 %

Procedure:
In a dichloromethane solution containing 5.1 g of N-Boc-hydroxyproline (Boc-Hyp-OH), 0.35 g of tert-butylamine, 7.4 g of HOBt and 6.0 g of EDC hydrochloride were added under ice cooling and the resultant mixture was stirred overnight at room temperature. The reaction mixture was treated similarly to that in Example 144 (Process 2) to give 2.59 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH:8]2[CH2:11][CH2:10][CH2:9]2)[C:6](=[O:12])[NH:5][C:4](=[O:13])[CH:3]=1.Cl.[N:15]([O-])=[O:16].[Na+]>O>[NH2:1][C:2]1[N:7]([CH:8]2[CH2:9][CH2:10][CH2:11]2)[C:6](=[O:12])[NH:5][C:4](=[O:13])[C:3]=1[N:15]=[O:16]
Reactant: O=N[O-]
Reactant: Nc1cc(=O)[nH]c(=O)n1C1CCC1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1c(N=O)c(=O)[nH]c(=O)n1C1CCC1
Reaction time: 3 h

Procedure:
3 g (0.0166 mol) of 6-amino-1-cyclobutyl-2,4-(1H,3H)-pyrimidinedione (VIII), was suspended in 25 ml water. To this was added 4 ml of 5N HCl and 1.3 g of NaNO2 (0.019 mol) which was dissolved in water. The reaction mixture was stirred for 3 hours and the red crystals were filtered off and washed with water. Yield 3.1 g (89%) (IX) NMR.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([N:13]([CH3:15])[NH2:14])[CH:4]=1.[CH3:18][CH:19]([CH3:23])[C:20](=O)[CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[F:17][C:2]([F:16])([F:1])[C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:12])[F:11])[N:6]=[C:5]([N:13]([CH3:15])[N:14]=[C:20]([CH:19]([CH3:23])[CH3:18])[CH3:21])[CH:4]=1
Reactant: CN(N)c1cc(C(F)(F)F)cc(C(F)(F)F)n1
Reactant: CC(=O)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=NN(C)c1cc(C(F)(F)F)cc(C(F)(F)F)n1)C(C)C

Procedure:
A solution of 1-[4,6-bis[trifluoromethyl]pyrid-2-yl]-1-methyl hydrazine (40.04 g; 0.15 mol), 3-methyl-2-butanone (14.2 g; 0.165 mol) and p-toluenesulphonic acid (0.32 g) in toluene (90 ml) was heated under reflux, with water removal (azeotrope), for 40 h. The solution was concentrated to yield a dark oil which was purified by flash-chromatography over silica (eluent: petroleum ether 60/80) to yield 3-methyl-2-butanone 1-[4,6-bis[trifluoromethyl]pyrid-2-yl]-1-methyl hydrazone as a red oil (10.9 g; 22%). ##STR26##
Reaction SMILES: C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:2].[Cl:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][N:16]=1.OO.NC(N)=O>C(Cl)Cl>[Cl:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][N+:16]=1[O-:2]
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: NC(N)=O
Agent: OO
Solvent: ClCCl
Product: O=[N+]([O-])c1cc[n+]([O-])c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
TFAA (6.15 ml, 43.5 mmol) was slowly added to a solution of 2-chloro-4-nitropyridine (3.45 g, 21.76 mmol) and urea hydrogen peroxide (4.30 g, 45.7 mmol) in CH2Cl2 at 0° C. under N2. The reaction was stirred for 30 min and then allowed to warm up to RT for 4 h. NH3 gas was bubbled into the mixture for 5 min and then the organic layer was washed with sat. NaHCO3, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel eluted with 0-2% 2M NH3 solution of MeOH in CH2Cl2 to give the product as a light-yellow solid (3.59 g, 95%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.39 (1H, d) 8.36 (1H, d) 8.04 (1H, dd). LCMS: m/z 175 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:17]=[CH2:18])=[N:4][CH:5]=[C:6]([CH2:8][O:9][Si](C(C)(C)C)(C)C)[CH:7]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[N:4][C:3]=1[CH:17]=[CH2:18]
Reactant: C=Cc1ncc(CO[Si](C)(C)C(C)(C)C)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=Cc1ncc(CO)cc1Cl
Yield: 95.9 %

Procedure:
A solution of 3-chloro-5-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-ethenylpyridine (707 mg, 2.491 mmol) and TBAF (3.74 ml, 3.74 mmol) in THF (20 ml) was stirred at room temperature overnight. The mixture was concentrated and purified by flash chromatography using Flashmaster II, a 68 g Merck silica gel cartridge, and mixtures of DCM and MeOH as eluent to afford (5-chloro-6-ethenyl-3-pyridinyl)methanol (405 mg, 94%).
Reaction SMILES: [N+:1]([C:4]1[CH:44]=[CH:43][CH:42]=[CH:41][C:5]=1[CH2:6][O:7][C:8](=[O:40])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[C:22]([C:33]([O:35]C(C)(C)C)=[O:34])[CH:23]=[C:24]([CH:32]=1)[C:25]([O:27]C(C)(C)C)=[O:26])([O-:3])=[O:2].FC(F)(F)C(O)=O>C(Cl)Cl>[N+:1]([C:4]1[CH:44]=[CH:43][CH:42]=[CH:41][C:5]=1[CH2:6][O:7][C:8](=[O:40])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:32]=[C:24]([C:25]([OH:27])=[O:26])[CH:23]=[C:22]([CH:21]=1)[C:33]([OH:35])=[O:34])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCCC(=O)OCc2ccccc2[N+](=O)[O-])cc(C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCCCCCCCCCOc1cc(C(=O)O)cc(C(=O)O)c1)OCc1ccccc1[N+](=O)[O-]

Procedure:
The previously prepared compound, di-tert-butyl 5-(11-(2-nitrobenzyloxy)-11-oxoundecyloxy)isophthalate, was dissolved in CH2Cl2 (10 mL) producing a yellow solution. Trifluoroacetic acid (TFA) (10 mL) was slowly added while stirring. The solution was stirred at room temperature for 1 hour. The solvent was removed by rotovap producing a white solid, which was washed four times with CH2Cl2 and dried under vacuum. A white power was produced. Yield: 0.127 g (100%). 1H-NMR (DMSO-d6) δ (ppm): 13.3 (s, 2H, OH), 8.1 (d, 1H, Ar), 8.0 (s, 1H, Ar), 7.8 (t, 1H, Ar), 7.7 (d, 1H, Ar), 7.6 (t, 11H, Ar), 7.6 (s, 2H, Ar), 5.4 (s, 2H, O—CH2), 4.0 (t, 2H, CH2—O), 2.4 (t, 2H, CH2—C═O), 1.7 (m, 2H, CH2), 1.5 (m, 2H, CH2), 1.4 (m, 2H, CH2), 1.2 (m, 10H, CH2). 13C-NMR (DMSO-d6) δ (ppm): 172.8, 166.7, 159.1, 147.8, 134.4, 132.9, 131.8, 129.9, 129.7, 125.2, 122.4, 119.3, 68.4, 62.6, 33.6, 29.2, 29.1, 29.0, 28.9, 28.8, 28.7, 25.7, 24.7. MS (ESI): (M)=500.4 (calc. 501.53).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20]Br>>[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][O:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1
Reactant: N#Cc1ccc(O)cc1F
Reactant: COC(=O)c1ccccc1CBr
Product: COC(=O)c1ccccc1COc1ccc(C#N)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 40, intermediate e, from 2-fluoro-4-hydroxy-benzonitrile (CAS Reg. No. 82380-18-5) and 2-bromomethyl-benzoic acid methyl ester (CAS Reg. No. 2417-73-4). Off-white solid (91%). MS (Turbo Spray): m/z=286.1 (M+H).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:25]([CH3:33])([CH2:26][CH2:27][C:28]=32)[C@@H:18]([C@H:19]([CH3:24])[CH2:20][CH2:21][CH2:22][NH2:23])[CH2:17][CH:16]=4)[C:10]1([CH3:35])[CH3:34])(C(C)(C)C)(C)C.Cl.[CH2:37]([OH:39])[CH3:38]>N1C=CC=CC=1.C(OC(=O)C)(=O)C>[CH3:35][C:10]1([CH3:34])[C@@H:9]([OH:8])[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@H:11]1[CH2:12][CH2:13][C:14]1[C:15]3[C@:25]([CH3:33])([CH2:26][CH2:27][C:28]=12)[C@@H:18]([C@H:19]([CH3:24])[CH2:20][CH2:21][CH2:22][NH:23][C:37](=[O:39])[CH3:38])[CH2:17][CH:16]=3
Reactant: C[C@H](CCCN)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Reactant: CCO
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NCCC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethyl-24-amino-5α-chola-8,14-diene (0.50 g) is acetylated in a mixture of 20 ml of pyridine and 7 ml of acetic anhydride and hydrolysed with HCl/ethanol. After aqueous work-up and crystallisation from ethanol/water, the title compound (0.24 g) is isolated. Melting point: 219-221° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12](F)[CH:11]=[C:10]([F:18])[CH:9]=1)[CH3:2].C(N(CC)CC)C.[CH2:28]([NH2:32])[CH2:29][CH2:30][CH3:31]>CN(C=O)C>[CH2:28]([NH:32][C:12]1[CH:11]=[C:10]([F:18])[CH:9]=[C:8]([O:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:19][CH3:20])[CH2:1][CH3:2])[C:13]=1[N+:14]([O-:16])=[O:15])[CH2:29][CH2:30][CH3:31]
Reactant: CCN(CC)CCCOc1cc(F)cc(F)c1[N+](=O)[O-]
Reactant: CCCCN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCNc1cc(F)cc(OCCCN(CC)CC)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a stirred solution of 6-(3-diethylaminopropoxy)-2,4-difluoronitrobenzene (11 mmol) and triethylamine (22 mmol) in DMF (20 mL), a solution of n-butylamine (11 mmol) in DMF (8 mL) was added dropwise at rt, and the mixture was stirred at rt for 10 h. The reaction was quenched by cold H2O (50 mL), and the resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with brine (3×50 mL) and dried (anhydrous Na2SO4). The solvent was removed in vacuo to afford the desired 2-n-butylamino-6-(3-diethylaminopropoxy)-4-fluoronitrobenzene which was used for further transformation.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[C:11]([CH2:23][OH:24])[C:10]=2[CH2:25][OH:26])[CH:4]=1.S(C1C=CC(C)=CC=1)(O[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=O)=O.O>CN(C)P(=O)(N(C)C)N(C)C>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[C:11]([CH2:23][O:24][CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:10]=2[CH2:25][OH:26])[CH:4]=1
Reactant: COc1cc2cc(CO)c(CO)c(-c3cccnc3)c2cc1OC
Reactant: Cc1ccc(S(=O)(=O)OCC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cc2cc(COCC(C)(C)C)c(CO)c(-c3cccnc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride in hexamethylphosphoric triamide (40 ml) is added a solution of 1-(3-pyridyl)-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene in hexamethylphosphoramide (10 ml) under ice-cooling. The mixture is warmed to room temperature, and then stirred for 30 minutes. To the reaction solution is added neo-pentyl tosylate (3.67 g), and the mixture is reacted at 100° C. for 30 minutes. The mixture is allowed to cool, and thereto is added water, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried, and concentrated. The resulting residue is subjected to silica gel column chromatography (eluent; chloroform:acetone=5:1), and the desired fractions are concentrated to give 1-(3-pyridyl)-2-hydroxymethyl-3-neo-pentyloxymethyl-6,7-dimethoxynaphthalene (1.5 g) as an oily product.
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)(O)[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C(N(S(F)(F)[F:32])CC)C>C(Cl)Cl>[F:32][C:15]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)([CH3:16])[CH2:14][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:25][CH2:24][C:5]1=2
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccncc2)CCN(C)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(C)(F)c2ccncc2)CCN(C)C1
Temperature: 2.5 °C

Procedure:
1-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-4-yl)propan-2-ol (150 mg) was dissolved in DCM (10 mL) and the solution was cooled to 0 to 5° C. Diethylaminosulfur trifluoride (0.15 mL) was added and the reaction mixture was allowed to warm to RT for 30 min. The reaction mixture was quenched with saturated aqueous sodium bicarbonate, the organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by HPLC.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:13]Br>C(O)(=O)C.C(O)(C(F)(F)F)=O>[Br:13][C:3]1[CH:4]=[CH:5][C:6]2[NH:7][C:8](=[O:12])[O:9][CH2:10][C:11]=2[C:2]=1[CH3:1]
Reactant: Cc1cccc2c1COC(=O)N2
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Br)ccc2c1COC(=O)N2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 5-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.695 g, 4.3 mmol) in acetic acid (5 mL), Br2 (0.805 g=5 mmol) solution in TFA (5 mL)+acetic acid (5 mL) was added at 10° C. Reaction mixture was stirred for 2 hours and poured over ice water. Yellow precipitate was filtered and dried at 120° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([NH2:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[CH:12](OCC)=[O:13]>>[CH:12]([NH:8][CH:6]1[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3][C:2]([CH3:11])([CH3:1])[CH2:7]1)=[O:13]
Reactant: CCOC=O
Reactant: CC1(C)CC(N)CC(C)(C)N1
Product: CC1(C)CC(NC=O)CC(C)(C)N1

Procedure:
78 g of 2,2,6,6-tetramethyl-4-aminopiperidine in 250 ml of ethyl formate were refluxed for 10.5 hours. The precipitate which separated out was filtered off under suction, washed with a little petroleum ether and recrystallized from toluene. 4-(Formylamino)-2,2,6,6-tetramethylpiperidine was isolated as a colorless solid of melting point 153° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].[C:11](OC(=O)C)(=O)C>>[CH3:3][C:2]1[C:1](=[O:4])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CC(=O)OC(C)=O
Reactant: CCC(=O)c1ccccc1
Product: CC1=Cc2ccccc2C1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 375.4 %

Procedure:
A mixture of propiophenone (30 g, 223.6 mmol) hexamethylenetetramine (HMTA) (43.8 g, 313 mmol) and acetic anhydride (41 g, 402 mmol) was heated at 80° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to 30° C. and quenched into a stirred mixture of methylene chloride (200 ml) and sodium hydroxide (200 of 2N solution). The organic layer was separated and washed with aqueous HCl (100 ml of 1N solution). The methylene chloride solution containing the product, 2-methyl-1-phenyl-prop-2-en-1-one was azeotropically dried by distilling CH2Cl2 to approximately 50 ml volume and was directly used in the next step without any further operation. The CH2Cl2 solution was added to concentrated H2SO4 (130 ml) at such a rate that the reaction temperature was maintained between 50°-60° C. The CH2Cl2 was removed by distillation and nitrogen sweep as soon as it was added. The reaction mixture was stirred at 50°-60° C. for one hour, cooled to 20° C. and quenched into a stirred mixture of methylene chloride (200 ml) and water (200 g). After separating the aqueous layer, the organic layer was concentrated in the rotary evaporator to produce 121 g (82%) of 2-methyl-inden-1-one (Example 1, Table 1).
Reaction SMILES: [F:1][C:2]1([F:44])[CH2:7][C@H:6]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([N:19](CC3C=CC(OC)=CC=3OC)[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:4][CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:44][C:2]1([F:1])[CH2:7][C@H:6]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C)c(O[C@H]3CC(F)(F)CC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@H]1CC(F)(F)CC[C@@H]1c1ccnn1C
Yield: 53.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S,2R)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide (198 mg, 0.313 mmol) prepared in Example 137a, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (80 mg, 53%) as a colorless solid.