Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH3:15])[C:9](=[O:14])[O:10][CH:11](Cl)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([O:30][C:31]1[O:35][C:34]([C:36]([OH:38])=[O:37])=[CH:33][CH:32]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].O.O.O.O.O.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[I-].[Na+]>CN(C)C=O>[CH2:16]([O:30][C:31]1[O:35][C:34]([C:36]([O:38][CH:11]([O:10][C:9](=[O:14])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:15])[CH3:12])=[O:37])=[CH:33][CH:32]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CC(Cl)OC(=O)N(C)Cc1ccccc1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OC(C)OC(=O)N(C)Cc2ccccc2)o1
Temperature: 60 °C
Reaction time: 14 h
Yield: 43 %

Procedure:
The above prepared 1-chloroethyl benzyl(methyl)carbamate was dissolved in N,N-dimethylformamide (5 mL) and then 5-(tetradecyloxy)furan-2-carboxylic acid (0.180 g, 0.544 mmol), tetrabutylammonium hydroxide pentahydrate (0.209 g, 0.60 mmol), and sodium iodide (˜15 mg) were added to the reaction vessel. The resulting suspension was heated to 60° C. with stirring for 14 hrs. HPLC analysis of the reaction solution indicated that all of the starting material had been converted to a product of lower polarity. The reaction was then quenched with brine (5 mL), water (5 mL) and EtOAc (70 mL). The organic phase was washed successively with water (30 mL) and brine (30 mL) and then dried and concentrated. The resulting crude material was purified by flash chromatography eluting with EtOAc in hexanes, 5-20% to yield 0.120 g (43%) of the title compound as a slightly brown oil. 1H NMR (300 MHz, CDCl3) δ: 7.15-7.40 (m, 6H), 7.05 (p, 1H), 5.30 (d, 1H), 4.40-4.60 (m, 2H), 4.10 (t, 2H), 2.85 (d, 3H) 1.7-1.9 (m, 2H), 1.79 (p, 2H), 1.55-1.62 (m, 3H), 1.18-1.50 (m, 22H), 0.89 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([Cl:16])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>N1C=CC=CC=1>[Cl:16][C:10]1[CH:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:25]([C:22]3[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=3)(=[O:27])=[O:26])[CH:7]=[N:6][CH:5]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccc(-c2cncc(N)c2)cc1Cl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2cncc(-c3ccc(C#N)c(Cl)c3)c2)cc1
Yield: 43.1 %

Procedure:
According to General Sulfonylation Procedure 2 in Example 1, to a solution of 4-(5-amino-pyridin-3-yl)-2-chloro-benzonitrile (20 mg, 87 μmol, leg) in anhydrous pyridine (500 μl) was added 4-methoxy-benzenesulfonyl chloride (19.8 mg, 96 μmol, 1.1 eq). The crude product was purified by Isco Cornbiflash® Companion™ flash chromatography system on normal phase (4 g SiO2, flow rate 18 mL/min), eluting with mixtures of dichloromethane/methanol, to give N-[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-4-methoxy-benzenesulfonamide (15 mg, >95% purity, yield: 43%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]=O>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C@@H:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17](=[O:19])[O:18][CH2:20]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1COC(=O)[C@@H]1Cc1ccccc1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
Tert-butoxycarbonyl-L-phenylalanine (20.00 g), paraformaldehyde (6.04 g) and pyridinium p-toluenesulfonate (0.95 g) were added to toluene (200 ml), and they were stirred under heating and reflux for 30 minutes. The reaction mixture was cooled to room temperature and washed with a saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The obtained toluene layer was dried over anhydrous sodium sulfate and then sodium sulfate was removed. The solvent was evaporated under reduced pressure. The concentrated solution was cooled to room temperature to crystallize the product. The crystals were separated and dried to obtain intended (4S)-N-tert-butoxycarbonyl-4-phenylmethyloxazolidin-5-one (15.10 g) (yield: 72%). 1H-NMR(CDCl3, 300 MHz) δ ppm: 1.51 (9H, s), 3.15 (d, 1H), 3.20-3.52 (m, 1H), 4.13-4.38 (m, 1H), 4.49 (bs, 1H), 5.06-5.38 (m, 1H), 7.12-7.22 (m, 2H), 7.22-7.35 (m, 3H)
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1.Br[CH:17]([CH3:31])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)=[O:19]>O1CCOCC1.CN(C=O)C>[N:7]1([CH:17]([CH3:31])[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)=[O:19])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: CC(Br)C(=O)Nc1cccc(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(C(=O)Nc1cccc(C(F)(F)F)c1)n1cnc2ccccc21
Reaction time: 4 h
Yield: 60 %

Procedure:
A solution of potassium tert-butoxide (0.25 mL of 1 M solution in THF, 0.25 mmol) was added to a solution of 1H-benzoimidazole (30 mg, 0.25 mmol) in anhydrous dioxane (10 mL) and anhydrous DMF (1 mL) under argon at ambient temperature. The mixture was stirred for 5 min before a solution of bromo-N-(3-trifluoromethyl-phenyl)-propionamide (59 mg, 0.2 mmol) in anhydrous dioxane (3 mL) was added. The mixture was stirred for 4 h, filtered and concentrated in vacuum. The crude product was purified on a preparative HPLC (XTerra C8 column 19×300 mm, 0.1 M aqueous NH4Ac/CH3CN). Product-containing fractions were pooled and lyophilized to afford 40 mg (60%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.8 (d, J=7.1 Hz, 3H), 5.1 (q, J=7.4 Hz, 1 H), 7.2 (m, 4 H), 7.4 (d, J=7.1 Hz, 1H), 7.5 (m, 2H,) 7.7 (m, 1H), 7.9 (s, 1H), 1/02 (s, 1 H).
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1.[H-].[Na+].O>CN(C)C=O>[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:13][CH2:12]1
Reactant: CN1CCC(O)CC1
Reactant: N#Cc1cccnc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC(Oc2ncccc2C#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
To a mixture of 2-fluoro-nicotinonitrile (400 mg, 3.3 mmol) and 1-methyl-piperidin-4-ol (380 mg, 3.3 mmol) in N,N-dimethylformamide (30 mL) was added NaH (60%) (160 mg, 4.0 mmol) in portions. The reaction was stirred overnight at rt. The mixture was poured into water, and extracted with ethyl acetate (2×). The solvent was removed, and the resulting residue was chromatographed using ethyl acetate/methanol (8:1) to give the title compound (210 mg, 29%). MS (DCI/NH3) m/z 218 (M+1)+
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[S:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.CN(C)[CH:41]=[O:42]>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[F:27][C:21]1[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=1[CH:9]([S:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=1)[C:5]1[C:6]([CH3:8])=[CH:7][C:2]([CH:41]=[O:42])=[N:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: CCOc1ccc(SC(c2cnc(Br)cc2C)c2cc(F)ccc2F)cc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1ccc(SC(c2cnc(C=O)cc2C)c2cc(F)ccc2F)cc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
To a solution of 2-bromo-5-[(2,5-difluorophenyl)[(4-ethoxyphenyl)thio]methyl]-4-methylpyridine (1.18 g, 2.62 mmol) in toluene (30 ml), a hexane solution of n-butyllithium (1.54 M, 2.04 ml, 3.14 mmol) was added in an argon atmosphere at −78° C. The reaction mixture was stirred for 30 minutes at −40° C., and then cooled again to −78° C., and N,N-dimethylformamide (0.243 ml, 3.14 mmol) was added thereto. After completion of dropwise addition, the reaction mixture was allowed to warm to −40° C., and water was added at the same temperature. Ethyl acetate was added to the reaction mixture, the organic layer was separated, and then the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=10:1 was concentrated under reduced pressure to obtain the title compound (786 mg, 1.97 mmol, 75%) as a white solid.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:27](O)[C@H:28]([C@H:30]([C@@H:32]([C@@H:34]([CH2:36][OH:37])[OH:35])[OH:33])[OH:31])[OH:29].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:27][CH:28]([OH:29])[CH:30]([OH:31])[CH:32]([OH:33])[CH:34]([OH:35])[CH2:36][OH:37])=[O:23])=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)C(O)C(O)C(O)CO)cc1

Procedure:
In the manner described in Example 7, 3.62 g. of 4-(n-hexadecylamino)benzoic acid, 1.82 g. of mannitol, and 2.06 g. of p-toluene sulfonic acid are reacted to yield a mixture of mono- and bis-acylated products. Pure 2,3,4,5,6-pentahydroxyhexyl 4-(n-hexadecylamino)benzoate is separated from the mixture by adsorption chromatography using silica gel as the adsorbant.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[NH:17][CH:16]=[C:15]([CH:18]=[O:19])[CH:14]=1)(=[O:6])=[O:5].C1OCCOCCOCCOCCOC1.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37]([S:41](Cl)(=[O:43])=[O:42])[CH:36]=1>>[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:17]([S:41]([C:37]2[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=2)(=[O:43])=[O:42])[CH:16]=[C:15]([CH:18]=[O:19])[CH:14]=1)(=[O:6])=[O:5]
Reactant: CS(=O)(=O)c1ccccc1-c1cc(C=O)c[nH]1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: CS(=O)(=O)c1ccccc1-c1cc(C=O)cn1S(=O)(=O)c1cccnc1

Procedure:
By a similar operation as in Reference Example 154 and using sodium hydride (60% in oil, 40 mg), 5-[2-(methylsulfonyl)phenyl]-1H-pyrrole-3-carbaldehyde (88.9 mg), 15-crown-5 (94.4 mg) and pyridin-3-ylsulfonyl chloride (69.7 mg), the title compound was obtained as a colorless amorphous form (yield 72.0 mg, 52%).
Reaction SMILES: [C-]#N.[K+].C([O-])(O)=O.[Na+].[C:9]([C:13]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][CH2:28][N:29]3[CH:34]=[C:33]([CH3:35])[C:32]([SH:36])=[N:31][C:30]3=[O:37])[CH2:21][CH2:20]2)[CH:16]=[C:15]([C:38]([F:41])([F:40])[F:39])[N:14]=1)([CH3:12])([CH3:11])[CH3:10].C1OCCOCCOCCOCCOCCOC1.Br[C:61]#[N:62]>C(Cl)Cl>[C:9]([C:13]1[N:18]=[C:17]([N:19]2[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][CH2:27][CH2:28][N:29]3[CH:34]=[C:33]([CH3:35])[C:32]([S:36][C:61]#[N:62])=[N:31][C:30]3=[O:37])[CH2:23][CH2:24]2)[CH:16]=[C:15]([C:38]([F:40])([F:41])[F:39])[N:14]=1)([CH3:10])([CH3:11])[CH3:12]
Reactant: Cc1cn(CCCCN2CCN(c3cc(C(F)(F)F)nc(C(C)(C)C)n3)CC2)c(=O)nc1S
Reactant: N#CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])O
Agent: [C-]#N
Solvent: ClCCl
Product: Cc1cn(CCCCN2CCN(c3cc(C(F)(F)F)nc(C(C)(C)C)n3)CC2)c(=O)nc1SC#N

Procedure:
A solution of KCN (325.6 mg, 5.0 mmol) in 5% strength NaHCO3 solution (7 ml) was added to 484.6 mg (1.0 mmol) of 1-(4-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-4-mercapto-5-methylpyrimidin-2(1H)-one from Example 2 in 20 ml of methylene chloride. Then a mixture of 2.0 mg of 18-crown-6 and 105.9 mg (1.0 mmol) of BrCN, in the minimum amount of methylene chloride necessary to dissolve, was added dropwise at 0° C. The organic phase was then separated off and washed twice with saturated aqueous brine. The organic phase was dried over Na2SO4 and filtered to remove the desiccant, and the solvent was evaporated to dryness in vacuo; yield: 420.0 mg. 1-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-5-methyl-2-oxo-1,2-dihydropyrimidin-4-yl thiocyanate was employed without additional purification in the next step.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:24][CH2:25][CH2:26][CH2:27]Br.[NH4+].[Cl-]>CN(C=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:15]3([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:9]=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[CH2:2][CH2:3]1
Reactant: BrCCCCBr
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])c(OCC2CC2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccc([N+](=O)[O-])c(OCC3CC3)c2)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.5 %

Procedure:
Ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (0.5 g) was dissolved in 10 mL anhydrous DMF and NaH (60% wt. in oil, 0.13 g, mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at 25° C. and 1,4-dibromobutane (0.24 g, mmol) was added drop wise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO4, filtered and concentrated under reduced pressure to give ethyl 1-(3-(cyclopropylmethoxy)-4-nitrophenyl)cyclopentanecarboxylate (380 mg) as a colorless oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:25])([CH3:24])[C@@H:11]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH:12]=[O:13])(=[O:7])=[O:6].CC(C)=[O:28]>>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:25])([CH3:24])[C@@H:11]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:12]([OH:28])=[O:13])(=[O:7])=[O:6]
Reactant: COc1ccc(CO[C@@H](C=O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Reactant: CC(C)=O
Product: COc1ccc(CO[C@@H](C(=O)O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Yield: 96 %

Procedure:
Following the general procedure for the oxidation of aldehydes to carboxylic acids of Description 13, (3R)-3-[(4-methoxyphenyl)methoxy]-2,2-dimethyl-4-oxobutyl (3-chloropropyl)sulfonate (13b) (2.0 g, 5.1 mmol) dissolved in 30 mL of acetone was reacted with 2.6 mL of Jones-reagent (2.0 M in water). After work-up, 2.0 g (96% yield) of the title compound (13) was obtained as a colorless oil. 1H NMR (400 MHz, CDCl3): δ=1.09 (s, 3H), 1.10 (s, 3H), 2.28-2.35 (m, 2H), 3.27-3.31 (m, 2H), 3.66-3.69 (m, 2H), 3.82 (s, 3H), 3.88 (s, 1H), 4.02 (d, J=9.2 Hz, 1H), 4.19 (d, J=9.2 Hz, 1H), 4.45 (d, J=10.8 Hz, 1H), 4.60 (d, J=10.8 Hz, 1H), 6.90 (d, J=8.8 Hz, 2H), 7.28 (d, J=8.8 Hz, 2H) ppm. MS (ESI) m/z 430.90 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][CH2:12][OH:13].[Br:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][CH2:19][N:20]2[C:25](=[O:28])[CH2:26]Cl>C1COCC1.C(=O)(O)[O-].[Na+]>[Br:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][CH2:19][N:20]2[C:25](=[O:28])[CH2:26][O:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH3:10])[C:4]=1[CH3:3]
Reactant: O=C(CCl)N1CCCc2c(Br)cccc21
Reactant: Cc1cccc(CCO)c1C
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(CCOCC(=O)N2CCCc3c(Br)cccc32)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 11.2 %

Procedure:
To a suspension of sodium hydride (35.1 mg, 1.46 mmol) in anhydrous THF (3.0 mL) under nitrogen was added 2-(2,3-dimethylphenyl)ethanol (220 mg, 1.46 mmol). The reaction mixture was stirred at room temperature for 15 min and then a solution of 1-(5-bromo-3,4-dihydroquinolin-1(2H)-yl)-2-chloroethanone (352 mg, 1.22 mmol) in anhydrous THF (3.0 mL) was added. The resulting mixture was stirred at room temperature for 18 h. After this time, the reaction mixture was diluted with saturated sodium bicarbonate (55 mL) and then extracted with ethyl acetate (60 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was purified by preparative HPLC (PHENOMENEX® Axia Luna, 5μ, C18, 30×250 mm; 25 min gradient from 80% A:20% B to 0% A:100% B and 5 min 100% B (A=90% H2O/10% MeOH+0.1% TFA); (B=90% MeOH/10% H2O+0.1% TFA); detection at 220 nm) to afford the title compound (55 mg, 11% yield) as white powder. LCMS, [M+H]+=402.1. 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J=8.0 Hz, 1H), 7.30 (br. s, 1H), 7.02-6.96 (m, 4H), 4.20 (s, 2H), 3.74-3.69 (m, 2H), 3.66 (t, J=7.4 Hz, 2H), 2.92 (t, J=7.4 Hz, 2H), 2.78 (t, J=6.9 Hz, 2H), 2.24 (s, 3H), 2.18 (s, 3H), 1.99-1.90 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[CH:25]1([C:31](O)=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:31]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:32])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@H]3CCCN3)c2c1N
Reactant: O=C(O)C1CCCCC1
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H]3CCCN3C(=O)C3CCCCC3)c2c1N

Procedure:
Prepared as in Example 24a from (R)-ethyl 4-amino-2-methyl-5-(pyrrolidin-2-ylmethoxy)-quinoline-3-carboxylate (Example 92b) and cyclohexanecarboxylic acid as brown solid (39%). MS 440 (MH+).
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[NH:18]2)=[C:9]1[CH3:28])(C)(C)C.Cl[CH2:31][C:32]1[N:33]=[C:34]([CH3:37])[S:35][CH:36]=1>>[CH3:28][C:9]1[N:8]([CH2:7][C:6]([OH:5])=[O:29])[C:16]2[C:11]([C:10]=1[CH:17]1[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[N:18]1[CH2:31][C:32]1[N:33]=[C:34]([CH3:37])[S:35][CH:36]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2ccccc2n1CC(=O)OC(C)(C)C
Reactant: Cc1nc(CCl)cs1
Product: Cc1nc(CN2C(c3c(C)n(CC(=O)O)c4ccccc34)c3ccccc3S2(=O)=O)cs1

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 3, step c) and 4-chloromethyl-2-methyl-thiazole. 1H NMR (DMSO-d6) δ 13.04 (bs, 1H), 8.00 (d, J=8.7 Hz, 1H), 7.66-7.58 (m, 2H), 7.37 (d, J=8.1 Hz, 1H), 7.19 (s, 1H), 7.08 (d, J=6.3 Hz, 1H), 7.01 (t, J=7.8 Hz, 1H), 6.87-6.76 (m, 2H), 6.18 (s, 1H), 5.00 (s, 2H), 4.51 (d, J=16.2 Hz, 1H), 3.92 (d, J=16.2 Hz, 1H), 2.58 (s, 3H), 2.31 (s, 3H); MS: ESI (negative): 466 (M−H).
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([NH2:12])=[CH:7][CH:8]=2)[CH2:3]1.Cl[C:14]1[N:19]=[C:18]2[N:20]([CH3:34])[C:21](=[O:33])[N:22]([C:25]3[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:32])[C:23](=[NH:24])[C:17]2=[CH:16][N:15]=1.ClC1N=C2NC(=O)N(C3C(Cl)=CC=CC=3Cl)C(=N)C2=CN=1>>[Cl:31][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:32])[C:25]=1[N:22]1[C:23](=[NH:24])[C:17]2[C:18](=[N:19][C:14]([NH:12][C:6]3[CH:5]=[C:4]4[C:9]([CH2:10][CH2:11][N:2]([CH3:1])[CH2:3]4)=[CH:8][CH:7]=3)=[N:15][CH:16]=2)[N:20]([CH3:34])[C:21]1=[O:33]
Reactant: CN1CCc2ccc(N)cc2C1
Reactant: Cn1c(=O)n(-c2c(Cl)cccc2Cl)c(=N)c2cnc(Cl)nc21
Agent: N=c1c2cnc(Cl)nc2[nH]c(=O)n1-c1c(Cl)cccc1Cl
Product: CN1CCc2ccc(Nc3ncc4c(=N)n(-c5c(Cl)cccc5Cl)c(=O)n(C)c4n3)cc2C1

Procedure:
28 mg of the entitled compound was obtained as a white solid according to the same method as in Example 2, for which, however, 2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine was used in place of 2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine in Example 2, and 7-chloro-3-(2,6-dichlorophenyl)-4-imino-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one obtained in Production Example 7 was used in place of 7-chloro-3-(2,6-dichlorophenyl)-4-imino-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[CH:2]1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C.[Si:46]([O:53][C:54]1[CH:55]=[C:56]([NH:61][C:62]([O:64][CH2:65][CH:66]2[CH2:71][CH2:70][N:69]([C:72]3[CH:77]=[CH:76][N:75]=[CH:74][CH:73]=3)[CH2:68][CH2:67]2)=[O:63])[C:57]([NH2:60])=[CH:58][CH:59]=1)([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47].C(=O)([O-])O.[Na+]>C(Cl)Cl.CN(C)C=O>[Si:46]([O:53][C:54]1[CH:55]=[C:56]([NH:61][C:62]([O:64][CH2:65][CH:66]2[CH2:71][CH2:70][N:69]([C:72]3[CH:73]=[CH:74][N:75]=[CH:76][CH:77]=3)[CH2:68][CH2:67]2)=[O:63])[C:57]([NH:60][C:10]([C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[CH:2][NH:1]3)=[CH:5][CH:6]=2)=[O:12])=[CH:58][CH:59]=1)([C:49]([CH3:52])([CH3:50])[CH3:51])([CH3:48])[CH3:47]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)c(NC(=O)OCC2CCN(c3ccncc3)CC2)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(NC(=O)c2ccc3cc[nH]c3c2)c(NC(=O)OCC2CCN(c3ccncc3)CC2)c1
Reaction time: 0.17 h
Yield: 41.7 %

Procedure:
A mixture of indole-6-carboxylic acid (71 mg, 0.44 mmol), bromotris(pyrrolidino)phosphonium hexafluorophosphate (204 mg, 0.44 mmol) and diisopropylethylamine (0.153 mL, 0.88 mmol) in dry methylene chloride (5 mL) was stirred 10 min. 4-(tert-Butyldimethylsilyloxy)-N2-[1-(4-pyridyl)piperidin-4-yl]methoxycarbonyl-1,2-benzenediamine (100 mg, 0.22 mmol) and N,N-dimethylformamide (2 mL) were added and the resulting mixture stirred 64 h at ambient temperature. Saturated aqueous sodium hydrogen carbonate solution (4 mL) was added, and the resultant mixture stirred for 30 min. The mixture was partitioned between ethyl acetate and water, the organic solution separated, dried (anhydrous magnesium sulfate), filtered, and concentrated in vacuo. The residue was chromatographed (silica gel, methylene chloride, 9:1 methylene chloride/methanol, 9:1:0.1 methylene chloride/methanol/ammonium hydroxide) to yield 55 mg (44%) of the title compound.