Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([Br:17])[CH:15]=[CH:16][C:11]=3[NH:10][C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].I[CH3:22]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([Br:17])[CH:15]=[CH:16][C:11]=3[N:10]([CH3:22])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(-n2c(=O)[nH]c3ccc(Br)cc32)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(-c2ccnc(N)n2)c2cc(Br)ccc21
Reaction time: 0.5 h
Yield: 115 %

Procedure:
To a solution of 1-(2-aminopyrimidin-4-yl)-6-bromo-2,3-dihydro-1H-1,3-benzodiazol-2-one (500 mg, 1.63 mmol) in DMF (10 ml) at 0° C. was added sodium hydride (60% oil suspension, 65.33 g, 1.63 mmol). The reaction mixture was allowed to warm to RT over 5 minutes before addition of iodomethane (0.1 ml, 1.63 mmol) and stirring for 30 minutes. The mixture was quenched by addition of water (5 mL), EtOAc was then added resulting in formation of a precipitate. The precipitate was collected by suction filtration. The filtrate was extracted with EtOAc (×2). The combined organic fractions were washed with water and dried (Na2SO4), filtered and concentrated in vacuo. Combining the extract residue and the precipitate gave the crude title compound (600 mg); 1H NMR (500 MHz, CDCl3) delta 3.23 (3H, s), 5.55 (2H, s), 6.72 (1H, d, J=8.3 Hz), 7.20-7.04 (1H, m), 7.42 (1H, d, J=5.7 Hz), 8.12 (1H, d, J=5.7 Hz), 8.39 (1H, d, J=1.8 Hz); LC-MS: m/z=+321.8 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.Cl.CN(C)[CH2:14][CH2:15]CN=C=NCC.C(O)C>ClCCl.CN(C)C1C=CN=CC=1>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:14][CH3:15])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(I)nc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1ccc(I)nc1
Temperature: 50 °C

Procedure:
To a suspension of 23.38 g (94.2 mmol) of 6-iodonicotinic acid in 100 ml of dichloromethane was added a solution of 19.86 g (103.6 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 250 ml of dichloromethane. To this suspension was added 12.40 g (15.8 ml, 269.3 mmol) of ethanol (95%) and 1.15 g (9.4 mmol) of 4-dimethylaminopyridine. The resulting solution mixture was then heated at 50° C. in an oil bath for 24.5 hours, concentrated in vacuo, partitioned between 200 ml of water and 250 ml of ethyl ether, and the layers were separated. The aqueous phase was washed with 2×150 ml-portions of ethyl ether. All organic phases were combined, washed once with 75 ml of brine solution, dried over MgSO4, filtered and concentrated in vacuo to a yellow solid. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) yielded the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:15]=[C:14]3[NH:27][CH3:28])[CH:8]=[CH:9][CH:10]=1.[CH3:29][O-:30].[Na+]>CO>[CH3:29][O:30][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:15]=[C:14]3[NH:27][CH3:28])[CH:8]=[CH:9][CH:10]=1
Reactant: CNc1nc(-c2cccnc2)nc2ccc(-c3cccc(OCCCl)c3)cc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CNc1nc(-c2cccnc2)nc2ccc(-c3cccc(OCCOC)c3)cc12
Temperature: 150 °C
Yield: 28.8 %

Procedure:
A solution of 6-(3-(2-chloroethoxy)phenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine (70 mg, 0.18 mmol) and sodium methoxide (97 mg, 1.8 mmol) in methanol (3 mL) was placed in a microwave reaction vial. The mixture was heated under microwave irradiation conditions at 150° C. for 30 minutes after which the solvent was removed in vacuo. The crude product was obtained, which was purified by column chromatography on basic silica gel (eluted with hexane/ethyl acetate 3:1→1:4) to give 20 mg of 6-(3-(2-methoxyethoxy)phenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine as an off-white powder (29%). LCMS m/z=387 (M+1) (Method D) (retention time=1.49 min). 1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 8.77 (d, J=8.2 Hz, 1H), 8.73-8.51 (m, 3H), 8.16 (d, J=8.7 Hz, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.60-7.32 (m, 4H), 7.01 (s, 1H), 4.21 (s, 2H), 3.70 (s, 2H), 3.33 (s, 3H), 3.19 (s, 3H),
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]#[N:9].[N:10]([O-])=[O:11].[Na+].O>C(O)=O.N([O-])=O.[Na+]>[C:8]([C:3]1[C:4]([CH3:7])=[N:5][S:6][C:2]=1[NH:1][N:10]=[O:11])#[N:9]
Reactant: O=N[O-]
Reactant: Cc1nsc(N)c1C#N
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: Cc1nsc(NN=O)c1C#N
Yield: 51533.2 %

Procedure:
First, 4 g (0.028 mol) of 5-amino-4-cyano-3-methylisothiazole was dissolved in 40 mL of 98% formic acid. While the mixture was stirred, an aqueous sodium nitrite solution (containing 2.1 g (0.03 mmol) of sodium nitrite in 6 mL of water) was added dropwise at 0° C. or less. After completion of dropwise addition, the mixture was continuously stirred at 0° C. further for one hour. To the solution, 100 mL of water was added to precipitate crystals, which were collected by filtration and washed with ice cold water. The crystals were dried in the air at room temperature overnight to obtain 2.6 g (56% in yield) of 4-cyano-3-methyl-5-nitrosoaminoisothiazole. To 2 g (0.012 mol) of the obtained nitrosoaminoisothiazole, 20 mL of methanol was added, stirred while heating to an inner temperature of 55 to 60° C. for one hour and cooled to room temperature to precipitate crystals, which were collected by filtration. The crystals were recrystallized from methanol to obtain 0.66 g (41% in yield) of triazene dissociative direct dye D-34.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[OH:4].[C:26]1([C:37](O)=[O:38])[CH:27]=[CH:28][CH:29]=[C:30]2[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:7]1[CH:6]=[C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:37]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=23)=[O:38])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(F)c1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(F)c1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol (448 mg, 1.24 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (234 mg, 1.24 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (357 mg, 1.86 mmol) and 1-hydroxybenzotriazole hydrate (190 mg, 1.24 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the objective substance (444 mg, 67%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH2:16])=[N:6][CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:9]=2)[CH2:3][CH2:2]1.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=O)[C:26](O)=[O:27])=[CH:20][CH:19]=1>>[CH:1]1([C:4]2[NH:9][C:8]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:7][N:6]3[C:26](=[O:27])[C:25]([CH2:24][C:21]4[CH:22]=[CH:23][C:18]([OH:17])=[CH:19][CH:20]=4)=[N:16][C:5]=23)[CH2:3][CH2:2]1
Reactant: O=C(O)C(=O)Cc1ccc(O)cc1
Reactant: Nc1ncc(-c2ccccc2)nc1C1CC1
Product: O=c1c(Cc2ccc(O)cc2)nc2c(C3CC3)[nH]c(-c3ccccc3)cn1-2

Procedure:
Synthesized using method A with 3-cyclopropyl-5-phenylpyrazin-2-amine and 3-(4-hydroxyphenyl)-2-oxopropanoic acid as starting materials. Exact mass calculated for C22H18N3O2− m/z− 356.14, found m/z− 356.
Reaction SMILES: Br[C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([C:15]42[N:19]=[C:18]([NH2:20])[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][C:10]([F:14])([F:13])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[C:24]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[N:31][CH:32]=1)#[C:25][CH3:26]>>[F:14][C:10]1([F:13])[CH2:9][CH2:8][C:7]2([C:15]3([N:19]=[C:18]([NH2:20])[C:17]([CH3:21])=[N:16]3)[C:22]3[C:5](=[CH:4][CH:3]=[C:2]([C:29]4[CH:30]=[N:31][CH:32]=[C:27]([C:24]#[C:25][CH3:26])[CH:28]=4)[CH:23]=3)[CH2:6]2)[CH2:12][CH2:11]1
Reactant: CC#Cc1cncc(B(O)O)c1
Reactant: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCC(F)(F)CC1
Product: CC#Cc1cncc(-c2ccc3c(c2)C2(N=C(C)C(N)=N2)C2(CCC(F)(F)CC2)C3)c1
Yield: 23.9 %

Procedure:
The title compound (26 mg, 24% yield) was prepared as described for Example 28c starting from 6′-bromo-4,4-difluoro-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine (Example 27, 100 mg, 0.26 mmol) and 5-(prop-1-ynyl)pyridin-3-ylboronic acid (Intermediate 15, 50.5 mg, 0.31 mmol). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.22-1.30 (m, 1 H), 1.51 (br. s., 2 H), 1.71 (br. s., 1 H), 1.78-1.97 (m, 4 H), 2.09 (s, 3 H), 2.19 (s, 3 H), 3.06 (d, 1 H), 3.15 (d, 1 H), 6.61 (s, 2 H), 6.85 (d, 1 H), 7.41 (d, 1 H), 7.56 (dd, 1 H), 7.91 (t, 1 H), 8.51 (d, 1 H), 8.67 (d, 1 H). MS (APCI+) m/z 419.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][CH:10]1CC([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:44].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(OC(C)C)(C)C>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@@H:10]1[Br:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])CC1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)OC(C)C
Product: Br[C@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -5 °C
Reaction time: 1.5 h

Procedure:
2,3,4,6-tetra-O-benzyl-D-galactopyranosylacetate (79.8 g) was dissolved in a mixture of toluene (160 ml) and isopropyl ether (520 ml), and the solution was cooled to −10 to 0° C. To this solution, an isopropyl ether solution (2.8 mmol/ml, about 100 ml) containing 2.0 equivalent volumes of HBr was added. After stirring for about 90 minutes at −10 to 0° C., an aqueous 5% sodium hydrogencarbonate solution was poured into the reaction solution, and excessive HBr was neutralized by stirring. The whole volume was transferred into a separation funnel for separation, then the water layer was discarded and washing was carried 2 times with an aqueous 10% sodium chloride solution. After concentration under vacuum, 2,3,4,6-tetra-O-benzyl-α-D-galactopyranosyl bromide (GalBr) was obtained as a syrup.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:3]=1.[Cl:20][C:21]1[C:22]([CH3:26])=[N:23][NH:24][CH:25]=1>>[Cl:20][C:21]1[C:22]([CH3:26])=[N:23][N:24]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH3:11])=[C:4]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:3]=2)[CH:25]=1
Reactant: Cc1n[nH]cc1Cl
Reactant: Cn1cnc2c(Nc3ccc(Cl)cc3)nc(Cl)nc21
Product: Cc1nn(-c2nc(Nc3ccc(Cl)cc3)c3ncn(C)c3n2)cc1Cl

Procedure:
Was prepared according to Example 6 from (2-chloro-9-methyl-9H-purin-6-yl)(4-chloro-phenyl)-amine and 4-chloro-3-methyl-1H-pyrazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([OH:13])=[CH:10]2)=[CH:5][CH:4]=1.[Cl-].[CH3:15][C:16]1[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=1[CH:18]=[N+:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([OH:13])=[C:10]2[CH:18]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=2[CH3:15])=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(O)cc2c1
Reactant: Cc1ccccc1C=[N+]1CCOCC1
Agent: [Cl-]
Product: COc1ccc2ccc(O)c(C(c3ccccc3C)N3CCOCC3)c2c1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 7-methoxy-2-naphthol and 4-(2-methyl-benzylidene)-morpholin-4-ium chloride, which had been prepared in accordance with example 18.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[CH:11][N:10]=2)[C:5]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:17][CH2:16]2)=[C:6]([C:13]#[N:14])[C:7]1=[O:12])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)cnc2[nH]c1=O
Product: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)cnc2n(Cc2ccccc2)c1=O

Procedure:
This compound was prepared from 6-fluoro-2-oxo-4-[4-(furan-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (99) and benzyl bromide according to General Procedure B. Yield 136 mg (18%), MP 216° C.; 1H-NMR (DMSO-d6): δ 3.72 (m, 4H), 3.95 (m, 4H), 5.53 (s, 2H), 6.66 (dd, J=2.0, 3.6 Hz, 1H), 7.08 (d, J=3.6 Hz, 1H), 7.21-7.28 (m, 5H), 7.89 (d, J=2.0 Hz, 1H), 8.18 (dd, J=2.8, 9.2 Hz, 1H), 8.77 (d, J=2.8 Hz, 1H); EIMS: 458 (M+1). Anal. (C25H20FN5O3) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:15])[O:13][CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Cl:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:29][N:30]=[C:31]=[O:32]>C(#N)C>[Cl:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:29][NH:30][C:31](=[O:32])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:15])[O:13][CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C=NCc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)NS(=O)(=O)c1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)NS(=O)(=O)c1ccc(NC(=O)NCc2ccc(Cl)c(Cl)c2)cc1

Procedure:
A solution of methyl 4-aminophenylsulfonylcarbamate (50 mg, 0.2 mmol), N,N-diisopropylethylamine (35 L, 0.2 mmol), 3,4-dichlorobenzylisocyanate (30 L, 0.2 mmol) in acetonitrile was stirred under an N2 atmosphere for 19 h. The mixture was concentrated and the residue purified by reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give methyl 4-(3-(3,4-dichlorobenzyl)ureido)phenylsulfonylcarbamate. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=431.01; tR=2.9 min.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(O)(=O)C.[F:27][C:28]([F:48])([F:47])[O:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:40][CH2:39][C:38]3([CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[C:37]2=[O:46])=[CH:32][CH:31]=1.[OH:49][C:50]([CH3:57])([CH2:55][CH3:56])[CH2:51][C:52](O)=[O:53]>>[OH:49][C:50]([CH3:57])([CH2:55][CH3:56])[CH2:51][C:52]([N:43]1[CH2:42][CH2:41][C:38]2([C:37](=[O:46])[N:36]([C:33]3[CH:34]=[CH:35][C:30]([O:29][C:28]([F:27])([F:47])[F:48])=[CH:31][CH:32]=3)[CH2:40][CH2:39]2)[CH2:45][CH2:44]1)=[O:53]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: CCC(C)(O)CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)O
Product: CCC(C)(O)CC(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
The title compound was prepared in analogy to example 13 step A (using TBTU instead of BOP as the coupling reagent) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and 3-hydroxy-3-methyl-pentanoic acid. Light brown oil. MS (ESI): 429.2 (MH+).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7](=[O:20])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[N:10][C:9]=1[O:15][CH2:16][CH:17]([F:19])[F:18]>OS(O)(=O)=O>[CH3:5][O:6][C:7](=[O:20])[C:8]1[CH:13]=[C:12]([N+:1]([O-:4])=[O:2])[C:11]([Cl:14])=[N:10][C:9]=1[O:15][CH2:16][CH:17]([F:19])[F:18]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(Cl)nc1OCC(F)F
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(Cl)nc1OCC(F)F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Fuming HNO3 (25 mL) is added at rt to 6-chloro-2-(2,2-difluoro-ethoxy)-nicotinic acid methyl ester (10.7 g, 42.5 mmol) in concentrated H2SO4 (50 mL) and stirred for 10 min. The reaction mixture is added dropwise to ice water, stirred and filtered. The filtercake is washed with water and dried at 50° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[C:10](O)[C:9]2[C:4](=[C:5]([O:14][CH3:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:10]1[C:9]2[C:4](=[C:5]([O:14][CH3:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[C:11]=1[CH3:12]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cccc2c(O)c(C)c(C)nc12
Solvent: CN(C)c1ccccc1
Product: COc1cccc2c(Cl)c(C)c(C)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2,3-dimethyl-4-hydroxy-8-methoxyquinoline (3.0 g) in phosphoryl chloride was dropwise added N,N-dimethylaniline (3.58 g) under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature, for 30 minutes at ambient temperature and then for 1 hour at 70° C. The solvent was removed, and saturated sodium bicarbonate solution and 10% solution of methanol in dichloromethan were added to the residue. The organic layer was dried over magnesium sulfate and concentrated. The residue wa purified by flash chromatography (Ethyl acetatein-hexane=1:2 v/v) to give 4-chloro-2,3-dimethyl-8-methoxyquinoline (3.02 g).
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H-].[Na+].[Br:11][C:12]1[CH:13]=[CH:14][C:15](F)=[C:16]([CH:19]=1)[C:17]#[N:18].O>CN(C)C=O>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[C:16]([CH:19]=1)[C:17]#[N:18]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: CCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(Br)cc1C#N
Reaction time: 1 h
Yield: 86.1 %

Procedure:
1-Heptanol (1.55 g) was dissolved in N,N-dimethylformamide (24 ml), and sodium hydride (0.321 g) was added at room temperature. The mixture was stirred for 1 hr, 5-bromo-2-fluorobenzonitrile (2.43 g) was added, and the mixture was further stirred for 50 min. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. To consume the starting material, 5-bromo-2-fluorobenzonitrile, the reaction was performed again under the same conditions, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1-5:1) to give the object product (3.10 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][CH2:12][NH:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH:23]([F:25])[F:24])[CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C=O.[C:28](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.CO>[CH3:28][N:13]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH:23]([F:25])[F:24])[CH:16]=1)[CH2:12][CH2:11][C:6]1[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: FC(F)COc1cccc(CNCCc2c[nH]c3cc(Cl)ccc23)c1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(Cl)Cl
Product: CN(CCc1c[nH]c2cc(Cl)ccc12)Cc1cccc(OCC(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Combine (2-(6-chloro-1H-indol-3-yl)ethyl)-(3-(2,2-difluoroethoxy)benzyl)amine (276 mg, 0.76 mmol) and formaldehyde (55.5 μL of a 38% aqueous solution, 0.76 mmol) in dichloroethane (15 mL) and stir at room temperature for 10 minutes; add in two portions sodium triacetoxyborohydride (321 mg, 1.51 mmol) over 10 minutes and stir at room temperature overnight before diluting with methanol (10 mL) and quenching with one drop of glacial acetic acid. Remove in vacuo the solvent, and redissolve the crude residue in methanol and directly load onto a 10 g SCX column. After washing thoroughly with methanol, elute the column with 2 N ammonia in methanol. Concentrate in vacuo the eluant to give the free base of the title compound as a straw-colored oil. Dissolve the free base (239 mg, 0.64 mmol) in methanol (20 mL) and treat with a solution of ammonium chloride (36 mg, 0.67 mmol) in methanol (5 mL). Sonicate the mixture for 10 minutes before removal of the solvent in vacuo to give the hydrochloride salt as a tacky yellow oil. Dissolve the oil in 10 mL of 1:1 acetonitrile-water and lyophilize overnight, providing a fluffy white solid and triturate with diethyl ether (10 mL) and acetonitrile (2 drops). Filtration and drying of the resulting precipitate afforded the desired hydrochloride as a white amorphous solid: mp: 63.8–65.8° C.; 1H NMR (400 MHz, dmso-d6): 11.10 (br s, 1H), 7.52 (d, 1H, J=8.4 Hz) 7.36 (d, 1H, J=2.0 Hz), 7.40–7.26 (m, 2H), 7.22 (d, 1H, J=2.4 Hz), 7.20–7.11 (m, 1H), 7.04 (br d, 1H, J=7.6 Hz), 6.96 (dd, 1H, J=8.6, 1.4 Hz), 6.38 (tt, 1H, J=54.4, 3.6, Hz), 4.50–4.02 (br m, 2H), 4.30 (td, 2H, J=14.4, 3.2 Hz), 3.15 (br s, 4H), 2.68 (br s, 3H); MS (ES+): m/e 378.9 (M+1); CHN (for C20H21ClF2N2O.HCl.0.7H2O) calcd: C 56.14, H 5.51, N 6.55; found: C 55.72, H 5.32, N 7.07.
Reaction SMILES: C(O[C:6]([C:8]1[C:9]([OH:19])=[C:10]2[CH:17]=[C:16]([CH3:18])[S:15][C:11]2=[C:12]([CH3:14])[N:13]=1)=[O:7])CCC.[NH2:20][CH2:21][C:22]([OH:24])=[O:23]>C[O-].[Na+].CO.Cl>[OH:19][C:9]1[C:8]([C:6]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:7])=[N:13][C:12]([CH3:14])=[C:11]2[S:15][C:16]([CH3:18])=[CH:17][C:10]=12
Reactant: CCCCOC(=O)c1nc(C)c2sc(C)cc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cc2c(O)c(C(=O)NCC(=O)O)nc(C)c2s1

Procedure:
4-Hydroxy-2,7-dimethyl-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester (30 mg, 0.11 mmol, example 5-b-A) and glycine (75 mg, 1.0 mmol) were suspended in 2.0 mL of 0.5 N NaOMe in methanol. The resultant mixture was heated to 120° C. for 10 min. using a CEM microwave reactor. The reaction mixture was cooled, and diluted with 0.25 N HCl until pH <3. The mixture was extracted two times with ethyl acetate, and the organic fractions were dried over anhydrous magnesium sulfate and concentrated to 27 mg of a pale yellow solid. MS: (−) m/z 279.01 (M−1).
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:18])[CH2:16]Br)[N:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=1)([O:21][CH2:22][CH3:23])=[O:20].[BH4-].[Na+]>C(Cl)Cl.CO.NC(N)=O>[C:19]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH:32][CH2:16][CH:15]([OH:18])[C:13]2[N:14]=[C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[S:11][CH:12]=2)=[CH:26][CH:25]=1)([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1ccc(CCN)cc1
Reactant: O=C(Nc1nc(C(=O)CBr)cs1)c1ccccc1
Agent: NC(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1ccc(CCNCC(O)c2csc(NC(=O)c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
9.6 g (0.03 mol) of 2-Benzoylamino-4-bromoacetyl-thiazole are dissolved in 100 ml of methylene chloride and, while stirring at room temperature, added dropwise to a solution of 11.5 g (0.06 mol) of 2-(4-carboethoxyphenyl)ethylamine in 150 ml of methylene chloride. After 1.5 hours, the mixture is cooled to 5° C., diluted with 200 ml of methanol and, for the reduction of the resulting amino-ketone, 3 g of sodium borohydride are added in small portions at 0°-5° C. After 3 hours the solution is evaporated to dryness, ice/water is added, and hydrochloric acid is used to acidify. After 10 minutes the mixture is made alkaline with sodium bicarbonate solution and extracted with methylene chloride. The extract is dried over sodium sulphate, concentrated and purified on a silica gel column using chloroform/methanol =9:1, with the addition of 2% ammonia-saturated ethanol, as eluant. The resulting product is induced to crystallise with petroleum ether.