Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[NH:4][N:3]=1.N1C=CC=CC=1.[F:18][C:19]1[CH:20]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[CH:22]=[C:23]([F:25])[CH:24]=1>O1CCCC1>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:26]([C:21]3[CH:20]=[C:19]([F:18])[CH:24]=[C:23]([F:25])[CH:22]=3)(=[O:28])=[O:27])[CH:9]=2)[NH:4][N:3]=1
Reactant: Nc1ccc2[nH]nc(N)c2c1
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Nc1n[nH]c2ccc(NS(=O)(=O)c3cc(F)cc(F)c3)cc12
Yield: 32.4 %

Procedure:
N-(3-Amino-1H-indazol-5-yl)-3,5-difluorobenzenesulfonamide can be obtained as described in Example 39 from 2.1 g of 3,5-diamino-1H-indazole, 20 ml of pyridine, 20 ml of tetrahydrofuran and 1.47 g of 3,5-difluorobenzenesulfonyl chloride. 0.727 g of N-(3-amino-1H-indazol-5-yl)-3,5-difluorobenzenesulfonamide is thus obtained in the form of a white solid melting at 232° C. (analysis C13H10F2N4O2S % calculated C, 48.15; H, 3.11; F, 11.72; N, 17.28; O, 9.87; S, 9.89. % found C, 47.95; H, 3.14; F, 11.79; N, 17.06; S, 9.52).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1.[CH3:32][NH:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C(O)C>O>[CH:34]1([N:33]([CH2:2][C:3]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[C:10]3[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=3)[N:4]=2)[CH3:32])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CNC1CCCCC1
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(CN(C)C2CCCCC2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Yield: 79.6 %

Procedure:
A mixture of ethyl 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (3.0 g), N-methyl-N-cyclohexylamine (2.28 g) and ethanol (45 ml) was stirred under reflux for 6 hours. The reaction mixture was poured into water and extracted with dichloromethane. The dichloromethane layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform gave ethyl 2-(N-cyclohexyl-N-methylaminomethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (2.80 g, 80%). This compound was recrystallized from ethanol. Colorless prisms, mp. 172°-174° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)=O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]([CH:30]([NH2:32])[CH3:31])[CH:26]=[C:27]([F:29])[CH:28]=1.C(N(CC)CC)C.C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[F:22][C:23]1[CH:24]=[C:25]([CH:30]([NH:32][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)[CH3:31])[CH:26]=[C:27]([F:29])[CH:28]=1
Reactant: CC(C)Oc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1
Reactant: CC(N)c1cc(F)cc(F)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(C(NC(C)c2cc(F)cc(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Yield: 94.4 %

Procedure:
Following a similar procedure to that described in Example (1a), 850 mg of 3-nitrophenyl 4-isopropoxyphenyl ketone, 936 mg of 1-(3,5-difluorophenyl)ethylamine, 1.66 ml of triethylamine, 0.39 ml of titanium tetrachloride, 788 mg of sodium cyanoborohydride and 0.26 ml of acetic acid were reacted, to obtain 1.20 g of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[CH:10][S:11][C:5]=2[N:4]=[CH:3]1.[C:19]12([CH2:29][C:30](Cl)=[O:31])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2>N1C=CC=CC=1>[C:19]12([CH2:29][C:30]([NH:1][N:2]3[C:7](=[O:8])[C:6]4[C:9]([C:12]5[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=5)=[CH:10][S:11][C:5]=4[N:4]=[CH:3]3)=[O:31])[CH2:26][CH:25]3[CH2:24][CH:23]([CH2:22][CH:21]([CH2:27]3)[CH2:20]1)[CH2:28]2
Reactant: Nn1cnc2scc(-c3ccc(F)cc3)c2c1=O
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Solvent: c1ccncc1
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1cnc2scc(-c3ccc(F)cc3)c2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.6 %

Procedure:
3-Amino-5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4(3H)-one (100 mg, 0.383 mmol) was stirred in pyridine (3 mL) at 25° C. 1-Adamantaneacetyl chloride (204.1 mg, 0.96 mmol) was slowly added and the reaction mixture was allowed to stir at 25° C. for 2 hours. The reaction mixture was concentrated to dryness. The resulting material was dissolved in DMSO (3 mL), filtered through a glass microfiber frit and purified by preparative HPLC [Waters XBridge RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 20-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide), with UV detection at 254 nm]. Fractions containing the desired product were pooled and concentrated under vacuum to afford the title compound as a white solid (68 mg, 41%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54-1.70 (m, 12H), 1.92 (br s, 3H), 2.07 (s, 2H), 7.19-7.27 (m, 2H), 7.49-7.56 (m, 2H), 7.62 (s, 1H), 10.90 (br s, 1H); MS (DCI/NH3) m/z 438 (M+H)+. Elemental Analysis calculated for C24H24FN3O2S: C, 65.88; H, 5.53; N, 9.60. Found C, 65.64; H, 5.48; N, 9.55.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7]O)=[CH:5][C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[N:3]1.S(Cl)([Cl:22])=O>C(Cl)(Cl)Cl>[Cl:22][CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CO
Solvent: ClC(Cl)Cl
Product: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CCl

Procedure:
In analogy to the procedure described for example 1 b], [2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-methanol (example 11 d]) was reacted with thionyl chloride in chloroform to yield 5-chloromethyl-1-methyl-3-(4-trifluoromethoxy-phenyl)-1H-pyrazole as colorless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].[Cl-]>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][S:20]([CH3:19])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: COCCOCCOCCO
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOCCOCCOS(C)(=O)=O

Procedure:
A solution of non-polydispersed triethylene glycol monomethyl ether molecules (4.00 mL, 4.19 g, 25.5 mmol) and triethylamine (4.26 mL, 3.09 g, 30.6 mmol) in dry dichloromethane (50 mL) was chilled in an ice bath and place under a nitrogen atmosphere. A solution of methanesulfonyl chloride (2.37 mL, 3.51 g, 30.6 mmol) in dry dichloromethane (20 mL) was added dropwise from an addition funnel. Ten minutes after the completion of the chloride addition, the reaction mixture was removed from the ice bath and allowed to come to room temperature. The mixture was stirred for an additional hour, at which time TLC (CHCl3 with 15% MeOH as the elutant) showed no remaining triethylene glycol monomethyl ether.
Reaction SMILES: [CH3:1][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[NH2:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][N:26]2[C:31]1[CH:32]=[C:33]([CH:39]=[CH:40][CH:41]=1)[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[O:19]1[C:20]2[C:12]([C:2]([CH3:11])([CH3:1])[CH2:3][C:4]([OH:5])([C:7]([F:8])([F:10])[F:9])[CH2:6][NH:21][C:22]3[CH:30]=[CH:29][CH:28]=[C:27]4[C:23]=3[CH:24]=[N:25][N:26]4[C:31]3[CH:32]=[C:33]([CH:39]=[CH:40][CH:41]=3)[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:13][CH:14]=[CH:15][C:16]=2[CH2:17][CH2:18]1
Reactant: CCOC(=O)c1cccc(-n2ncc3c(N)cccc32)c1
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cccc2c1OCC2
Product: CCOC(=O)c1cccc(-n2ncc3c(NCC(O)(CC(C)(C)c4cccc5c4OCC5)C(F)(F)F)cccc32)c1

Procedure:
Prepared similarly to Example 1 from racemic 7-{1,1-dimethyl-2-[2-(trifluoromethyl)-2-oxiranyl]ethyl}-2,3-dihydro-1-benzofuran (which may be prepared according to WO 04/063163) and ethyl 3-(4-amino-1H-indazol-1-yl)benzoate (Intermediate 6).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[CH2:14](Br)[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:16]([O:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[C:4]([OH:6])=[O:5])[CH:15]=[CH2:14]
Reactant: CCOC(=O)c1cc(C)ccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(C)cc1C(=O)O

Procedure:
The reaction of ethyl 2-hydroxy-5-methyl-benzoate and allyl bromide in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 2-Allyloxy-5-methyl-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.52 (s, —CO2H); 7.43 (m, 1 arom. H); 7.26 (m, 1 arom. H); 6.98 (m, 1 arom. H); 5.99 (m, —CH═CH2); 5.46, 5.22 (2 d-like, CH═CH2); 4.56 (d-like, CH2—CH═CH2); 2.23 (s, —CH3). 13C-NMR (100 MHz, d6-DMSO): 167.39 (C═O); 154.91; 133.52; 133.20; 130.91; 129.05; 121.34; 116.83; 113.79; 68.69; 19.78.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Si:13]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[C:28]([Cl:36])[C:27]=1[NH2:37])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C1COCC1>N1C=CC=CC=1>[Si:13]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[C:26]2[C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[N:29]=[C:28]([Cl:36])[C:27]=2[N:37]=[C:1]1[OH:2])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)[Si](C)(C)OCCCCNc1c(N)c(Cl)nc2ccccc12
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCn1c(O)nc2c(Cl)nc3ccccc3c21
Temperature: 80 °C
Yield: 52.1 %

Procedure:
1,1′-Carbonyldiimidazole (32.6 g, 201 mmol) was added to a solution of N4-[4-(tert-butyldimethylsilanyloxy)butyl]-2-chloroquinoline-3,4-diamine (50.96 g, 134.1 mmol), THF (250 mL), and pyridine (250 mL), and the reaction was heated at 80° C. overnight and allowed to cool. The volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (600 mL), and the resulting solution was washed sequentially with brine (2×400 mL) and water (2×400 mL) and then concentrated under reduced pressure. The resulting solid was triturated with diethyl ether (1 L), collected by filtration, washed with diethyl ether (800 mL), and dried under vacuum for 30 minutes to provide 28.39 g of 1-[4-(tert-butyldimethylsilanyloxy)butyl]-4-chloro-1H-imidazo[4,5-c]quinolin-2-ol as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:14]2[C:22]3[C:17](=[C:18]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)([CH2:12][CH3:13])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[Cl:61][CH2:62][CH2:63][NH2:64]>CN(C)C=O>[Cl:61][CH2:62][CH2:63][NH:64][C:9](=[O:11])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)([N:14]1[C:22]2[C:17](=[C:18]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1)[CH2:12][CH3:13]
Reactant: CCC(C(=O)O)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reactant: NCCCl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(C(=O)NCCCl)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the product of Step A (40 mg, 0.1 mmol), HATU (57 mg, 0.15 mmol), N,N-diisopropylethylamine (26 mg, 0.2 mmol) and 2-chloroethanamine (16 mg, 0.2 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature overnight. The crude product was purified by CombiFlash (Mobile phase: acetonitrile/water (0.03% TFA)) to afford the title compound as a white amorphous solid. LC/MS m/z=467.9[M+H]+.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][CH:8]2[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(F)(F)F.C[CH2:25][O:26]CC>CO>[OH:13][CH:8]([C:7]([O:26][CH3:25])([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C1OC1(c1ccccc1)c1ccccc1
Reactant: CCOCC
Agent: FB(F)F
Solvent: CO
Product: COC(=O)C(O)C(OC)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
5 g (19.6 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate were dissolved in 50 ml of absolute methanol, and, at 0° C., 0.1 ml of boron trifluoride etherate was added. The mixture was stirred at 0° C. for 2 h and at room temperature for a further 12 h. The solvent was removed by distillation, the residue was taken up in ethyl acetate, and the solution was washed with sodium bicarbonate solution and water and dried over magnesium sulfate. After removal of the solvent by distillation, 5.5 g (88%) of a pale yellow oil remained.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([OH:17])=[C:14]([Cl:16])[CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:18].[Na+].O>CN(C=O)C>[C:1]([O:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([OH:17])=[C:12]([I:18])[CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [I-]
Reactant: O=C(Oc1ccc(O)c(Cl)c1)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Oc1cc(Cl)c(O)c(I)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3 g of 5-benzoyloxy-1-chloro-2-hydroxybenzene were dissolved in 35 ml of DMF. 2.17 g of sodium iodide and 3.29 g of chloramin T were added. After one hour of stirring at room temperature, about 500 ml of water were added to the mixture, which was then extracted with ethyl acetate. The organic phase was washed with 5% strength sodium thiosulfate solution, dried and concentrated using a rotary evaporator. The resulting product was clean enough for the next reaction. Yield: 3.81 g (84%)
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:20])([F:19])[S:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1)(=[O:7])=[O:6].Cl>O>[CH3:1][NH:2][S:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][S:5]([C:4]([F:20])([F:19])[F:3])(=[O:7])=[O:6])=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: CN
Reactant: O=S(=O)(Cl)c1ccc(NS(=O)(=O)C(F)(F)F)cc1
Agent: Cl
Solvent: O
Product: CNS(=O)(=O)c1ccc(NS(=O)(=O)C(F)(F)F)cc1
Reaction time: 8 h
Yield: 44.1 %

Procedure:
A mixture of a 40% aqueous solution of methylamine (0.7 g), 4-(trifluoromethanesulfonamido)benzenesulfonyl chloride (1.5 g) and water (20 ml) was allowed to stand overnight and made acidic with hydrochloric acid to precipitate crystals, which were then recrystallized from a mixture of water and ethanol to give 0.65 g of N-methyl-4-(trifluoromethanesulfonamido)benzenesulfonamide. M.P., 156°-157° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.C([Mg]Br)C.[C:11](Cl)(=[O:14])[CH2:12][CH3:13]>>[CH3:1][C:2]1[N:3]=[C:4]([C:11](=[O:14])[CH2:12][CH3:13])[S:5][CH:6]=1
Reactant: Cc1cscn1
Reactant: CCC(=O)Cl
Agent: CC[Mg]Br
Product: CCC(=O)c1nc(C)cs1

Procedure:
b. 4-Methyl-2-propionyl-thiazole was prepared according to the method described in Bull. 20, 702 (1953) by reacting 4-methyl-thiazole with ethyl-magnesium bromide and acylating the obtained Grignard intermediate with propionyl chloride. The product has a b.p. of 83°-88° C./9 mm. Hg.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[CH2:10][CH:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38]>CN(C=O)C>[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH:38][C:17]([C@H:14]1[CH2:13][CH2:12][C@@H:11]([CH2:10][C:2]2[NH:1][C:9]3[C:4]([N:3]=2)=[N:5][CH:6]=[CH:7][CH:8]=3)[CH2:16][CH2:15]1)=[O:19]
Reactant: NCc1ccccc1F
Reactant: O=C(O)C1CCC(Cc2nc3ncccc3[nH]2)CC1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1F)[C@H]1CC[C@@H](Cc2nc3ncccc3[nH]2)CC1
Reaction time: 1 h

Procedure:
To a solution of 4-(1H-imidazo[4,5-b]pyridin-2-ylmethyl)-cyclohexanecarboxylic acid (Compound AAB) (275 mg, 1.05 mmol), EDC (200 mg, 1.05 mmol) and HOAt (142 mg, 1.05 mmol) in anhydrous DMF (4 mL) was added 2-fluorobenzylamine (131 mg, 1.05 mmol) and the resulting reaction mixture was stirred for 1 h. The reaction mixture was partitioned between saturated aqueous NaHCO3 and EtOAc and the organic layer washed 2× with water. The EtOAc was dried with MgSO4 and concentrated to give a yellow solid. Preparative chromatography eluting with chloroform:methanol gave the cis 4-(1H-imidazo[4,5-b]pyridin-2-ylmethyl)-cyclohexanecarboxylic acid 2-fluoro-benzylamide as a white solid: mass spectrum m/z 367 [(M+H)+; calcd for C21H24N4OF: 366].
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)/[C:5](=[N:15]/O)/[C:4]=2[CH:3]=1.BrC1C=CC2C(C=1)=NC([OH:32])=C1C=2C=CC=C1>O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:4](=[C:5]([OH:32])[N:15]=[C:6]3[C:11]=2[CH:10]=[CH:9][CH:8]=[CH:7]3)[CH:3]=1
Reactant: O/N=C1/c2ccccc2-c2ccc(Br)cc21
Reactant: Oc1nc2cc(Br)ccc2c2ccccc12
Solvent: O
Product: Oc1nc2ccccc2c2ccc(Br)cc12
Temperature: 185 °C

Procedure:
To the solid product from Step 1, (9Z)-2-bromo-9H-fluoren-9-one oxime (106 mg, 0.387 mmol) was added polyphosphoric acid (5 g). The mixture was then heated to 185° C. for 2 h. After cooling to r.t., water was added and the resulting solid was collected by filtration to give a 1:1 mixture of the title compounds and the regioisomeric 3-bromophenanthridin-6-ol. LRMS (M+H)+=274.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:32])[N:27]3[CH2:30][OH:31])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1.C(N(CC)CC)C.[CH2:40]([N:47]=[C:48]=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:40]([NH:47][C:48](=[O:49])[O:31][CH2:30][N:27]1[C:28]2[C:23](=[CH:22][CH:21]=[C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][N:9]([C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=4[Cl:1])[CH2:10][CH2:11]3)[CH:29]=2)[CH2:24][CH2:25][C:26]1=[O:32])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C=NCc1ccccc1
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1CO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccccc1)OCN1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: 35 °C
Reaction time: 24 h

Procedure:
To a solution of hemi-aminal A1 from Example 1 (4 g, 8.4 mmol), 4-dimethylaminopyridine (0.15 g, 1.3 mmol) and triethylamine (1.1 mL, 7.5 mmol) in dichloromethane (30 mL) was added benzylisocyanate (1.03 mL, 8.3 mmol) and the reaction mixture stirred for 24 hours. The reaction mixture was then heated at 35° C. for 20 hours, cooled and washed with water/brine (1:1, 50 mL). The organic phase was dried over MgSO4, filtered and evaporated under vacuum. The residue was further purified by chromatography on silica eluting with ethyl acetate/dichloromethane/methanol (1:1:0.1) to give the desired product as an off white foam (530 mg, 14% yield). 1H NMR (CDCl3, 300 MHz) δ 1.58-1.88 (m, 4H), 2.48 (t, 2H), 2.60-2.72 (m, 6H), 2.85 (m, 2H), 300-3.12 (m, 4H), 3.96 (t, 2H), 4.40 (d, 2H), 5.13 (NH), 5.96 (s, 2H), 6.58 (dd, 1H), 6.79 (d, 1H), 6.92-6.98 (m, 1H), 7.04 (d, 1H), 7.12-7.16 (m, 1H), 7.23-7.35 (m, 6H); m/z (M+H) 611.12 and 613.10.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([S:21](=[O:24])(=[O:23])[NH2:22])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][NH2:10])[CH2:2][CH2:3][CH3:4].[BH4-].[Na+].[C:27]([OH:30])(=O)[CH3:28].O>CO>[CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([S:21](=[O:24])(=[O:23])[NH2:22])[C:13]=1[O:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][NH:10][CH2:11][C:8]1[CH:7]=[CH:6][CH:28]=[C:27]([OH:30])[CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: CCCCNc1cc(CN)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCNc1cc(CNCc2cccc(O)c2)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
A solution of 3-n-butylamino-4-phenoxy-5-sulfamylbenzylamine (1.05 g; prepared as described in Example 289) and m-hydroxybenzaldehyde (0.45 g) in methanol (7 ml) is refluxed for 16 hours. The resulting solution is cooled to 0°-5° C. whereafter sodium borohydride (0.25 g) is added in portions during 5 minutes while stirring. After stirring at 22°-25° C. for a further 3 hours, acetic acid (0.5 ml) followed by water (20 ml) are added to precipitate crude (3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)-3-hydroxybenzylamine. After filtration and recrystallization from ethanol, it is obtained with a melting point of 174°-175° C.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:5]=2[N:6]=1.[Cl:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1F>>[Cl:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[S:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:5]=2[N:6]=1
Reactant: O=C(O)c1ccc2sc(S)nc2c1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Product: O=C(O)c1ccc2sc(Sc3ccc([N+](=O)[O-])cc3Cl)nc2c1

Procedure:
2-(2-chloro-4-nitro-phenylsulfanyl)-benzothiazol-5-carboxylic acid was prepared (66%) from 2-mercapto-benzothiazol-5-carboxylic acid (240) and 2-chloro-1-fluoro-4-nitrobenzene, obtained from Aldrich, in a similar manner as described in example 251.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[S:8])[NH:5][C:4](=[O:9])[CH:3]=1.[Cl-].Cl[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH+:19]([CH3:21])[CH3:20].O.[OH-].[Na+]>CS(C)=O>[CH3:20][N:19]([CH3:21])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][S:8][C:6]1[NH:5][C:4](=[O:9])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: C[NH+](C)c1ccccc1CCl
Reactant: Cc1cc(=O)[nH]c(=S)[nH]1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(=O)[nH]c(SCc2ccccc2N(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
After dissolving 0.71 g (5 mmol) of 6-methyl-2-thiouracil [Ann. 236, 1 (1986)] and 1.03 g (5 mmol) of (2-chloromethylphenyl)-dimethylammonium chloride (J. Chem. Soc. 1954, 4127) in 10 ml of dimethylsulfoxide, the reaction mixture is stirred at room temperature for 1 hour and then poured into 60 ml of water. After adjusting the pH value of the mixture to 6-8 by adding aqueous 1 N sodium hydroxide solution the precipitate is filtered and the crude base (1.3 g) is recrystallized from benzene to give 1.08 g (78.4%) of the title compound, m.p.: 152°-154° C. (white crystals).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:10]=[C:11](/[CH:13]=[C:14](\[CH3:20])/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]=2)=[CH:4][CH:3]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=2[CH2:42]Br)=[CH:30][CH:29]=1>>[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=2[CH2:42][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[CH:10]=[C:11](/[CH:13]=[C:14](\[CH3:20])/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]=3)=[CH:4][CH:3]=2)=[CH:32][CH:33]=1
Reactant: COc1ccc(-c2ccc(Cl)cc2)c(CBr)c1
Reactant: CCOC(=O)/C(C)=C/c1cn(C2CCCCC2)c(-c2ccc(O)cc2)n1
Product: CCOC(=O)/C(C)=C/c1cn(C2CCCCC2)c(-c2ccc(OCc3cc(OC)ccc3-c3ccc(Cl)cc3)cc2)n1
Yield: 48.9 %

Procedure:
According to the procedure for preparation of 4.4, phenol 13.3 (73 mg, 0.206 mmol) was alkylated with (4′-chloro-4-methoxy-1,1′-biphenyl-2-yl)methyl bromide (71 mg, 0.227 mmol), to yield 59 mg (49%) of 13.4. MS (ESI) 585.4 (MH+).