Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].Br[C:27]1[CH:28]=[C:29]([C:33]2[CH:38]=[C:37]([C:39]3[CH:43]=[CH:42][N:41]([CH3:44])[N:40]=3)[N:36]=[C:35]([NH:45][CH3:46])[CH:34]=2)[CH:30]=[N:31][CH:32]=1>COCCOC.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:27]3[CH:28]=[C:29]([C:33]4[CH:38]=[C:37]([C:39]5[CH:43]=[CH:42][N:41]([CH3:44])[N:40]=5)[N:36]=[C:35]([NH:45][CH3:46])[CH:34]=4)[CH:30]=[N:31][CH:32]=3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CNc1cc(-c2cncc(Br)c2)cc(-c2ccn(C)n2)n1
Reactant: CC(C)N1CCN(Cc2ccc(B(O)O)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: CNc1cc(-c2cncc(-c3ccc(CN4CCN(C(C)C)CC4)cc3)c2)cc(-c2ccn(C)n2)n1

Procedure:
To a solution of 4-(4-Isopropyl-piperazin-1-ylmethyl)-phenyl boronic acid (Intermediate B3) (1.5 eq, 0.218 mmol, 0.057 g) and 2M Na2CO3 (3.0 eq, 0.436 mmol, 0.218 ml) in DME (1 ml) is added [5-Bromo-6′-(1-methyl-1H-pyrazol-3-yl)-[3,4′]bipyridinyl-2′-yl]-methyl-amine (Example 2.178, step1) (1 eq, 0.145 mmol, 0.050 g) followed by [1,1′-Bis(diphenylphosphino)-ferrocene]dichloropalladium (II), complex with DCM (0.1 eq, 0.015 mmol, 0.012 g). The reaction mixture is heated using microwave radiation at 90° C. for 90 mins. The reaction mixture is dissolved in DCM and washed with water. The organic layer is washed with brine, dried over drying agent MgSO4, filtered and the organic solvent is reduced in vacuo. The crude residue is purified by reverse phase column chromatography (Isolute™ C18, 0-50% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 482.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[CH:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1)([O-])=O.[In].[Cl-].[NH4+]>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[CH:7]=[C:8]([NH2:10])[CH:9]=1
Reactant: O=[N+]([O-])c1cc(Nc2ccc(Br)cc2)cc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [In]
Agent: [NH4+]
Solvent: CCO
Product: Nc1cc(N)cc(Nc2ccc(Br)cc2)c1
Reaction time: 12 h
Yield: 93.5 %

Procedure:
To a solution of (3,5-dinitrophenyl) (4-bromophenyl)amine (0.34 g, 1.0 mmol) in ethanol (10 mL) was added indium (2.0 g, 17 mmol) followed by saturated ammonium chloride solution (3 mL) and the mixture stirred 12 h. At this time, TLC showed the reaction complete. The reaction mixture was then filtered through celite, concentrated and the residue dissolved in 50 mL CH2Cl2. The organic solution was washed with 50 mL water followed by 50 mL brine, dried over magnesium sulfate, filtered and concentrated to give 0.26 g (93%) of a brown oil, Rf 0.1 (1:1 hexane:ethyl acetate), which was carried directly to the next step.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][N:9]([C:12]3[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=3)[C:8](=[O:21])[CH:7]=2)[CH2:3][CH2:2]1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([NH:29][C:18]([C:14]1[S:13][C:12]([N:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)=[CH:7][C:8]2=[O:21])=[N:16][C:15]=1[CH3:17])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1nc(-n2ccc(OCC3CC3)cc2=O)sc1C(=O)O
Reactant: NCc1ccccc1
Product: Cc1nc(-n2ccc(OCC3CC3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 58 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-(cyclopropylmethoxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with benzylamine, the title compound was obtained as a white solid in 58% yield: mp 218-220° C. (hexane/ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 8.77 (t, J=5.9 Hz, 1H), 8.58 (d, J=8.1 Hz, 1H), 7.35-7.18 (m, 5H), 6.34 (dd, J=8.1, 2.7 Hz, 1H), 6.05 (d, J=2.7 Hz, 1H), 4.38 (d, J=5.9 Hz, 2H), 3.88 (d, J=7.2 Hz, 2H), 2.53 (s, 3H), 1.26-1.10 (m, 1H), 0.52-0.50 (m, 2H), 0.32-0.27 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 167.8, 161.9, 161.6, 153.8, 150.3, 139.9, 131.9, 128.7, 127.7, 127.2, 123.6, 104.4, 96.8, 73.9, 43.1, 17.5, 9.9, 3.6; MS (ES+) m/z 396.2 (M+1).
Reaction SMILES: Cl.Cl.[C:3]([NH:7][C:8](=[O:22])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:10]=1)([CH3:6])([CH3:5])[CH3:4].C(N(C(C)C)C(C)C)C.[N+:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)([O-:34])=[O:33]>ClCCl>[C:3]([NH:7][C:8](=[O:22])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]2[CH2:17][CH2:18][N:19]([C:39](=[O:40])[C:38]3[CH:37]=[CH:36][C:35]([N+:32]([O-:34])=[O:33])=[CH:43][CH:42]=3)[CH2:20][CH2:21]2)[CH:10]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc([N+](=O)[O-])cc3)CC2)c1
Reaction time: 0.17 h
Yield: 94.9 %

Procedure:
N-tert-Butyl-3-(piperazin-1-ylmethyl)benzamide dihydrochloride (0.50 g, 1.44 mmol) was suspended in stirred dichloromethane (20 mL) at 0° C. (ice-bath) under an argon atmosphere. N-ethyl-N-isopropylpropan-2-amine (1.0 mL, 5.75 mmol) was added slowly. After 10 minutes stirring, the resulting solution was treated with a suspension of 4-nitrobenzoyl chloride (0.267 g, 1.44 mmol) In dichloromethane (10 ml). The ice-bath was removed and stirring continued for 1 hour. The solution was diluted with dichloromethane (70 mL) and washed with water (×4). The organic phase was dried on magnesium sulfate, filtered and concentrated under vacuum to give the title compound (0.58 g) as a yellow foam.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]O)=[CH:7][CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:33]>>[Cl:33][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=1
Reactant: COCCc1ccc(CO)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COCCc1ccc(CCl)cc1

Procedure:
[4-(2-Methoxyethyl)phenyl]methanol (415 mg) synthesized in Reference Example 42 was dissolved in carbon tetrachloride (8 mL), triphenylphosphine (720 mg) was added thereto, and the mixture was heated under reflux for 4 hr. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in hexane, the insoluble material was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=20:1) to give the title compound (225 mg) as a colorless oil.
Reaction SMILES: [N:1]([CH:4]([CH3:30])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)[N:14]=2)=[CH:9][CH:8]=1)=[N+]=[N-]>CO.O=[Pt]=O>[NH2:1][CH:4]([CH3:30])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)[N:14]=2)=[CH:9][CH:8]=1
Reactant: CC(CCc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cc1)N=[N+]=[N-]
Agent: O=[Pt]=O
Solvent: CO
Product: CC(N)CCc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cc1

Procedure:
The title compound was prepared from {4-[4-(3-azido-butyl)-phenyl]-pyrimidin-2-yl}-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine by hydrogenation using PtO2 in MeOH. Yield: 39 mg (87%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8]([CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:16]=2)[CH2:11][CH2:12][CH2:13][CH3:14])=[O:9])[CH:5]=[CH:4][C:3]=1[O:31][CH2:32][C:33]([O:35]CC)=[O:34].[OH-].[Na+].Cl>C1COCC1.CO.O>[CH3:1][C:2]1[CH:7]=[C:6]([S:8]([CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:16]=2)[CH2:11][CH2:12][CH2:13][CH3:14])=[O:9])[CH:5]=[CH:4][C:3]=1[O:31][CH2:32][C:33]([OH:35])=[O:34]
Reactant: CCCCC(c1cccc(-c2ccc(C(F)(F)F)cc2)n1)S(=O)c1ccc(OCC(=O)OCC)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(c1cccc(-c2ccc(C(F)(F)F)cc2)n1)S(=O)c1ccc(OCC(=O)O)c(C)c1

Procedure:
A stirred solution of ethyl ({2-methyl-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)sulfinyl]phenyl}oxy)acetate (27 mg, 0.05 mmol) in THF (1 mL) and methanol (1 mL) was added, drop-wise, aqueous NaOH (2M, 1 mL). After 2 hours 50 minutes the mixture was concentrated producing a ‘chalk-white’ solid which was diluted with water (2 mL) and acidified with aqueous HCl (2M, 2 mL). The aqueous layer was extracted with DCM (2×2 mL then 1 mL) using a hydrophobic frit and the combined organic layer concentrated under vacuum yielding the title compound as a mixture of two diastereoisomers (24 mg).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][N:6]([CH2:23][C:24]2[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32]CC)=[O:31])=[C:26]([CH3:37])[CH:25]=2)[C:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO.C1COCC1>[CH:1]1([CH2:4][CH2:5][N:6]([CH2:23][C:24]2[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[C:26]([CH3:37])[CH:25]=2)[C:7]2[CH:8]=[C:9]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:17][CH:18]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)COc1ccc(CN(CCC2CC2)c2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(CN(CCC2CC2)c2cccc(-c3ccc(C(F)(F)F)cc3)c2)ccc1OCC(=O)O
Yield: 84.9 %

Procedure:
To a solution of ethyl [4-({(2-cyclopropylethyl)[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amino}methyl)-2-methylphenoxy]acetate (141 mg, 0.28 mmol) in MeOH (2 mL) and THF (2 mL) at room temperature was added 2M NaOH (1 mL, 2 mmol). The resultant mixture was stirred for 1.5 h, then the solvents were removed in vacuo. The residue was partitioned between CH2Cl2 (2×20 mL) and 2M HCl (20 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed, affording the title compound as a white solid (115 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.[NH2:13][C:14]1[C:22]2[C:17](=[N:18][CH:19]=[N:20][C:21]=2[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[NH:16][N:15]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO.O>[Cl:30][C:26]1[CH:25]=[C:24]([NH:23][C:21]2[N:20]=[CH:19][N:18]=[C:17]3[NH:16][N:15]=[C:14]([NH:13][CH2:6][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=4)[C:22]=23)[CH:29]=[CH:28][CH:27]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: COc1cc(C=O)cc(OC)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc(OC)c1
Reaction time: 5 h

Procedure:
99.7 mg (0.60 mmol) of 3,5-dimethoxy-benzaldehyde are added to a solution of 130 mg (0.50 mmol) of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine in 26 ml of methanol and 120 mg (2.0 mmol) of acetic acid. As the reaction mixture is stirred, a solid precipitates which can be dissolved again by the addition of 52 ml of DMEU. 220 mg (3.5 mmol) of NaCNBH3 are added thereto and stirring is then continued for 5 hours at RT. Since not all of the 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine has been reacted (HPLC), 220 mg of NaCNBH3 are added twice more and stirring is continued for 5 hours each time. The reaction solution is then poured into 1 liter of water, stirred vigorously for 1 hour and filtered. Crystallization of the filtration residue from acetone yields 4-(3-chloro-phenylamino)-3-(3,5-dimethoxybenzylamino)-1H-pyrazolo[3,4-d]pyrimidine; m.p. 208-209° C.; HPLC: TRet (Grad20-100)=11.7; FAB-MS: (M+H)+ =411.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[C:13](Cl)[C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=2)=[CH:4][CH:3]=1.C([N:23](C(C)C)CC)(C)C.CC1CCCO1.[OH-].[Na+].[Cl-].[Na+]>CN1CCCC1=O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[C:13]([NH2:23])[C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: FC(F)(F)c1cnc(Oc2ccc(Cl)cc2)nc1Cl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CC1CCCO1
Solvent: CCN(CC)CC
Product: Nc1nc(Oc2ccc(Cl)cc2)ncc1C(F)(F)F
Temperature: 25 °C

Procedure:
b-1.) To a suspension or solution of 2-(4-chlorophenyloxy)-4-chloro-5-trifluoromethylpyrimidine (e.g. 1.0 eq) and a suitable inorganic or organic auxiliary base, such as e.g. diisopropylethylamine, triethylamine or an alkali- or earth alkali-metal carbonate (e.g. sodium carbonate, e.g. 5 eq), in a suitable solvent, such as e.g. a solvent described herein as being suitable for nucleophilic aromatic substitution reactions (e.g. 1-methyl-2-pyrrolidinone [NMP]), an appropriate amine of formula V or a suitable salt thereof (e.g. 1.1 eq.) is added at low temperature, e.g. at 0° C. to 5° C. The reaction mixture is stirred under warming up to ambient temperature. The product can be isolated according to procedures familiar to the skilled person. An appropriate organic extractant, e.g. 2-methyl tetrahydrofurane, is added. After clearfiltration (if required), a 1 N sodium hydroxid solution and a saturated sodium chloride solution are added. The organic phase is separated and the solvent is evaporated under reduced pressure. The corresponding crude 2-(4-chlorophenyloxy)-4-amino-5-trifluoromethylpyrimidine derivative of formula IV is obtained as product which may contain NMP as residual solvent.
Reaction SMILES: B(O)O.Br[C:5]1[N:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][CH:6]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O>>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:5]1[N:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][CH:6]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: O=Cc1cccc(Br)n1
Agent: OBO
Product: O=Cc1cccc(-c2ccccc2C(F)(F)F)n1

Procedure:
6-(2-(trifluoromethyl)phenyl)picolinaldehyde was prepared using the general boronic acid coupling procedure for 6-bromopicolinaldehyde and (2-(trifluoromethyl)phenyl)boronic acid (43.5 mg, 135.1 mg theoretical, 32.2%). LC-MS m/z 252.2 (M+1).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[CH2:13]1[O:19][CH2:18][C@@H:16]([OH:17])[C@H:14]1[OH:15]>C(Cl)Cl>[CH3:8][S:9]([O:15][C@H:14]1[C@@H:16]([O:17][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:18][O:19][CH2:13]1)(=[O:11])=[O:10]
Reactant: O[C@@H]1COC[C@@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1COC[C@H]1OS(C)(=O)=O
Reaction time: 0.17 h

Procedure:
Triethylamine (12.0 ml) and methanesulfonyl chloride (3.6 ml) were successively added dropwise to a solution of 1,4-anhydroerythritol (5.0 g) in methylene chloride (50 ml) under ice cooling, and the mixture was stirred for 10 minutes under ice cooling. The reaction mixture was diluted with methylene chloride and washed with 10% hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous solution of sodium chloride. After the resultant organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (9.2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13]([NH2:31])=[N:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][C:20]([O:23]CC5C=CC=CC=5)=[CH:19][CH:18]=4)[C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1>Br.C(O)(=O)C>[NH2:31][C:13]1[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=3)=[CH:9][S:10][C:11]=2[C:16]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:15][N:14]=1
Reactant: Nc1ccc(-c2csc3c(-c4ccc(OCc5ccccc5)cc4)cnc(N)c23)cc1
Agent: Br
Solvent: CC(=O)O
Product: Nc1ccc(-c2csc3c(-c4ccc(O)cc4)cnc(N)c23)cc1
Yield: 125.1 %

Procedure:
A suspension of Example 138 (132 mg) in 48% HBr (2 mL) and acetic acid (4 mL) was heated to 80° C. for 3 hours. The resulting homogeneous solution was concentrated and the residue was triturated from ethanol/diethyl ether to provide 130 mg of the desired product the dihydrobromide salt. 1H NMR (300 MHz, DMSO-d6) δ 3.67 (s, 2H), 6.95-6.98 (m, 6H), 7.34 (d, J=8.48 Hz, 2H), 7.51 (d, J=8.82 Hz, 2H), 7.85 (d, J=8.82 Hz, 2H), 9.83 (s, 1H); MS (ESI(+)) m/e 334 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:17][C:16]=1[Cl:27]>O>[Cl:27][C:16]1[C:15]([CH2:14][OH:13])=[CH:20][CH:19]=[C:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:17]=1
Reactant: COC(=O)c1ccc(-c2ccccc2)nc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(-c2ccccc2)nc1Cl
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
To the mixture of lithium aluminum hydride (120 mg, 2.5 mmol) and tetrahydrofuran (10 ml), a mixture of 2-chloro-6-phenyl-nicotinic acid methyl ester (620 mg, 2.5 mmol) synthesized in Example 24 and tetrahydrofuran (2.4 ml) was gradually added under nitrogen atmosphere at 0° C. (an outer temperature), and the obtained reaction mixture was stirred at the same temperature for 30 minutes. Water was gradually added dropwise thereto at the same temperature, and the obtained reaction mixture was stirred at room temperature for 1 hour. Impurities were removed by filtration with Celite, and the solvents were evaporated under reduced pressure from the filtrate. The obtained residue was purified with silica gel column chromatography (heptane:ethyl acetate=2:1), thereby obtaining the entitled compound (470 mg, 86%).
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].[CH3:18][N:19]([CH3:24])[CH2:20][CH:21]([NH2:23])[CH3:22].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:18][N:19]([CH3:24])[CH2:20][CH:21]([NH:23][C:8]1[CH:9]=[CH:10][C:5]([C:4]([N:3]([CH2:16][CH3:17])[CH2:1][CH3:2])=[O:15])=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13])[CH3:22]
Reactant: CCN(CC)C(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(N)CN(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C(=O)c1ccc(NC(C)CN(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
A mixture of N,N-diethyl-4-fluoro-3-nitrobenzamide (0.500 g, 2.08 mmol), N1,N1-dimethyl-1,2-propanediamine (0.636 g, 6.24 mmol), DIPEA (2.2 mL, 12.5 mmol) and DMF (12 mL) was stirred 4 hours at room temperature. The reaction was then concentrated in vacuo, the residue was dissolved in 2 N NaOH (30 mL) and extracted with CH2Cl2 (3×40 mL). The combined organic phases were washed with brine (10 mL) dried over MgSO4, filtered, and concentrated in vacuo. The crude reaction mixture was purified by silica gel column chromatography (100% CH2Cl2 to 5% MeOH/CH2Cl2) to provide the title compound (0.621 g, 93%) as a bright yellow solid. 1H-NMR (CDCl3): δ 8.33 (d, J=6.4 Hz, 1H), 8.27 (d, J=2.0 Hz, 1H), 7.55 (dd, J=8.8 Hz, J=2.0 Hz, 1H), 6.91 (d, J=9.6 Hz, 1H), 3.79 (heptet, J=7.2 Hz, 1H), 3.45 (br d, J=5.2 Hz, 4H), 2.55 (dd, J=12.0 Hz, J=7.6 Hz, 1H), 2.39 (dd, J=12.4 Hz, J=5.8 Hz, 1H), 2.29 (s, 6H), 1.69 (br s, 1H), 1.31 (d, J=6.8 Hz, 2H), 1.22 (t, J=7.4 Hz, 6H). MS (ESI) (M+H)+=323.
Reaction SMILES: C1(C)C=CC=CC=1.Br.[Br:9][CH2:10][CH2:11][CH2:12][NH2:13].C(N(CC)CC)C.[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22]>C(OCC)(=O)C>[Br:9][CH2:10][CH2:11][CH2:12][NH:13][C:28](=[O:29])[C:27]1[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:32][CH:31]=1
Reactant: NCCCBr
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(NCCCBr)c1ccc([N+](=O)[O-])cc1
Yield: 70.3 %

Procedure:
30 mL of toluene was added to 3-bromopropylamine hydrobromide (1.20 g, 5.50 mmol), and triethylamine (1.53 mL, 11.0 mmol) was added dropwise with stirring under ice cooling. After the dropwise addition was completed, 4-nitrobenzoyl chloride (928 mg, 5.50 mmol) was added little by little, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with an aqueous saturated sodium hydrogencarbonate solution, a 0.1 N aqueous hydrochloric acid solution, and saturated sodium chloride solution. The organic layer was dried with anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to give the title compound (1.11 g; yield, 77%) as light yellow crystals.
Reaction SMILES: [Cl:1][C:2]1([C:22]([O:24]CC)=[O:23])[CH:7]=[CH:6][C:5]([N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[C:9](=[O:11])[NH2:10])=[CH:4][CH2:3]1.[OH-].[K+]>CO>[Cl:1][C:2]1([C:22]([OH:24])=[O:23])[CH:3]=[CH:4][C:5]([N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])[C:9](=[O:11])[NH2:10])=[CH:6][CH2:7]1
Reactant: CCOC(=O)C1(Cl)C=CC(N(C(N)=O)c2ccccc2C(F)(F)F)=CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)N(C1=CCC(Cl)(C(=O)O)C=C1)c1ccccc1C(F)(F)F
Reaction time: 12 h
Yield: 91.5 %

Procedure:
To a slurry of N-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-ethoxycarbonylphenyl) urea (Method C1e; 5.93 g, 15.3 mmol) in MeOH (75 mL) was added an aqueous KOH solution (2.5 N, 10 mL, 23 mmol). The resulting mixture was heated at the reflux temp. for 12 h, cooled to room temp., and concentrated under reduced pressure. The residue was diluted with water (50 mL), then treated with a 1 N HCl solution to adjust the pH to 2 to 3. The resulting solids were collected and dried under reduced pressure to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-carboxyphenyl) urea as a white solid (5.05 g, 92%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[I:16]Cl.O>C(O)(=O)C>[I:16][C:7]1[C:6]([F:9])=[CH:5][C:3]([NH2:4])=[C:2]([F:1])[CH:8]=1
Reactant: Nc1cc(F)ccc1F
Reactant: ClI
Solvent: O
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: Nc1cc(F)c(I)cc1F
Yield: 66.6 %

Procedure:
2,5-Difluoroaniline (38 g) was dissolved in acetic acid (120 ml), and then pyridine (25 g) was added thereto, followed by stirring. A mixed solution of iodine monochloride (50 g) with acetic acid (30 ml) was added dropwise thereto. After stirring at room temperature for 1 hour, the mixed solution was further stirred at 70° to 80° C. for 2 hours. Then, the reaction solution was poured into water, and the precipitated crystals were filtered, followed by washing with water. The resulting crystals were dissolved in chloroform, and then washed with water twice, further with 10% potassium hydroxide aqueous solution twice, and furthermore with water twice, followed by distilled off chloroform therefrom. The residue was distilled under reduced pressure (b.p. 130° to 140° C./20 mmHg), and then recrystallized from methanol, to give 4-iodo-2,5-difluoroaniline (50 g).