Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:48]=[N:47][CH:46]=[CH:45][N:44]=2)=[CH:38][C:37]=1[CH3:49].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:49])=[CH:38][C:39]([C:43]6[CH:48]=[N:47][CH:46]=[CH:45][N:44]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(-c2cnccn2)cc(C)c1Br
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cnccn6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-(4-bromo-3,5-dimethyl-phenyl)-pyrazine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 9): tR=1.31 min; Mass spectrum (ESI+): m/z=525 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:15][CH:14]=3)[CH:8]=2)[C:3]=1[OH:28].[CH2:29](Br)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>CCOCC>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:17][CH:18]=3)[CH:8]=2)[C:3]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCOc1ccc(-c2ccc3c(O)c(F)c(F)cc3c2)cc1
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(-c2ccc3c(OCCCCCCCC)c(F)c(F)cc3c2)cc1

Procedure:
From 2,3-difluoro-6-(4-octyloxyphenyl)naphthalen-1-ol and 1-octyl bromide by means of the Williamson ether synthesis.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:28]1([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=2)[CH2:30][CH2:29]1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:22])[CH3:23])[CH:16]=2)[CH2:24][C:25]([N:31]([CH:28]2[CH2:30][CH2:29]2)[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=2)=[O:26])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1cccc(CNC2CC2)c1
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Product: COc1cccc(CN(C(=O)CN(c2cccc(N(C)C)c2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)C2CC2)c1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with cyclopropyl-(3-methoxy-benzyl)-amine
Reaction SMILES: [H][H].[CH:3]([OH:11])=[CH:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH3:10]>[Ni].C(O)CCCCCCC>[CH2:3]([OH:11])[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: [H][H]
Reactant: CCCCC=CC=CO
Agent: [Ni]
Solvent: CCCCCCCCO
Product: C=CCCCC=CCO
Temperature: 130 °C

Procedure:
A one-liter stainless steel autoclave equipped with thermometer, magnetic stirrer, liquid metering and feeding pump, hydrogen gas inlet, off gas flow meter, and liquid outlet was charged with 1.5 g of nickel-on-diatomaceous earth catalyst (Nissan-Girdler's G-69; Ni content 52 percent by weight) and 100 g of n-octanol. After sufficiently replacing the atmosphere with hydrogen gas, the system was heated to 160° C. with stirring. Then, the octadienol mixture obtained by the procedure mentioned above under (iii) was continuously fed to the system at the rate of 70 g per hour at the temperature of 160° C., hydrogen pressure of 10 kg/cm2 (gauge), rate of stirring of 500 rpm and off gas flow rate of 30 liters per hour, with stirring for 7 hours. After effecting the hydrogenation reaction in this manner, octadienol mixture feeding, hydrogen gas introduction and stirring were discontinued, and the reaction mixture was immediately removed from the system via the liquid outlet. After removing the catalyst by filtration, the mixture was analyzed by gas chromatography, whereupon it was revealed that the average conversion of octadienols to octanols was 98.5 percent and that the hydrogenation product contained small amounts of intermediary hydrogenation products, namely octenols. The filtrate obtained upon separation of the catalyst by filtration was charged into the above-mentioned autoclave. The autoclave was connected via the liquid feeding pump to a column hydrogenation reactor (50 mm in inside diameter and 250 mm in column length) packed with a nickel-on-diatomaceous earth (Nissan-Girdler's G-49B; Ni content 55 percent by weight) in the form of cylinders (3/16"×1/8"), containing 123 g of n-octanol, and fitted with a jacket. The autoclave and packed column were heated to 130° C., and hydrogen was introduced to the pressure of 5 kg/cm2 (gauge). The autoclave contents were saturated with hydrogen gas by stirring at the rate of 400 rpm. After the internal temperature and hydrogen pressure respectively became constant, the mixture was continuously fed from the autoclave to the bottom of the packed column hydrogenation reactor at the rate of 450 ml/hr (corresponding to the liquid space velocity of 3 hr-1). The hydrogenated mixture was continuously taken out from the top of the packed column into a one-liter reservoir autoclave by the overflow method. The finishing hydrogenation was carried out under said conditions continuously for 90 minutes. Gas chromatography and ultraviolet absorption spectrometry of the mixture taken out did not reveal the presence of octenols and octanals within the limits of analytical error.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]([C:9]2[N:10]=[C:11]3[N:21]([CH:22]=2)[CH2:20][CH2:19][O:18][C:17]2[C:12]3=[CH:13][CH:14]=[C:15]([C:23](=[O:25])[CH3:24])[CH:16]=2)=[N:7][CH:6]=[N:5]1.[CH3:26][N:27]([CH:29](OC)OC)[CH3:28]>>[CH3:26][N:27]([CH3:29])/[CH:28]=[CH:24]/[C:23]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[C:11]1[N:21]([CH:22]=[C:9]([C:8]3[N:4]([CH2:3][CH2:2][OH:1])[N:5]=[CH:6][N:7]=3)[N:10]=1)[CH2:20][CH2:19][O:18]2)=[O:25]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc2c(c1)OCCn1cc(-c3ncnn3CCO)nc1-2
Product: CN(C)/C=C/C(=O)c1ccc2c(c1)OCCn1cc(-c3ncnn3CCO)nc1-2
Temperature: 130 °C
Reaction time: 48 h
Yield: 104.9 %

Procedure:
A mixture of 1-{4-[1-(2-hydroxyethyl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-12-yl}ethan-1-one (115 mg, 0.290 mmol) and DMF-DMA (69 mg, 0.58 mmol) in xylenes (10 mL) was stirred at 130° C. for 48 h under nitrogen atmosphere. The mixture was then concentrated under reduced pressure, the residue was purified by reverse phase Combiflash eluting with a 0-40% gradient of CH3CN in 0.3% NH4HCO3 to give (2E)-3-(dimethylamino)-1-{4-[1-(2-hydroxyethyl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-12-yl}prop-2-en-1-one (120 mg, 90% yield). LCMS (ESI) m/z: 395.1 [M+H+].
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1.[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.[K]>CN(C)C=O>[N:4]1[C:3]([CH2:2][N:16]2[C:12](=[O:22])[C:13]3[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15]2=[O:17])=[CH:11][N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: ClCc1cn2ccccc2n1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1cn2ccccc2n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
1.5 g (9 mmol) of 2-(chloromethyl)imidazo[1,2-a]pyridine were solubilised in 55 ml of dimethylformamide with magnetic stirring, 1.834 g (9.9 mmol) of potassium phthalimide were added portion wise and then the mixture was stirred at 60° C. for 2 h. The obtained solid was isolated by filtration, washed with 30 ml of diisopropyl ether and dried in a vacuum bell jar in order to obtain 1.81 g (yield=67%) of 2-(imidazo[1,2-a]pyridin-2-ylmethyl)isoindoline-1,3-dione as a white solid. LC-MS: m/z=278 (MH+); UV purity at 254 nm=93%. 1H NMR (300 MHz, DMSO) δ 8.45 (d, J=6.8 Hz, 1H), 7.96-7.67 (m, 5H), 7.45 (dd, J=9.1, 0.5 Hz, 1H), 7.33-7.14 (m, 1H), 6.84 (td, J=6.8, 1.1 Hz, 1H), 4.88 (s, 2H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:32])[O:13][CH2:14][C@@H:15]([N:18]([CH3:31])[C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[Cl:30])=[O:20])[CH2:16][NH2:17])[N:2]=1.FC(F)(F)S(O[CH2:39][CH:40]([F:42])[F:41])(=O)=O.CCN(C(C)C)C(C)C>C1COCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:32])[O:13][CH2:14][C@@H:15]([N:18]([CH3:31])[C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[Cl:30])=[O:20])[CH2:16][NH:17][CH2:39][CH:40]([F:42])[F:41])[N:2]=1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CN)COC(=O)Nc1cc2ccccc2cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CNCC(F)F)COC(=O)Nc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.4 %

Procedure:
To a solution of (S)-3-amino-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)propyl isoquinolin-3-ylcarbamate (200 mg, 0.44 mmol) in THF (2.0 mL) were added 2,2-difluoroethyl trifluoromethanesulfonate (94 mg, 0.44 mmol) and DIEA (0.15 mL, 0.88 mmol) at RT The reaction mixture was stirred at RT for 30 min. The solvent was removed. The resulting residue was dissolved in MeOH and mixture was purified on RP-HPLC using a mixture of acetonitrile and water to give (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-3-(2,2-difluoroethylamino)propyl isoquinolin-3-ylcarbamate (130 mg, 56% for two steps). LRMS (M+H+) m/z 524.2.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]=O.[BH4-].[Na+]>CO>[N:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:2]=1[CH2:1][NH:4][CH:6]([NH:5][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=1)[CH3:11]
Reactant: O=Cc1ccccn1
Reactant: NCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(NCc1ccccn1)NCc1ccccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
This ligand was prepared according to a modified procedure described by Bernal et al in J. Chem. Soc., Dalton Trans, 22, 3667 (1995). First N,N′-bis(pyridin-2ylmethyl)-ethanediamine (bispicen) was synthesised by the following procedure. Ethylenediamine (26 ml, 0.38 mol) was dissolved in 200 ml dry methanol. To this mixture 74 ml (0.76 mol) pyridincarboxaldehyde was added. The mixture was refluxed for 2 h, after which the mixture was left to cool to RT and in small portions 40 g of NaBH4 was added. The mixture was subsequently stirred for 16 h at RT. The methanol was evaporated and 500 ml of water was added. The aqueous mixture was extracted with three portions of dichloromethane (100 ml) and the dichloromethane solution was dried over sodium sulphate, filtered off and the solvent was removed. The dark oil containing N,N′-bis(pyridin-2ylmethyl)-ethanediamine (73.7 g; 81%) was analysed by NMR and used without further purification. 1H-nmr (CDCl3): δ2.20 (br, NH); 2.78 (s, 4H); 3.85 (s, 4H); 7.00-7.40 (m, 4H); 7.58 (m, 2H); 8.45 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8](OCC)=O)=[CH:5][C:6]=1[CH3:7].[CH2:13]=O.O.N>C(O)(=O)C.I.[PH2](O)=O>[CH3:8][C:4]1[NH:3][C:2]([CH3:1])=[C:6]([CH3:7])[C:5]=1[CH3:13]
Reactant: C=O
Reactant: CCOC(=O)c1cc(C)c(C)[nH]1
Agent: I
Agent: N
Agent: O=[PH2]O
Solvent: O
Solvent: CC(=O)O
Product: Cc1[nH]c(C)c(C)c1C
Yield: 53 %

Procedure:
A solution of 2,3-dimethyl-5-carbethoxy-pyrrole (0.82 g) in acetic acid (10 ml), hydriodic acid (10 ml), hypophosphorous acid (2 ml) and paraformaldehyde (0.6 g) was stirred and heated at 100° under nitrogen for 3 hr. then poured into water. The mixture was made alkaline with ammonia and extracted with ether. The ether was evaporated and the residue distilled (65°, 15 mm) to give the product (53%) m.p. 105°-107°.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH3:10])=[N:6][O:7][C:8]=1[NH2:9].[S:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([S:20](Cl)(=[O:22])=[O:21])=[CH:12]1>C1COCC1>[Cl:3][C:4]1[C:5]([CH3:10])=[N:6][O:7][C:8]=1[NH:9][S:20]([C:13]1[C:14]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[S:11][CH:12]=1)(=[O:22])=[O:21]
Reactant: Cc1noc(N)c1Cl
Reactant: O=S(=O)(Cl)c1csc2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2csc3ncccc23)c1Cl
Yield: 96.6 %

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)thieno[2,3-b]pyridine-3-sulfonamide was prepared by the method of Example 1(C) using NaH (0.16 g, 6.8 mmoles), THF (10 ml), 4-chloro-3-methyl-5-aminoisoxazole (0.36 g, 2.7 mmoles) and thieno[2,3-b]pyridine-3-sulfonyl chloride (0.70 g, 3.0 mmoles) to provide 0.86 g (96%) of the title compound as a tan solid. Recrystallization of 56 mg from EtOAc/hexanes provided 43 mg of a light tan solid, m.p. 176-177° C.
Reaction SMILES: [N+:1]([C:4]1[O:5][C:6]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=3)=[CH:15][C:7]=2[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-:3])=[O:2].B.O.O1CCCC1.S(=O)(=O)(O)O>O1CCCC1>[OH:27][CH2:26][CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[CH:17]=[CH:18][C:6]3[O:5][C:4]([N+:1]([O-:3])=[O:2])=[C:8]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:7]=3[CH:15]=2)=[CH:24][CH:23]=1
Reactant: O=C(O)Cc1ccc(-c2ccc3oc([N+](=O)[O-])c(-c4ccccc4)c3c2)cc1
Agent: B
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1oc2ccc(-c3ccc(CCO)cc3)cc2c1-c1ccccc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of 2 g. (0.00536 mole) of 4-(2-nitro-3-phenylbenzofuran-5-yl)phenylacetic acid (the product of step D of Example 1 hereof) in 100 ml. of tetrahydrofuran is cooled to 0° C. and 20 ml. of a borane solution in tetrahydrofuran is added while under a nitrogen atmosphere over 10 minutes. After warming to 20° C. the mixture is stirred for 16 hours. The solution is cooled to 0° C., 50 ml. of 1:1 water-tetrahydrofuran mixture and 15 ml. of 3 N sulfuric acid are each added slowly and the mixture is stirred at 20° C. for 45 minutes. Evaporation provides a residue which crystallizes when triturated with hexane. Chromatography through silica gel in chloroform, eluting with chloroform, provides 5-[4-(2-hydroxyethyl)phenyl]-2-nitro-3-phenylbenzofuran, m.p. 86°-87° C.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]([OH:14])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Br[CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[I-].[K+]>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH2:20][CH2:19][CH2:18][CH:17]=[CH2:16])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Reactant: C=CCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCCCOc1ccc(C(C)=O)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.3 %

Procedure:
Under dry condition, 3.58 g (18.41 mmol) of 5-acetylsalicylic acid, methyl ester is dissolved in 25 mL of dry N,N-dimethylformamide. To this solution is added 3.07 g (20.58 mmol) of 5-bromo-1-pentene, 6.83 (20.58 mmol) of potassium carbonate, and 0.246 g (1.65 mmol) of potassium iodide, and the reaction mixture is stirred for 24 hours at ambient temperature. Another portion of 5-bromopentene is added to the reaction, followed by one-half portions of the other two reagents above, and stirring is continued for 72 hours. The mixture is then evaporated under high vacuum at 70° C. The residue is partitioned between ether/water and the organic phase is separated, dried with magnesium sulfate, filtered, and evaporated under vacuum to leave 4.60 g (95%) of 5-acetyl-2-(4-pentenyloxy)benzoic acid, methyl ester as a yellow liquid: IR (neat) 1735, 1710, 1680 cm-1 ; 1HNMR (CDCl3) is consistent with the desired product; MS (FAB) m/e 263 (M+ +H). Analysis calculated for C15H18O4 : C, 68.69; H, 6.92; O, 24.40. Found: C, 68.60; H, 6.92; O, 24.46.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]([N+:12]([O-])=O)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[H][H]>CCOC(C)=O.[Pd]>[NH2:12][C:5]1[CH:4]=[C:3]([O:15][CH3:16])[C:2]([OH:1])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(O)c(OC)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(O)c(OC)cc1N
Yield: 91.9 %

Procedure:
According to the procedure described in Example 6A Step 3, a mixture of methyl 5-hydroxy-4-methoxy-2-nitrobenzoate (3.88 g, 17.1 mmol) and Pd/C in EtOAc (100 mL) was stirred under 1 atmosphere of hydrogen at room temperature overnight, to afford methyl 2-amino-5-hydroxy-4-methoxybenzoate as a solid (3.1 g, 92%). 1H NMR (300 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.08 (s, 1H), 6.31 (s, 1H), 6.24 (s, 1H), 3.74 (s, 3H), 3.72 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]3([CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]([CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[C:10]2=[O:28])=[CH:5][C:4]=1[C:29]([F:32])([F:31])[F:30])#[N:2].CO.[OH-].[Na+]>O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]3([CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]([CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:10]2=[O:28])=[CH:5][C:4]=1[C:29]([F:30])([F:32])[F:31])#[N:2]
Reactant: CCOC(=O)CCCN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C12CCOCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(N2C(=O)N(CCCC(=O)O)C3(CCOCC3)C2=O)cc1C(F)(F)F
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
522 mg of the product of Example 6 and 20 ml of methanol were mixed together and the solution was heated to 30° C., then returned to ambient temperature 2 ml of 2N sodium hydroxide were added and the reaction medium stood for 4 hours and 30 minutes, then was poured into 30 ml of water and adjusted to pH 2-3. Extraction was carried out 3 times with ethyl acetate and the organic phase was washed with water, then with salt water, dried and purified on silica with methylene chloride-methanol 9-1 as eluant. Then, solidification was carried out by trituration in 0.2 ml of isopropanol and 5 ml of ether to obtain 345 mg of the expected product (white crystals) melting at 151°-152° C.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([C:23](=[O:25])[CH3:24])[CH:12]=[C:13]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:14]=1[O:15][CH2:16][O:17][CH3:18].[C:26](Cl)(=[O:28])[CH3:27]>O1CCCC1>[C:23]([C:11]1[CH:12]=[C:13]([C:19]([CH3:20])([CH3:21])[CH3:22])[C:14]([O:15][CH2:16][O:17][CH3:18])=[C:9]([NH:8][C:26](=[O:28])[CH3:27])[CH:10]=1)(=[O:25])[CH3:24]
Reactant: COCOc1c(N)cc(C(C)=O)cc1C(C)(C)C
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCOc1c(NC(C)=O)cc(C(C)=O)cc1C(C)(C)C
Reaction time: 0.17 h
Yield: 89.1 %

Procedure:
Triethylamine (60 ml, 430 mmol) was added to a solution of the 1-[3-amino-5-(tert-butyl)-4-(methoxymethoxy)phenyl]-1-ethanone (53.9 g, 215 mmol) in tetrahydrofuran (270 ml) while cooling on ice under a nitrogen atmosphere and then acetyl chloride (23 ml, 323 mmol) was added dropwise. After stirring at the same temperature for 10 minutes, the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, water was added to the residue and then extraction was performed with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid water, water, saturated aqueous sodium hydrogencarbonate and brine in that order. After drying with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to yield the title compound (56.2 g, 89.3% yield) as light brown needle-like crystals.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[Cl:18][C:19]1[N:24]=[CH:23][C:22]([NH:25][CH3:26])=[C:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH:20]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:18][C:19]1[N:24]=[CH:23][C:22]([N:25]([CH3:26])[C:6](=[O:7])[C:5]2[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=2)=[C:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH:20]=1
Reactant: CNc1cnc(Cl)cc1-c1ccccc1C
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1cc(Cl)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
3,5-Bis-trifluoromethylbenzoyl chloride (76 mg, 0.28 mmol, CAS RN 1271-19-8) was added to a solution of 6-chloro-N-methyl-4-o-tolylpyridin-3-amine (30 mg, 0.13 mmol, prepared as described in WO2005/002577) and DIPEA (50 μL, 0.29 mmol) in THF (1.5 mL). The reaction mixture was stirred overnight, filtered and all volatiles removed in vacuo. The desired product was isolated by flash chromatography on silica gel (25% EtOAc in n-hexane) as a waxy solid (48 mg, 79%). MS (ESI): m/z=472.9 [M+H]+.
Reaction SMILES: [CH:1]([C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][N:20]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:18].[N:20]1[CH:19]=[CH:24][C:23]([N:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]2/[CH:1]=[CH:2]/[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[N:22][CH:21]=1
Reactant: Clc1ccncn1
Reactant: C(=Cc1nc2ccccc2[nH]1)c1ccccc1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: C(=C/c1nc2ccccc2n1-c1ccncn1)\c1ccccc1

Procedure:
Free base of the titled compound was prepared from 2-styryl-1H-benzimidazole and 4-chloropyrimidine according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method B). The free base was treated with a 10% methanol solution of hydrogen chloride and concentrated to dryness. The residue was recrystallized from ethyl acetate/n-hexane to give the titled compound.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.[NH2:26][NH:27][C:28]([NH2:30])=[S:29].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:26][NH:27][C:28]([NH2:30])=[S:29])=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: NNC(N)=S
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: NC(=S)NNC(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.1 %

Procedure:
To a solution of 4-phenylbenzoic acid (10.0 g), 1-hydroxybenzotriazole (7.5 g) and thiosemicarbazide (5.1 g) in dimethylformamide (50 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl) carbodiimide hydrochloride (14.45 g) and stirred for 12 hours at ambient temperature. The reaction mixture was pulverized with water. The precipitate was collected by filtration and dried under reduced pressure to give 1-(4-phenylbenzoyl)-3-thiosemicarbazide (10.274 g).